Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport.

Expert Opin Ther Targets. 2017 Jul 06;:

Authors: Zhang J, Karimy JK, Delpire E, Kahle KT

Abstract
INTRODUCTION: The mammalian SPS1-related proline/alanine-rich serine-threonine kinase SPAK (STK39) modulates the transport across and between epithelial cells in response to environmental stimuli such osmotic stress and inflammation. Research over the last decade has established a central role for SPAK in the regulation of ion and water transport in the distal nephron, colonic crypts, and pancreatic ducts, and has implicated deregulated SPAK signaling in NaCl-sensitive hypertension, ulcerative colitis and Crohn's disease, and cystic fibrosis. Areas covered: We review recent advances in our understanding of the role of SPAK kinase in the regulation of epithelial transport. We highlight how SPAK signaling - including its upstream Cl(-)sensitive activators, the WNK kinases, and its downstream ion transport targets, the cation- Cl(-)cotransporters contribute to human disease. We discuss prospects for the pharmacotherapeutic targeting of SPAK kinase in specific human disorders that feature impaired epithelial homeostasis. Expert opinion: The development of novel drugs that antagonize the SPAK-WNK interaction, inhibit SPAK kinase activity, or disrupt SPAK kinase activation by interfering with its binding to MO25α/β could be useful adjuncts in essential hypertension, inflammatory colitis, and cystic fibrosis.

PMID: 28679296 [PubMed - as supplied by publisher]

High-Frequency Distortion-Product Otoacoustic Emission Repeatability in a Patient Population.

Ear Hear. 2017 Jul 01;:

Authors: Dreisbach L, Zettner E, Chang Liu M, Meuel Fernhoff C, MacPhee I, Boothroyd A

Abstract
OBJECTIVES: Distortion-product otoacoustic emissions (DPOAEs) are repeatable over time at lower frequencies (≤8 kHz) and higher frequencies (>8 kHz) in healthy, normal-hearing subjects. The purpose of this study was to examine the repeatability of DPOAEs measured with high-frequency (HF) stimuli in a patient population. It was hypothesized that HF DPOAEs would be repeatable over four trials.
DESIGN: DPOAEs were measured in 40 cystic fibrosis (CF) patients (17 females and 23 males) with measurable behavioral thresholds and present DPOAEs for at least 2 of the high frequencies tested (8 to 16 kHz). A depth-compensated simulator sound pressure level (SPL) method of calibration was utilized. Each patient attended four trials, in which a complete set of data were collected. At each trial, three different DPOAE paradigms were completed. First, a discrete frequency sweep was measured between 8 and 16 kHz with a ratio (f2/f1) of 1.2 and levels of 65/50 dB SPL for L1/L2. Next, ratio and level sweeps were obtained at the two highest frequencies with a present DPOAE determined from the discrete frequency sweep, and the results were used to calculate DPOAE group delay and DPOAE detection thresholds, respectively. Ratio sweeps were collected with f2/f1 varied from 1.1 to 1.3 and stimulus levels of 60/45 dB SPL (L1/L2). Level sweeps were collected with an f2/f1 of 1.22 and L2 = 50 and L1 varied between 20 and 70 dB SPL. Differences and correlations between trials, SE of the measurement, and confidence intervals were calculated, as well as a repeated-measures analysis of variance.
RESULTS: DPOAE response and behavioral threshold variability in CF patients were not significantly different across four trials. It can be expected in 95% of CF patients that differences between trials of DPOAE levels, group delay, and detection thresholds and behavioral thresholds are less than 6.26 dB, 0.87 msec, 9.34 dB, and 9.60 dB, respectively.
CONCLUSIONS: HF DPOAEs were repeatable across four test trials for all three paradigms measured in a group of CF patients. These results are encouraging for the measurement of HF DPOAEs to be monitored in those exposed to ototoxic agents.

PMID: 28678077 [PubMed - as supplied by publisher]

Personalized or Precision Medicine? The Example of Cystic Fibrosis.

