phenylephrine-hydrochloride and Cystic-Fibrosis

Exocrine pancreatic insufficiency in children can lead to lifelong complications related to malnutrition and poor growth. The clinical presentation can be subtle in the early stages of insufficiency as the large functional capacity of the pancreas is gradually lost. The pediatrician plays a crucial role in the early identification of these children to ensure a timely referral so that a diagnosis can be made and therapy initiated. Early nutritional therapy allows for prevention and correction of deficiencies, which leads to improved outcomes and survival. When insufficiency is suspected, the workup should start with an indirect test of exocrine pancreatic function, such as fecal elastase, to establish the diagnosis. Once a diagnosis is established, further testing to delineate the etiology should be pursued, with cystic fibrosis being high on the differential list and assessed for with a sweat test. Assessment of anthropometry at every visit is key, as is monitoring of laboratory parameters and physical examination findings that are suggestive of malabsorption and malnutrition. The mainstay of management is administration of exogenous pancreatic enzymes to facilitate digestion and absorption. [Pediatr Ann. 2019;48(11):e441-e447.].

Topics: Acyl-CoA Dehydrogenase, Long-Chain; Anus, Imperforate; Child; Child Nutrition Disorders; Chymotrypsin; Congenital Bone Marrow Failure Syndromes; Cystic Fibrosis; Dietary Fats; Ectodermal Dysplasia; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Feces; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Intellectual Disability; Lipid Metabolism, Inborn Errors; Mitochondrial Diseases; Muscular Diseases; Nose; Nutrition Assessment; Pancreas; Pancreatic Diseases; Pancreatic Elastase; Pancreatic Function Tests; Pancreatitis, Chronic; Shwachman-Diamond Syndrome; Steatorrhea; Trypsinogen

The nasal epithelium of the mouse closely mimics the bioelectrical phenotype of the human airways. Ion transport across the nasal epithelium induces a nasal transepithelial potential difference. Its measurement by a relatively non-invasive method adapted from humans allows in vivo longitudinal measurements of CFTR-dependent ionic transport in the murine nasal mucosa. This test offers a useful tool to assess CFTR function in preclinical studies for novel therapeutics modulating CFTR activity. Here we extensively review work done to assess transepithelial transport in the murine respiratory epithelium in the basal state and after administration of CFTR modulators. Factors of variability and discriminative threshold between the CF and the WT mice for different readouts are discussed.

Topics: Animals; Biological Transport; Cystic Fibrosis; Disease Models, Animal; Epithelium; Humans; Nasal Mucosa; Nose

Pediatric sinonasal anatomy changes and develops from birth to adolescence. This article elucidates the normal anatomy and patterns of development in the pediatric population. Issues in pediaric sinusitis include indications for imaging, the nonspecificity of sinus opacification, and the importance of clinical information. Sinonasal physiology is briefly discussed to offer insight into the interpretation of radiographic findings. Cystic fibrosis, polyps, and choanal atresia, representing the spectrum of common pediatric sinonasal inflammatory disorders are illustrated, and the spectrum of orbital and intracranial complications of sinusitis is reviewed.

Topics: Adolescent; Child; Child, Preschool; Choanal Atresia; Cystic Fibrosis; Diagnostic Imaging; Humans; Infant; Infant, Newborn; Nasal Polyps; Nose; Paranasal Sinuses; Polyps; Rhinitis; Sinusitis

The use of positive-pressure nasal ventilation in combination with LTOT in stable COPD patients with hypercapnic respiratory failure controls hypoventilation and improves daytime ABGs, sleep, and quality of life. Nasal ventilation in COPD is unlikely to produce benefit unless used with supplemental oxygen therapy at night. The patients who show the greatest reduction in overnight PaCO2 with ventilation are the patients most likely to benefit from long-term ventilatory support. Although there is now evidence for short-term benefit from NPPV in hypercapnic COPD, large multicenter studies with survival, exacerbations, and hospital admissions as the primary end points are required to evaluate longer-term effects of this potentially important intervention.

Topics: Bronchiectasis; Cystic Fibrosis; Home Care Services; Humans; Hypercapnia; Long-Term Care; Lung Diseases, Obstructive; Nose; Oxygen Inhalation Therapy; Positive-Pressure Respiration; Respiratory Mechanics; Ventilators, Negative-Pressure

Topics: Biomarkers; Cystic Fibrosis; Diagnosis, Differential; Diagnostic Imaging; Humans; Immunologic Deficiency Syndromes; Mucociliary Clearance; Nasal Cavity; Nose; Pressure; Pulmonary Ventilation; Rhinitis; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sinusitis; Smell; Sound

Topics: Adolescent; Adult; Aerosols; Airway Resistance; Bronchodilator Agents; Child; Cystic Fibrosis; Humans; Humidity; Hypoxia; Infant; Larynx; Nose; Pharynx; Respiration; Respiratory Function Tests; Respiratory Therapy; Sputum; Trachea; Viscosity

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although impairment of mucociliary clearance contributes to severe morbidity and mortality in people with CF, a clear understanding of the pathophysiology is lacking. This is, in part, due to the absence of clinical imaging techniques capable of capturing CFTR-dependent functional metrics at the cellular level. Here, we report the clinical translation of a 1-μm resolution micro-optical coherence tomography (μOCT) technology to quantitatively characterize the functional microanatomy of human upper airways. Using a minimally invasive intranasal imaging approach, we performed a clinical study on age- and sex-matched CF and control groups. We observed delayed mucociliary transport rate at the cellular level, depletion of periciliary liquid layer, and prevalent loss of ciliation in subjects with CF. Distinctive morphological differences in mucus and various forms of epithelial injury were also revealed by μOCT imaging and had prominent effects on the mucociliary transport apparatus. Elevated mucus reflectance intensity in CF, a proxy for viscosity in situ, had a dominant effect. These results demonstrate the utility of μOCT to determine epithelial function and monitor disease status of CF airways on a per-patient basis, with applicability for other diseases of mucus clearance.

Topics: Case-Control Studies; Cilia; Cystic Fibrosis; Granulocytes; Humans; Imaging, Three-Dimensional; Inflammation; Mucociliary Clearance; Mucus; Nose; Tomography, Optical Coherence

Güney E, Emiralioğlu N, Cinel G, Yalçın E, Doğru D, Kiper N, Özçelik HU. Nasal nitric oxide levels in primary ciliary dyskinesia, cystic fibrosis and healthy children. Turk J Pediatr 2019; 61: 20-25. Primary ciliary dyskinesia (PCD) is a rare, inherited disorder characterized by recurrent respiratory tract infections. The measurement of nasal nitric oxide (nNO) is an important test for the diagnosis of PCD. In this study, we aim to evaluate NIOX-MINOÒ, which is an easily applicable method for measuring nNO, in the diagnosis of patients with PCD and define diagnostic cut-off levels. Furthermore, determining the normal limits of nNO in healthy children and investigating nNO levels of children with cystic fibrosis (CF) are the other aims of this study. The children included in this study were 5 to 18.5 years old, 46 of them had PCD, 44 had CF and 200 were healthy children. To our knowledge, this work contains the widest population compared to previous studies. Subjects receiving steroids or antibiotics or those with any acute respiratory tract infection, asthma or allergic rhinitis were not included in the study. Mean nNO levels were found as 10.4, 22.8 and 21.0 ppb in PCD, CF and healthy children, respectively. The nNO levels for PCD patients were found significantly lower than children with CF and the control groups (p < 0.05). In this study, the diagnostic nNO cut-off level between PCD and the other two groups was determined to be < 11.5 ppb with %83.6 specificity and %67.4 sensitivity. The screening of nNO with NIOX-MINO method provides early diagnose before mucosal biopsy of patients who are suspected to have PCD and therefore, prevents co-morbidities and prolongs survival with early treatment.

Topics: Adolescent; Biomarkers; Breath Tests; Case-Control Studies; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Kartagener Syndrome; Male; Nitric Oxide; Nose; Sensitivity and Specificity

Nasal potential difference (NPD) is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. We evaluated methods to detect changes in chloride and sodium transport by NPD based on a secondary analysis of a Phase II CFTR-modulator study. Thirty-nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (Kalydeco™; also known as VX-770) in four doses or placebo twice daily for at least 14 days. All data were analyzed by a single investigator who was blinded to treatment assignment. We compared three analysis methods to determine the best approach to quantify changes in chloride and sodium transport: (1) the average of both nostrils; (2) the most-polarized nostril at each visit; and (3) the most-polarized nostril at screening carried forward. Parameters of ion transport included the PD change with zero chloride plus isoproterenol (CFTR activity), the basal PD, Ringer's PD, and change in PD with amiloride (measurements of ENaC activity), and the delta NPD (measuring CFTR and ENaC activity). The average and most-polarized nostril at each visit were most sensitive to changes in chloride and sodium transport, whereas the most-polarized nostril at screening carried forward was less discriminatory. Based on our findings, NPD studies should assess both nostrils rather than a single nostril. We also found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects (± 2.8 mV). Therefore, we have confirmed an assay of reasonable reproducibility for detecting chloride-transport improvements in response to CFTR modulation.