Front Pharmacol. 2017;8:390

Authors: Marson FAL, Bertuzzo CS, Ribeiro JD

Abstract
The advent of the knowledge on human genetics, by the identification of disease-associated variants, culminated in the understanding of human variability. With the genetic knowledge, the specificity of the clinical phenotype and the drug response of each individual were understood. Using the cystic fibrosis (CF) as an example, the new terms that emerged such as personalized medicine and precision medicine can be characterized. The genetic knowledge in CF is broad and the presence of a monogenic disease caused by mutations in the CFTR gene enables the phenotype-genotype association studies (including the response to drugs), considering the wide clinical and laboratory spectrum dependent on the mutual action of genotype, environment, and lifestyle. Regarding the CF disease, personalized medicine is the treatment directed at the symptoms, and this treatment is adjusted depending on the patient's phenotype. However, more recently, the term precision medicine began to be widely used, although its correct application and understanding are still vague and poorly characterized. In precision medicine, we understand the individual as a response to the interrelation between environment, lifestyle, and genetic factors, which enabled the advent of new therapeutic models, such as conventional drugs adjustment by individual patient dosage and drug type and response, development of new drugs (read through, broker, enhancer, stabilizer, and amplifier compounds), genome editing by homologous recombination, zinc finger nucleases, TALEN (transcription activator-like effector nuclease), CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated endonuclease 9), and gene therapy. Thus, we introduced the terms personalized medicine and precision medicine based on the CF.

PMID: 28676762 [PubMed - in process]

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR.

Physiol Rep. 2017 Jul;5(13):

Authors: Figueira MF, Castiglione RC, de Lemos Barbosa CM, Ornellas FM, da Silva Feltran G, Morales MM, da Fonseca RN, de Souza-Menezes J

Abstract
Diabetic nephropathy (DN) occurs in around 40% of those with diabetes. Proteinuria is the main characteristic of DN and develops as a result of increased permeability of the glomerulus capillary wall and/or decreased proximal tubule endocytosis. The goal of this work was to evaluate renal function and the expression of megalin, cubilin, CFTR (cystic fibrosis transmembrane conductance regulator), and ClC-5 in the proximal tubule and renal cortex of rats with type 1 diabetes. Male Wistar rats were randomly assigned to control (CTRL) and diabetic (DM) groups for 4 weeks. Renal function was assessed in 24-h urine sample by calculating clearance and fractional excretion of solutes. The RNA and protein contents of ClC-5, CFTR, megalin, and cubilin were determined in the renal proximal tubule and cortex using real-time polymerase chain reaction and western blotting techniques, respectively. The results showed higher creatinine clearance and higher urinary excretion of proteins, albumin, and transferrin in the DM group than in the CTRL group. Furthermore, the renal cortex and proximal tubule of diabetic animals showed downregulation of megalin, cubilin, ClC-5, and CFTR, critical components of the endocytic apparatus. These data suggest dysfunction in proximal tubule low-molecular-weight endocytosis and protein glomerulus filtration in the kidney of diabetic rats.

PMID: 28676554 [PubMed - in process]

D-BMAP18 Antimicrobial Peptide Is Active In vitro, Resists to Pulmonary Proteases but Loses Its Activity in a Murine Model of Pseudomonas aeruginosa Lung Infection.

Front Chem. 2017;5:40

Authors: Mardirossian M, Pompilio A, Degasperi M, Runti G, Pacor S, Di Bonaventura G, Scocchi M

Abstract
The spread of antibiotic resistant-pathogens is driving the search for new antimicrobial compounds. Pulmonary infections experienced by cystic fibrosis (CF) patients are a dramatic example of this health-care emergency. Antimicrobial peptides could answer the need for new antibiotics but translating them from basic research to the clinic is a challenge. We have previously evaluated the potential of the small membranolytic peptide BMAP-18 to treat CF-related infections, discovering that while this molecule had a good activity in vitro it was not active in vivo because of its rapid degradation by pulmonary proteases. In this study, we synthesized and tested the proteases-resistant all-D enantiomer. In spite of a good antimicrobial activity against Pseudomonas aeruginosa and Stenotrophomonas maltophilia clinical isolates and of a tolerable cytotoxicity in vitro, D-BMAP18 was ineffective to treat P. aeruginosa pulmonary infection in mice, in comparison to tobramycin. We observed that different factors other than peptide degradation hampered its efficacy for pulmonary application. These results indicate that D-BMAP18 needs further optimization before being suitable for clinical application and this approach may represent a guide for optimization of other anti-infective peptides eligible for the treatment of pulmonary infections.