Topics: Adult; Amino Acid Substitution; Aminophenols; Biological Transport; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Demography; Epithelial Sodium Channels; Female; Humans; Male; Membrane Potentials; Middle Aged; Mutation; Nose; Placebos; Quinolones; Sample Size; Sodium; Solutions; Young Adult

Using nebulization, only a small proportion of the dose reaches the lungs, while the remainder is swallowed, exhaled into the atmosphere, or remains in the nebulizer. It was the purpose of this study to investigate whether wearing a noseclip during inhalation can improve lung deposition. Relative lung deposition was compared by inhalation of the marker substance, sodium cromoglycate (SCG), and measurement of urinary excretion of SCG. The SCG absorption half-life allows one to differentiate indirectly between a more or less peripheral deposition. Ten CF patients (9-18 years old) inhaled, under routine conditions, a solution containing 20 mg of SCG in a randomized crossover design through a mouthpiece, without and with a noseclip being worn. Following inhalation without and with a noseclip, no statistically significant difference was seen in the amount of SCG excreted in urine (0.9 +/- 0.4 mg vs. 1.0 +/- 0.5 mg; p = 0.402) and absorption half-life (93 +/- 25 min vs. 113 +/- 36 min; p = 0.083). In conclusion, wearing a noseclip during inhalation under conditions relevant to practice does not increase the amount deposited into the lungs of CF patients and, also, there has been no indication of a more peripheral lung deposition.

Topics: Administration, Inhalation; Adolescent; Biological Availability; Child; Cromolyn Sodium; Cross-Over Studies; Cystic Fibrosis; Female; Humans; Lung; Male; Nebulizers and Vaporizers; Nose; Respiratory Function Tests; Sensitivity and Specificity; Surgical Instruments; Treatment Outcome

Analysis of exhaled breath condensate may provide new insights into pulmonary inflammatory processes. A new collection method via suction of nasally expired air especially suitable for younger children was presented recently. Here we compare this nasal suction method with the more widely used oral collection method regarding the amount of condensate collected as well as the concentrations of hydrogen peroxide (H2O2), nitrite and nitrate, respectively.. Exhaled breath condensate was collected from 11 healthy adults for the measurements of the amount of condensate and H2O2 concentration and from 17 children for the measurements of nitrite and nitrate. Condensate was collected via nasal suction and oral exhalation from each subject.. Overall, no differences between both collection methods were found for all variables assessed except the concentration of H2O2, whereas the latter closely correlated (Spearman r = 0.88, p = 0.0007) between both collection methods. No correlation was found for the amount of condensate collected and the concentration of nitrite and nitrate. The Bland-Altman limits of agreement scattered over a wide range with clinical impact, proving significant differences between both collection methods for all variables measured.. Although nasal and oral collection method proved again suitable for the collection of exhaled breath condensate, the variability of the results obtained precludes the interchangeable usage of the inflammatory markers assessed here.

Topics: Adult; Biomarkers; Breath Tests; Child; Cystic Fibrosis; Exhalation; Humans; Hydrogen Peroxide; Mouth; Nitrates; Nitrites; Nose

The levels of exhaled and nasal nitric oxide (eNO and nNO) in groups of patients with inflammatory lung diseases are well documented but the diagnostic use of these measurements in an individual is unknown.. The levels of nNO and eNO were compared in 31 children with primary ciliary dyskinesia (PCD), 21 with non-CF bronchiectasis (Bx), 17 with cystic fibrosis (CF), 35 with asthma (A), and 53 healthy controls (C) using a chemiluminescence NO analyser. A diagnostic receiver-operator characteristic (ROC) curve for PCD using NO was constructed.. The median (range) levels of nNO in parts per billion (ppb) in PCD, Bx, CF, and C were 60.3 (3.3-920), 533.6 (80-2053), 491.3 (31-1140), and 716 (398-1437), respectively; nNO levels were significantly lower in PCD than in all other groups (p<0.05). The median (range) levels of eNO in ppb in PCD, Bx, CF, A, and C were 2.0 (0.2-5.2), 5.4 (1.0-22.1), 2.6 (0.8-12.9), 10.7 (1.6-46.7), and 4.85 (2.5-18.3), respectively. The difference in eNO levels in PCD reached significance (p<0.05) when compared with those in Bx, A and C but not when compared with CF. Using the ROC curve, nNO of 250 ppb showed a sensitivity of 97% and a specificity of 90% for the diagnosis of PCD.. eNO and nNO cannot be used diagnostically to distinguish between most respiratory diseases. However, nNO in particular is a quick and useful diagnostic marker which may be used to screen patients with a clinical suspicion of PCD.