PMID: 28674688 [PubMed - in process]

Corrigendum: Novel variation at chr11p13 associated with cystic fibrosis lung disease severity.

Hum Genome Var. 2017;4:17016

Authors: Dang H, Gallins PJ, Pace RG, Guo XL, Stonebraker JR, Corvol H, Cutting GR, Drumm ML, Strug LJ, Knowles MR, O'Neal WK

Abstract
[This corrects the article DOI: 10.1038/hgv.2016.20.].

PMID: 28674633 [PubMed - in process]

In Vitro Activity of Ceftolozane-Tazobactam and Other Antimicrobial Agents Against Burkholderia cepacia Complex and Burkholderia gladioli.

Antimicrob Agents Chemother. 2017 Jul 03;:

Authors: Mazer DM, Young C, Kalikin LM, Spilker T, LiPuma JJ

Abstract
We tested the activity of ceftolozane-tazobactam and 13 other antimicrobial agents against 221 strains of Burkholderia cepacia complex and Burkholderia gladioli. Most strains (82%) were cultured from persons with cystic fibrosis, and most (85%) were recovered since 2011. The ceftolozane-tazobactam MIC was ≤ 8 μg/ml for 77% of the strains. However, the MIC range was broad (≤0.5 to >64 μg/ml; MIC50/90, 2/32 μg/ml). Significant differences in susceptibility to some antimicrobial agents were observed between species.

PMID: 28674053 [PubMed - as supplied by publisher]

Iron chelation as novel treatment for lung inflammation in cystic fibrosis.

Med Hypotheses. 2017 Jul;104:86-88

Authors: Aali M, Caldwell A, House K, Zhou J, Chappe V, Lehmann C

Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disorder that results in defective cystic fibrosis transmembrane conductance regulator (CFTR) protein expression and function in various tissues. The leading cause of CF mortality and morbidity is the progressive destruction of the lungs due to recurrent infections and chronic inflammation. CFTR defect also affects immune cells, including neutrophils, resulting in ineffective, severe and persistent inflammatory response. Since unopposed recruitment of neutrophils significantly contributes to lung tissue damage through the generation of reactive oxygen species (ROS), we hypothesize that the administration of iron chelators could serve as a novel treatment to attenuate chronic inflammation in CF lungs since iron is significantly involved in ROS production by neutrophils. Ideally, the iron chelator should sequester host iron effectively, prevent bacterial access to chelator-bound iron and penetrates lung tissues efficiently, e.g. by inhalational route of administration.

PMID: 28673599 [PubMed - in process]

Free and Nanoencapsulated Tobramycin: Effects on Planktonic and Biofilm Forms of Pseudomonas.

Microorganisms. 2017 Jun 26;5(3):

Authors: Sans-Serramitjana E, Jorba M, Fusté E, Pedraz JL, Vinuesa T, Viñas M

Abstract
Cystic fibrosis (CF) is a genetic disorder in which frequent pulmonary infections develop secondarily. One of the major pulmonary pathogens colonizing the respiratory tract of CF patients and causing chronic airway infections is Pseudomonasaeruginosa. Although tobramycin was initially effective against P. aeruginosa, tobramycin-resistant strains have emerged. Among the strategies for overcoming resistance to tobramycin and other antibiotics is encapsulation of the drugs in nanoparticles. In this study, we explored the antimicrobial activity of nanoencapsulated tobramycin, both in solid lipid nanoparticles (SLN) and in nanostructured lipid carriers (NLC), against clinical isolates of P. aeruginosa obtained from CF patients. We also investigated the efficacy of these formulations in biofilm eradication. In both experiments, the activities of SLN and NLC were compared with that of free tobramycin. The susceptibility of planktonic bacteria was determined using the broth microdilution method and by plotting bacterial growth. The minimal biofilm eradication concentration (MBEC) was determined to assess the efficacy of the different tobramycin formulations against biofilms. The activity of tobramycin-loaded SLN was less than that of either tobramycin-loaded NLC or free tobramycin. The minimum inhibitory concentration (MIC) and MBEC of nanoencapsulated tobramycin were slightly lower (1-2 logs) than the corresponding values of the free drug when determined in tobramycin-susceptible isolates. However, in tobramycin-resistant strains, the MIC and MBEC did not differ between either encapsulated form and free tobramycin. Our results demonstrate the efficacy of nanoencapsulated formulations in killing susceptible P. aeruginosa from CF and from other patients.