Topics: Adolescent; Asthma; Biomarkers; Breath Tests; Bronchiectasis; Child; Cystic Fibrosis; Forced Expiratory Volume; Humans; Kartagener Syndrome; Nitric Oxide; Nose; ROC Curve

We have administered a recombinant adenovirus vector (AdCFTR) containing the normal human CFTR cDNA to the nasal and bronchial epithelium of four individuals with cystic fibrosis (CF). We show that this vector can express the CFTR cDNA in the CF respiratory epithelium in vivo. With doses up to 2 x 10(9) pfu, there was no recombination/complementation or shedding of the vector or rise of neutralizing antibody titres. At 2 x 10(9) pfu, a transient systemic and pulmonary syndrome was observed, possibly mediated by interleukin-6. Follow-up at 6-12 months demonstrated no long term adverse effects. Thus, it is feasible to use an adenovirus vector to transfer and express the CFTR cDNA in the respiratory epithelium of individuals with CF. Correction of the CF phenotype of the airway epithelium might be achieved with this strategy.

Topics: Adenoviridae; Adult; Base Sequence; Bronchi; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA, Complementary; DNA, Recombinant; Epithelium; Female; Genetic Therapy; Genetic Vectors; Humans; Interleukin-6; Lung; Male; Membrane Proteins; Molecular Sequence Data; Nose; Radiography; Respiratory System

Mucociliary clearance is an important component of pulmonary defence. Maximum clearance is thought to depend on an optimal depth of the sol layer, allowing the most efficient interaction between the cilia and the overlying mucus layer. Sodium absorption, the major ion transport in human airways, is thought to be important in the regulation of the depth of the sol layer. In the airways of patients with cystic fibrosis sodium absorption is increased and mucociliary clearance decreased. Amiloride, a sodium channel blocker, has been shown to improve pulmonary mucociliary clearance in patients with cystic fibrosis. However, its effects on nasal mucociliary clearance in either normal subjects or those with cystic fibrosis are unknown. A study was therefore performed to investigate whether nebulised amiloride improves nasal mucociliary clearance in normal or cystic fibrosis subjects.. Nasal mucociliary clearance was measured by the saccharin clearance technique in 12 normal subjects and 12 with cystic fibrosis. For the control study measurements were made on two consecutive days and the mean time for each subject averaged. For the drug study measurements were also made on two consecutive days, after administration of nasally nebulised amiloride or placebo (saline) in a double blind manner. Nasal potential difference was measured in eight patients with cystic fibrosis after the administration of amiloride or placebo to assess the efficacy of deposition and duration of action.. Baseline values of mucociliary clearance were significantly faster in the normal subjects than in those with cystic fibrosis. In both groups mucociliary clearance was increased after both saline and amiloride, with no significant difference between either treatment. As previously reported, baseline nasal potential difference was significantly more negative in the subjects with cystic fibrosis. Amiloride significantly reduced the potential difference for at least 60 minutes in these subjects.. Nebulised saline significantly improves nasal mucociliary clearance in both normal subjects and those with cystic fibrosis. Amiloride did not appear to exert any additional effects in either group of subjects, despite evidence of its efficacy of deposition.

Topics: Adolescent; Adult; Amiloride; Cystic Fibrosis; Double-Blind Method; Electrophysiology; Humans; Mucociliary Clearance; Nose; Saccharin; Sodium Chloride

Hispanic people with cystic fibrosis (CF) have decreased life expectancy and earlier acquisition of Pseudomonas aeruginosa compared to non-Hispanic white individuals with CF. Racial and ethnic differences in the airway microbiome of CF may contribute to known health disparity, but have not been studied. The objective was to describe differences in the upper airway microbial community in Hispanic and non-Hispanic white children with CF.. This prospective, observational cohort study of 59 Hispanic and non-Hispanic white children with CF, ages 2-10 years old, was performed at Texas Children's Hospital (TCH) from February 2019 to January 2020. Oropharyngeal swabs were collected from the cohort during clinic visit. Swab samples underwent sequencing (16S V4 rRNA), diversity analysis, and taxonomic profiling. Key demographic and clinical data were collected from the electronic medical record and the CF Foundation Patient Registry (CFFPR). Statistical analysis compared sequencing, demographic, and clinical data.. We found no significant difference in Shannon diversity or relative abundance of bacterial phyla between Hispanic and non-Hispanic children with CF. However, a low abundant taxa- "uncultured bacterium" belonging to the order Saccharimonadales was significantly higher in Hispanic children (mean relative abundance = 0.13%) compared to the non-Hispanic children (0.03%). Hispanic children had increased incidence of P. aeruginosa (p = 0.045) compared to non-Hispanic children.. We did not find a significant difference in the airway microbial diversity between Hispanic and non-Hispanic white children with CF. However, we found a greater relative abundance of Saccharimonadales and higher incidence of P. aeruginosa in Hispanic children with CF.

Topics: Bacteria; Child; Child, Preschool; Cystic Fibrosis; Humans; Microbiota; Nose; Prospective Studies; Pseudomonas aeruginosa; Trachea

The nasal and bronchial epithelium are unified parts of the respiratory tract that are affected in the monogenic disorder cystic fibrosis (CF). Recent studies have uncovered that nasal and bronchial tissues exhibit intrinsic variability, including differences in mucociliary cell composition and expression of unique transcriptional regulatory proteins which relate to germ layer origin. In the present study, we explored whether intrinsic differences between nasal and bronchial epithelial cells persist in cell cultures and affect epithelial cell functioning in CF. Comparison of air-liquid interface (ALI) differentiated epithelial cells from subjects with CF revealed distinct mucociliary differentiation states of nasal and bronchial cultures. Moreover, using RNA sequencing we identified cell type-specific signature transcription factors in differentiated nasal and bronchial epithelial cells, some of which were already poised for expression in basal progenitor cells as evidenced by ATAC sequencing. Analysis of differentiated nasal and bronchial epithelial 3D organoids revealed distinct capacities for fluid secretion, which was linked to differences in ciliated cell differentiation. In conclusion, we show that unique phenotypical and functional features of nasal and bronchial epithelial cells persist in cell culture models, which can be further used to investigate the effects of tissue-specific features on upper and lower respiratory disease development in CF.

Topics: Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Nose; Respiratory Mucosa

Individualized therapy for cystic fibrosis (CF) patients can be achieved with an in vitro disease model to understand baseline Cystic Fibrosis Transmembrane conductance Regulator (CFTR) activity and restoration from small molecule compounds. Our group recently focused on establishing a well-differentiated organoid model directly derived from primary human nasal epithelial cells (HNE). Histology of sectioned organoids, whole-mount immunofluorescent staining, and imaging (using confocal microscopy, immunofluorescent microscopy, and bright field) are essential to characterize organoids and confirm epithelial differentiation in preparation for functional assays. Furthermore, HNE organoids produce lumens of varying sizes that correlate with CFTR activity, distinguishing between CF and non-CF organoids. In this manuscript, the methodology for culturing HNE organoids are described in detail, focusing on the assessment of differentiation using the imaging modalities, including the measurement of baseline lumen area (a method of CFTR activity measurement in organoids that any laboratory with a microscope can employ) as well as the developed automated approach to a functional assay (which requires more specialized equipment).

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Ion Transport; Nose; Organoids

Nasal irrigation is a grade A recommendation treatment, which is essential in many pathological conditions. Very heterogeneous practices are observed in paediatrics as a result of poor instruction in this technique. We propose to describe the nasal irrigation technique developed by a team of respiratory physiotherapists in Lille for the management of cystic fibrosis and bronchiolitis. This technique is intended for children over the age of 6 months, as it requires an oral breathing reflex and cough reflex that are not systematically acquired before this age. Nasal irrigation is performed on a 30° upward inclined plane on a calm and cooperative child, away from meals. The child is maintained gently, without pressure, in the fencing position with the head turned away from the practitioner. Using a continuous flow spray, the practitioner grasps the top of the upper nostril and irrigates the nostril for an average of 3 s (6mL per nostril). These steps are then repeated until satisfactory patency is achieved in both nostrils. This technique constitutes a practical tool to help healthcare professionals and parents perform nasal irrigation in young children over the age of 6 months.