PMID: 28672861 [PubMed - in process]

Expanded Cystic Fibrosis Therapy.

JAMA. 2017 Jul 04;318(1):20

Authors: Voelker R

PMID: 28672301 [PubMed - in process]

Interventions for chronic kidney disease in people with sickle cell disease.

Cochrane Database Syst Rev. 2017 Jul 03;7:CD012380

Authors: Roy NB, Fortin PM, Bull KR, Doree C, Trivella M, Hopewell S, Estcourt LJ

Abstract
BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD.Chronic kidney disease is defined as abnormalities of kidney structure or function, present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD.Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, and increases in prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease.
OBJECTIVES: To assess the effectiveness of any intervention in preventing or reducing kidney complications or chronic kidney disease in people with SCD (including red blood cell transfusions, hydroxyurea and angiotensin-converting enzyme inhibitor (ACEI)), either alone or in combination with each other.
SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 05 April 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 13 April 2017.
SELECTION CRITERIA: Randomised controlled trials comparing interventions to prevent or reduce kidney complications or chronic kidney disease in people with SCD. There were no restrictions by outcomes examined, language or publication status.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data and assessed the risk of bias.
MAIN RESULTS: We included two trials with 215 participants. One trial was published in 2011 and included 193 children aged 9 months to 18 months, and compared treatment with hydroxyurea to placebo. The second trial was published in 1998 and included 22 adults with normal blood pressure and microalbuminuria and compared ACEI to placebo.We rated the quality of evidence as low to very low across different outcomes according to GRADE methodology. This was due to trials having: a high or unclear risk of bias including attrition and detection bias; indirectness (the available evidence was for children aged 9 months to 18 months in one trial and a small and select adult sample size in a second trial); and imprecise outcome effect estimates of significant benefit or harm. Hydroxyurea versus placebo We are very uncertain if hydroxyurea reduces or prevents progression of kidney disease (assessed by change in glomerular filtration rate), or reduces hyperfiltration in children aged 9 to 18 months, mean difference (MD) 0.58 (95% confidence interval (CI) -14.60 to 15.76 (mL/min per 1.73 m²)) (one study; 142 participants; very low-quality evidence).In children aged 9 to 18 months, hydroxyurea may improve the ability to concentrate urine, MD 42.23 (95% CI 12.14 to 72.32 (mOsm/kg)) (one study; 178 participants; low-quality evidence).Hydroxyurea may make little or no difference to SCD-related serious adverse events including: incidence of acute chest syndrome, risk ratio (RR) 0.39 (99% CI 0.13 to 1.16); painful crisis, RR 0.68 (99% CI 0.45 to 1.02); and hospitalisations, RR 0.83 (99% CI 0.68 to 1.01) (one study, 193 participants; low-quality evidence).No deaths occurred in the trial. Quality of life was not reported. ACEI versus placeboWe are very uncertain if ACEI reduces proteinuria in adults with SCD who have normal blood pressure and microalbuminuria, MD -49.00 (95% CI -124.10 to 26.10 (mg per day)) (one study; 22 participants; very low-quality evidence). We are very uncertain if ACEI reduce or prevent kidney disease as measured by creatinine clearance. The authors state that creatinine clearance remained constant over six months in both groups, but no comparative data were provided (very low-quality evidence).All-cause mortality, serious adverse events and quality of life were not reported.
AUTHORS' CONCLUSIONS: In young children aged 9 months to 18 months, we are very uncertain if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration, but it may improve young children's ability to concentrate urine and may make little or no difference on the incidence of acute chest syndrome, painful crises and hospitalisations.We are very uncertain if giving ACEI to adults with normal blood pressure and microalbuminuria has any effect on preventing or reducing kidney complications.This review identified no trials that looked at red cell transfusions nor any combinations of interventions to prevent or reduce kidney complications.Due to lack of evidence this review cannot comment on the management of either children aged over 18 months or adults with any known genotype of SCD.We have identified a lack of adequately-designed and powered studies, and no ongoing trials which address this critical question. Trials of hydroxyurea, ACEI or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction kidney complications in people with SCD.