Topics: Child; Child, Preschool; Cystic Fibrosis; Humans; Infant; Nasal Lavage; Nose; Pediatrics

Topics: Adult; Chronic Disease; Cystic Fibrosis; Disease Progression; Endoscopy; Female; Humans; Male; Nose; Olfaction Disorders; Prospective Studies; Quality of Life; Rhinitis; Sinusitis; Smell

We have demonstrated previously that intracellular transport is impaired in cystic fibrosis (CF) epithelial cells. This impairment is related to both growth and inflammatory regulation in CF cell and animal models. Understanding how transport in CF cells is regulated and identifying means to manipulate that regulation are key to identifying new therapies that can address key CF phenotypes. It was hypothesized that resveratrol could replicate these benefits since it interfaces with multiple pathways identified to affect microtubule regulation in CF. It was found that resveratrol treatment significantly restored intracellular transport as determined by monitoring both cholesterol distribution and the distribution of rab7-positive organelles in CF cells. This restoration of intracellular transport is due to correction of both microtubule formation rates and microtubule acetylation in cultured CF cell models and primary nasal epithelial cells. Mechanistically, the effect of resveratrol on microtubule regulation and intracellular transport was dependent on peroxisome proliferator-activated receptor-γ signaling and its ability to act as a pan-histone deacetylase (HDAC) inhibitor. Resveratrol represents a candidate compound with known anti-inflammatory properties that can restore both microtubule formation and acetylation in CF epithelial cells.

Topics: 1-Methyl-3-isobutylxanthine; Acetylation; Biological Transport; Carbazoles; Cells, Cultured; Cholesterol; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Intracellular Space; Microtubules; Nose; Phosphodiesterase Inhibitors; PPAR gamma; Resorcinols; Resveratrol; Signal Transduction; Sirtuins; Stilbenes; Tubulin

Topics: Courage; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Nose; Sweat

ORKAMBI, a combination of the corrector, lumacaftor, and the potentiator, ivacaftor, partially rescues the defective processing and anion channel activity conferred by the major cystic fibrosis-causing mutation, F508del, in in vitro studies. Clinically, the improvement in lung function after ORKAMBI treatment is modest and variable, prompting the search for complementary interventions. As our previous work identified a positive effect of arginine-dependent nitric oxide signaling on residual F508del-Cftr function in murine intestinal epithelium, we were prompted to determine whether strategies aimed at increasing arginine would enhance F508del-cystic fibrosis transmembrane conductance regulator (CFTR) channel activity in patient-derived airway epithelia. Now, we show that the addition of arginine together with inhibition of intracellular arginase activity increased cytosolic nitric oxide and enhanced the rescue effect of ORKAMBI on F508del-CFTR-mediated chloride conductance at the cell surface of patient-derived bronchial and nasal epithelial cultures. Interestingly, arginine addition plus arginase inhibition also enhanced ORKAMBI-mediated increases in ciliary beat frequency and mucociliary movement, two in vitro CF phenotypes that are downstream of the channel defect. This work suggests that strategies to manipulate the arginine-nitric oxide pathway in combination with CFTR modulators may lead to improved clinical outcomes. SIGNIFICANCE STATEMENT: These proof-of-concept studies highlight the potential to boost the response to cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, lumacaftor and ivacaftor, in patient-derived airway tissues expressing the major CF-causing mutant, F508del-CFTR, by enhancing other regulatory pathways. In this case, we observed enhancement of pharmacologically rescued F508del-CFTR by arginine-dependent, nitric oxide signaling through inhibition of endogenous arginase activity.

Topics: Aminophenols; Aminopyridines; Animals; Arginase; Arginine; Benzodioxoles; Bronchi; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytosol; Drug Combinations; Humans; Intestinal Mucosa; Mice; Mutation; Nitric Oxide; Nose; Quinolones

Different interfaces (mouthpiece/nose clip vs. facemask) are used during multiple breath washout (MBW) tests in young children.. We investigated the effect of interface choice and breathing modalities on MBW outcomes in healthy adults and preschool children.. In adults (n = 26) facemask breathing significantly increased LCI, compared to mouthpiece use (mean difference (95% CI) 0.4 (0.2; 0.6)), with results generalizable across sites and different equipment. Exclusively nasal breathing within the facemask increased LCI, as compared to oral breathing. In preschoolers (2-6 years, n = 46), no significant inter-test difference was observed across interfaces for LCI or FRC. Feasibility and breathing stability were significantly greater with facemask (incorporating dead space volume minimization), vs. mouthpiece. This was more pronounced in subjects <4 years of age.. Both nasal vs. oral breathing and mouthpiece vs. facemask affect LCI measurements in adults. This effect was minimal in preschool children, where switching between interfaces is most likely to occur.