PMID: 28672087 [PubMed - as supplied by publisher]

Comparison of FEV1 reference equations for evaluating a cystic fibrosis therapeutic intervention.

Pediatr Pulmonol. 2017 Jul 03;:

Authors: Konstan MW, Wagener JS, VanDevanter DR, Pasta DJ, Millar SJ, Morgan WJ, Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis

Abstract
OBJECTIVES: The Global Lung Function Initiative (GLI, 2012) developed reference equations for forced expiratory volume in 1 s (FEV1 ). Previous equations were developed by groups led by Knudson (1983), Wang (1993), Hankinson (1999), and Stanojevic (2008).1,2,4,6 We assessed how different prediction equations affect the conclusions from a therapeutic intervention study that evaluated the rate of percent predicted FEV1 (ppFEV1 ) decline.
METHODOLOGY: Using data from the Epidemiologic Study of cystic fibrosis (CF), we re-analyzed our previous study evaluating the relationship of dornase alfa (DA) use with ppFEV1 using the Knudson, Wang & Hankinson, Stanojevic, and GLI equations. The change in intercept and change in slope of ppFEV1 from a 2-year pre-index period and 2-year post-index period were compared between the treated (N = 2483) and comparator groups (N = 6992, from 4110 unique patients).
RESULTS: Change in intercept for the comparator group was similar across equations except that Wang & Hankinson values were more negative. The difference in change in intercept between the DA and comparator groups ranged from 3.38 to 4.02% predicted. The change in slope for the comparator group ranged from -0.58 to +0.30 ppFEV1 /year, but the difference in change in slope between the DA and comparator groups was in a narrower range from +0.53 to +0.89 ppFEV1 /year.
CONCLUSIONS: Although individual patient results are impacted by the choice of reference equations, the study conclusions from this evaluation of a therapeutic intervention were minimally affected. GLI equations are recommended for future studies, but prior results based on other equations should be accepted as reliable.

PMID: 28672067 [PubMed - as supplied by publisher]

Clinical Model of Exercise-Related Dyspnea in Adult Patients With Cystic Fibrosis.

J Cardiopulm Rehabil Prev. 2017 Jun 30;:

Authors: Stevens D, Neyedli HF

Abstract
PURPOSE: Dyspnea is a highly distressing symptom of pulmonary disease that can make performing physical activities challenging. However, little is known regarding the strongest predictors of exercise-related dyspnea in adult cystic fibrosis (CF). Therefore, the purpose of the present study was to determine the best clinical model of exercise-related dyspnea in this patient group.
METHODS: A retrospective analysis of pulmonary function and cardiopulmonary exercise testing data from patients with CF being followed up at the Adult CF Program at St Michael's Hospital, Toronto, Canada, from 2002 to 2008 were used for the analysis.
RESULTS: Patients (n = 88) were male 66%; aged 30.4 ± 9.4 years; body mass index (BMI) 23.1 ± 3.3 kg/m; forced expiratory volume in 1 second (FEV1) 70% ± 19% predicted; and peak oxygen uptake 74% ± 20% predicted. A multivariate linear regression model assessing the effects of age, sex, BMI, airway obstruction (FEV1), perceived muscular leg fatigue, and dynamic hyperinflation explained 54% of the variance in dyspnea severity at peak exercise (P < .01). Relative importance analysis showed that the presence of dynamic hyperinflation and perceived muscular leg fatigue were the largest contributors.
CONCLUSIONS: Pulmonary rehabilitation programs may consider strategies to reduce dynamic hyperinflation and promote muscular function to best improve exercise-related dyspnea in this patient group.The best predictors of exercise-related dyspnea in adult cystic fibrosis are unclear. In this study, a multivariate linear regression model showed that dynamic hyperinflation and perception of muscular leg fatigue were the greatest contributors to exercise-related dyspnea. Pulmonary rehabilitation programs that target these responses may best improve exercise-related dyspnea in this patient group.

PMID: 28671937 [PubMed - as supplied by publisher]

Inhaled colistin monotherapy for respiratory tract infections in adults without cystic fibrosis: a systematic review and meta-analysis.

Int J Antimicrob Agents. 2017 Jun 29;:

Authors: Vardakas KZ, Voulgaris GL, Samonis G, Falagas ME

Abstract
BACKGROUND: Inhaled colistin is becoming increasingly popular against respiratory tract infections due to multidrug resistant (MDR) Gram-negative bacteria since it may overcome the problems associated with IV administration.
OBJECTIVE: To investigate the effectiveness and safety of inhaled colistin as monotherapy (without concomitant intravenous administration of colistin) in the treatment of respiratory tract infections due to MDR or colistin only susceptible Gram-negative bacteria.
METHODS: PubMed and Scopus databases were searched. A systematic review and meta-analysis was conducted.
RESULTS: Twelve studies (373 patients receiving inhaled colistin for respiratory tract infection) were included. Ten studies evaluated patients with pneumonia (including 8 with ventilator-associated pneumonia) and 2 with ventilator-associated tracheobronchitis. Patients with infections due to MDR Acinetobacter baumannii and Pseudomonas aeruginosa were mainly studied. Daily dose of inhaled colistin and treatment duration varied in the individual studies. The pooled all-cause mortality was 33.8% (95% CI 24.6% - 43.6%), clinical success was 70.4% (58.5% - 81.1%) and eradication of Gram-negative bacteria was shown in 71.3% (57.6% - 83.2%) of cases.
CONCLUSIONS: Inhaled colistin monotherapy may deserve further consideration as a mode for colistin administration for the treatment of respiratory tract infections due to MDR A. baumannii and P. aeruginosa.

PMID: 28669836 [PubMed - as supplied by publisher]

Association between Nasal Obstruction and Risk of Depression in Chronic Rhinosinusitis.

Otolaryngol Head Neck Surg. 2017 Jul;157(1):150-155

Authors: Phillips KM, Hoehle LP, Bergmark RW, Campbell AP, Caradonna DS, Gray ST, Sedaghat AR

Abstract
Objective Chronic rhinosinusitis (CRS) is associated with an increased risk for depression. Since nasal obstruction is a symptom of CRS that is treatable, we sought to characterize its impact on the risk for depression in CRS. Study Design Prospective cross-sectional cohort of 94 patients with CRS. Setting Academic tertiary care rhinology clinic. Subjects and Methods Patients with CRS without vasculitis, cystic fibrosis, sarcoidosis, immunodeficiency, or sinonasal malignancy. Risk for depression was assessed with the 2-item Patient Health Questionnaire (PHQ-2) while nasal obstruction was assessed with the Nasal Obstruction Symptom Evaluation (NOSE) instrument. Multivariate logistic regressions were performed to seek association between NOSE and PHQ-2 scores. Analysis of receiver operating characteristic (ROC) curves defined a NOSE threshold for detecting participants with PHQ-2 greater than 1. Results Of the 94 participants, the mean NOSE score was 47.3, and 29.8% of patients had a PHQ-2 score greater than 1. We found an elevated NOSE score was associated with having a PHQ-2 score greater than 1 (adjusted odds ratio, 1.03; 95% CI, 1.01-1.05; P = .001). Alternatively, a 23-point increase in NOSE score was associated with a 1.5-fold increase in PHQ-2 score (adjusted relative risk, 1.02; 95% CI, 1.01-1.03; P < .001). ROC analysis identified an optimal NOSE threshold of 42.5 for detecting participants with PHQ-2 greater than 1, with 82.1% sensitivity and 50.0% specificity. Conclusions The impact of nasal obstruction is associated with an increased risk for depression in patients with CRS. Assessing for severe nasal obstruction may help to identify those patients with CRS with the highest risk for depression.

PMID: 28669305 [PubMed - in process]

A New SERPINA-1 Missense Mutation Associated with Alpha-1 Antitrypsin Deficiency and Bronchiectasis.

Lung. 2017 Jul 01;:

Authors: Carpagnano GE, Santacroce R, Palmiotti GA, Leccese A, Giuffreda E, Margaglione M, Foschino Barbaro MP, Aliberti S, Lacedonia D

Abstract
Alpha-1-antitrypsin deficiency (AATD) is a genetic condition caused by SERPINA1 mutations, which culminates into lower protease inhibitor activity in the serum and predisposes to emphysema. Clinical manifestations of AATD are often associated to ZZ (p.Glu342Lys) and SZ (p.Glu264Val) genotypes and less frequently to rare deficiency or null alleles in heterozygous and homozygous states. We report a case of a 52-year-old woman with bronchiectasis without other potential causes other than an electrophoresis that showed a decrease of alpha-1 globin band and AAT levels below the normal value (78 mg/dl; v.n. 90-200 mg/dl). No S or Z mutation was identified, but sequencing analysis found a novel missense variant Ile74Asn (c.221T > A) in heterozygous state on an M3 allele (Glu400Asp) in the exon 2 of the SERPINA-1gene, probably leading to a dysfunctional protein. This mutation has never been previously identified, and it is interesting to note the association with bronchiectasis in the absence of emphysema.

PMID: 28668972 [PubMed - as supplied by publisher]

Bronchocele density in cystic fibrosis as an indicator of allergic broncho-pulmonary aspergillosis: A preliminary study.

Eur J Radiol. 2017 Aug;93:195-199

Authors: Occelli A, Soize S, Ranc C, Giovannini-Chami L, Bailly C, Leloutre B, Boyer C, Baque-Juston M

Abstract
OBJECTIVE: Allergic broncho-pulmonary aspergillosis (ABPA) is a severe and under-diagnosed complication of cystic fibrosis (CF). The aim of the study was to determine whether the mucus content of bronchoceles in cystic fibrosis complicated with ABPA reveals a higher density than the mucus content of non-ABPA cystic fibrosis.
MATERIALS AND METHODS: We studied retrospectively 43 computed tomography scans (CT scans) of a pediatric population of cystic fibrosis patients. We measured the mucus attenuation in Hounsfield Units (HU) of all bronchoceles >5mm in diameter.
RESULTS: We found bronchoceles >5mm in 13/43 patients. 5/13 patients had a positive diagnosis of ABPA. The median HU value of bronchoceles was higher in patients with than without ABPA [98 HU (26-135) vs 28 HU (10-36); P=0,02]. Moreover, all patients with a bronchocele density >36HU were ABPA positive.
CONCLUSIONS: CF complicated with ABPA shows higher attenuation bronchoceles on CT scans of the chest. Systematic density measurements of bronchoceles could help to raise the difficult diagnosis of ABPA in patients suffering from cystic fibrosis. Larger series could confirm a threshold in HU which could become a new imaging criterion for the diagnosis of ABPA.

PMID: 28668415 [PubMed - in process]

Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease.

J Immunol. 2017 Jun 30;:

Authors: Lewis BW, Sultana R, Sharma R, Noël A, Langohr I, Patial S, Penn AL, Saini Y

Abstract
Secondhand smoke (SHS) exposure has been linked to the worsening of ongoing lung diseases. However, whether SHS exposure affects the manifestation and natural history of imminent pediatric muco-obstructive airway diseases such as cystic fibrosis remains unclear. To address these questions, we exposed Scnn1b transgenic (Scnn1b-Tg(+)) mice to SHS from postnatal day (PND) 3-21 and lung phenotypes were examined at PND22. Although a majority of filtered air (FA)-exposed Scnn1b-Tg(+) (FA-Tg(+)) mice successfully cleared spontaneous bacterial infections by PND22, the SHS-exposed Scnn1b-Tg(+) (SHS-Tg(+)) mice failed to resolve these infections. This defect was associated with suppressed antibacterial defenses, i.e., phagocyte recruitment, IgA secretion, and Muc5b expression. Whereas the FA-Tg(+) mice exhibited marked mucus obstruction and Th2 responses, SHS-Tg(+) mice displayed a dramatic suppression of these responses. Mechanistically, downregulated expression of IL-33, a stimulator of type II innate lymphoid cells, in lung epithelial cells was associated with suppression of neutrophil recruitment, IgA secretions, Th2 responses, and delayed bacterial clearance in SHS-Tg(+) mice. Cessation of SHS exposure for 21 d restored previously suppressed responses, including phagocyte recruitment, IgA secretion, and mucous cell metaplasia. However, in contrast with FA-Tg(+) mice, the SHS-Tg(+) mice had pronounced epithelial necrosis, alveolar space consolidation, and lymphoid hyperplasia; indicating lagged unfavorable effects of early postnatal SHS exposure in later life. Collectively, our data show that early postnatal SHS exposure reversibly suppresses IL-33 levels in airspaces which, in turn, results in reduced neutrophil recruitment and diminished Th2 response. Our data indicate that household smoking may predispose neonates with muco-obstructive lung disease to bacterial exacerbations.

PMID: 28667160 [PubMed - as supplied by publisher]

Orkambi® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue.

EMBO Mol Med. 2017 Jun 30;:

Authors: Molinski SV, Ahmadi S, Ip W, Ouyang H, Villella A, Miller JP, Lee PS, Kulleperuma K, Du K, Di Paola M, Eckford PD, Laselva O, Huan LJ, Wellhauser L, Li E, Ray PN, Pomès R, Moraes TJ, Gonska T, Ratjen F, Bear CE

Abstract
The combination therapy of lumacaftor and ivacaftor (Orkambi(®)) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508 It has been predicted that Orkambi(®) could treat patients with rarer mutations of similar "theratype"; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function-similar to ΔF508-CFTR, are unlikely to yield a robust Orkambi(®) response. While in silico and biochemical studies confirmed that this mutation could be corrected and potentiated by lumacaftor and ivacaftor, respectively, this combination led to a minor in vitro response in patient-derived tissue. A CRISPR/Cas9-edited bronchial epithelial cell line bearing this mutation enabled studies showing that an "amplifier" compound, effective in increasing the levels of immature CFTR protein, augmented the Orkambi(®) response. Importantly, this "amplifier" effect was recapitulated in patient-derived nasal cultures-providing the first evidence for its efficacy in augmenting Orkambi(®) in tissues harboring a rare CF-causing mutation. We propose that this multi-disciplinary approach, including creation of CRISPR/Cas9-edited cells to profile modulators together with validation using primary tissue, will facilitate therapy development for patients with rare CF mutations.

PMID: 28667089 [PubMed - as supplied by publisher]

Individualizing duration of antibiotic therapy in community-acquired pneumonia.

Pulm Pharmacol Ther. 2017 Jun 27;:

Authors: Aliberti S, Ramirez J, Giuliani F, Wiemken T, Sotgiu G, Tedeschi S, Carugati M, Valenti V, Marchioni M, Camera M, Piro R, Del Forno M, Milani G, Faverio P, Richeldi L, Deotto M, Villani M, Voza A, Tobaldini E, Bernardi M, Bellone A, Bassetti M, Blasi F

Abstract
International experts suggest tailoring antibiotic duration in community-acquired pneumonia (CAP) according to patients' characteristics. We aimed to assess the effectiveness of an individualized approach to antibiotic duration based on time in which CAP patients reach clinical stability during hospitalization. In a multicenter, non-inferiority, randomized, controlled trial hospitalized adult patients with CAP reaching clinical stability within 5 days after hospitalization were randomized to a standard vs. individualized antibiotic duration. In the Individualized group, antibiotics were discontinued 48 h after the patient reached clinical stability, with at least five days of total antibiotic treatment. Early failure within 30 days was the primary composite outcome. 135 patients were randomized to the Standard group and 125 to the Individualized group. The trial was interrupted by the safety committee because of an apparent inferiority of the Individualized group over the Standard treatment: 14 (11.2%) patients in the Individualized group experienced early failure vs. 10 (7.4%) patients in the Standard group, p = 0.200, at the intention-to-treat analysis. 30-day mortality rate was four-time higher in the Individualized group than the Standard group. Shortening antibiotic duration according to patients' characteristics still remains an open question.

PMID: 28666965 [PubMed - as supplied by publisher]