Topics: Adult; Anatomy, Regional; Breath Tests; Child; Child, Preschool; Cystic Fibrosis; Equipment Design; Face; Feasibility Studies; Female; Functional Residual Capacity; Humans; Male; Masks; Mouth; Nose; Respiration; Respiratory Function Tests

To assess whether DNA methylation levels account for the noninherited phenotypic variations observed among cystic fibrosis (CF) patients.. Using the 450 K BeadChip, we profiled DNA methylation in nasal epithelial cells collected from 32 CF patients and 16 controls.. We detected substantial DNA methylation differences up to 55% (median β change 0.13; IQR: 0.15-0.11) between CF patients and controls. DNA methylation levels differed between mild and severe CF patients and correlated with lung function at 50 CpG sites.. In CF samples, dynamic changes of DNA methylation occurred in genes responsible for the integrity of the epithelium and the inflammatory and immune responses, were prominent in transcriptionally active genomic regions and were over-represented in enhancers active in lung tissues. ( Clinicaltrials.gov NCT02884622).

Topics: Adult; CpG Islands; Cystic Fibrosis; DNA Methylation; Epithelial Cells; Female; Gene Expression; Humans; Male; Nose

Cystic fibrosis (CF) patients almost regularly reveal sinonasal pathology. The purpose of this study was to assess association between objective and subjective measurements of sinonasal involvement comparing nasal airflow obtained by active anterior rhinomanometry (AAR), nasal endoscopic findings, and symptoms assessed with the Sino-Nasal Outcome Test-20 (SNOT-20).. Nasal cavities were explored by anterior rigid rhinoscopy and findings were compared to inspiratory nasal airflow measured by AAR to quantify nasal patency and subjective health-related quality of life in sinonasal disease obtained with the SNOT-20 questionnaire. Relations to upper and lower airway colonization with Pseudomonas aeruginosa, medical treatment, and sinonasal surgery were analysed.. A total of 124 CF patients were enrolled (mean age 19.9 ± 10.4 years, range 4-65 years). A significant association of detection of nasal polyposis (NP) in rhinoscopy was found with increased primary nasal symptoms (PNS) which include "nasal obstruction," "sneezing," "runny nose," "thick nasal discharge," and "reduced sense of smell." At the same time patients with pathologically decreased airflow neither showed elevated SNOT-20 scores nor abnormal rhinoscopic findings. Altogether, rhinomanometric and rhinoscopic findings are not significantly related.. Among SNOT-20 scores the PNS subscore is related to rhinoscopically detected polyposis and sinonasal secretion. Therefore, we recommend including short questions regarding PNS into CF-routine care. At the same time our results show that a high inspiratory airflow is not associated with a good sensation of nasal patency. Altogether, rhinomanometry is not required within routine CF-care, but it can be interesting as an outcome parameter within clinical trials. Pediatr Pulmonol. 2017;52:167-174. © 2016 Wiley Periodicals, Inc.

Topics: Adolescent; Adult; Aged; Carrier State; Child; Child, Preschool; Cystic Fibrosis; Endoscopy; Female; Humans; Male; Middle Aged; Nasal Cavity; Nasal Obstruction; Nose; Olfaction Disorders; Pseudomonas aeruginosa; Pseudomonas Infections; Quality of Life; Rhinomanometry; Sneezing; Surveys and Questionnaires; Young Adult

Patients with cystic fibrosis (CF) have similar or lower exhaled nitric oxide (FeNO) and lower nasal nitric oxide (nNO) levels than controls. There are divergent results on alveolar NO (Calv. To compare FeNO, Calv. Measurements of FeNO at multiple exhalation flow rates, nNO and spirometry were done in 38 patients (18 adults) with CF. Blood cell counts and CF clinical characteristics were recorded. Thirty-eight healthy controls and 38 asthma patients, gender- and age-matched, were included as reference groups.. FeNO levels were lower in CF patients (7.2 [4.7-11.2] ppb) than in healthy controls (11.4 [8.3-14.6] ppb) and asthma patients (14.7 [8.7-24.7] ppb) (both p < 0.005). These differences were consistent in adults. No difference in Calv. CF patients have lower FeNO and nNO and similar Calv

Topics: Adolescent; Adult; Anthropometry; Blood Cell Count; Breath Tests; Child; Cystic Fibrosis; Demography; Exhalation; Female; Humans; Male; Nitric Oxide; Nose; Respiratory Function Tests; Young Adult

Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR. For example, markedly diminished steady state amounts of F508del CFTR compared to WT CFTR are present in recombinant bronchial epithelial cell lines, even when much higher levels of mutant transcript are present. In human primary airway cells, the paucity of Band B F508del is even more pronounced, although F508del and WT mRNA concentrations are comparable. Therefore, to augment levels of "repairable" F508del CFTR and identify small molecules that then correct this pool, we developed compound library screening protocols based on automated protein detection. First, cell-based imaging measurements were used to semi-quantitatively estimate distribution of F508del CFTR by high content analysis of two-dimensional images. We evaluated ~2,000 known bioactive compounds from the NIH Roadmap Molecular Libraries Small Molecule Repository in a pilot screen and identified agents that increase the F508del protein pool. Second, we analyzed ~10,000 compounds representing diverse chemical scaffolds for effects on total CFTR expression using a multi-plate fluorescence protocol and describe compounds that promote F508del maturation. Together, our findings demonstrate proof of principle that agents identified in this fashion can augment the level of endoplasmic reticulum (ER) resident "Band B" F508del CFTR suitable for pharmacologic correction. As further evidence in support of this strategy, PYR-41-a compound that inhibits the E1 ubiquitin activating enzyme-was shown to synergistically enhance F508del rescue by C18, a small molecule corrector. Our combined results indicate that increasing the levels of ER-localized CFTR available for repair provides a novel route to correct F508del CFTR.

Topics: Alleles; Benzoates; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Endoplasmic Reticulum; Furans; Gene Deletion; HEK293 Cells; HeLa Cells; High-Throughput Screening Assays; Humans; Hydroxamic Acids; Microscopy, Fluorescence; Protein Folding; Protein Structure, Tertiary; Pyrazoles; RNA, Messenger; Small Molecule Libraries; Ubiquitination; Vorinostat

The most common mutation of CFTR, affecting approximately 90% of CF patients, is a deletion of phenylalanine at position 508 (F508del, ΔF508). Misfolding of ΔF508-CFTR impairs both its trafficking to the plasma membrane and its chloride channel activity. To identify small molecules that can restore channel activity of ΔF508-CFTR, we synthesized and evaluated eighteen novel hydroxypyrazoline analogues as CFTR potentiators. To elucidate potentiation activities of hydroxypyrazolines for ΔF508-CFTR, CFTR activity was measured using a halide-sensitive YFP assay, Ussing chamber assay and patch-clamp technique. Compounds 7p, 7q and 7r exhibited excellent potentiation with EC50 value <10 μM. Among the compounds, 7q (a novel CFTR potentiator, CP7q) showed the highest potentiation activity with EC50 values of 0.88 ± 0.11 and 4.45 ± 0.31 μM for wild-type and ΔF508-CFTR, respectively. In addition, CP7q significantly potentiated chloride conductance of G551D-CFTR, a CFTR gating mutant; its maximal potentiation activity was 1.9 fold higher than the well-known CFTR potentiator genistein. Combination treatment with CP7q and VX-809, a corrector of ΔF508-CFTR, significantly enhanced functional rescue of ΔF508-CFTR compared with VX-809 alone. CP7q did not alter the cytosolic cAMP level and showed no cytotoxicity at the concentration showing maximum efficacy. The hydroxypyrazolines may be potential development candidates for drug therapy of cystic fibrosis.

Topics: Aminopyridines; Animals; Bacterial Proteins; Benzodioxoles; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Chlorides; Cyclic AMP; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Gene Deletion; Genistein; Humans; Luminescent Proteins; Mutation; Nose; Patch-Clamp Techniques; Phenylalanine; Pyrazoles; Rats; Structure-Activity Relationship; Sulfonamides

Topics: Cystic Fibrosis; Humans; Infant; Microbiota; Nose

Nasal potential difference (NPD) measurement is part of the diagnostic criteria for cystic fibrosis (CF) and now used routinely as an endpoint in clinical trials of correcting the basic defect in CF. Intestinal current measurement (ICM), measured ex vivo on a rectal biopsy, has been used to study cystic fibrosis transmembrane conductance regulator (CFTR) function but has not been compared to NPD in the same subject in adults and children. The aim of the study is to evaluate the potential usefulness of ICM as a marker of CFTR function for treatment studies compared NPD in patients with CF and in healthy control subjects.. ICM and NPD were performed on healthy controls and patients with CF. The healthy adults were individuals undergoing routine screening colonoscopy at the Beth Israel Deaconess Medical Center. The healthy children were undergoing colonoscopy for suspicion of inflammation in Hadassah Hebrew University Medical Center. The CF adults were recruited from Boston Children's Hospital CF Center and CF Center Worcester Mass, the children with CF from Hadassah CF Center.. ICM measurements in healthy control subjects (n = 16) demonstrated a mean (±SE) carbachol response of 16.0 (2.2) μA/cm, histamine response of 13.2 (2.1) μA/cm and a forskolin response of 6.3 (2.0) μA/cm. Basal NPD of -15.9 (1.9) and response to Cl free + isoproterenol of -13.8 (2.0). These responses were inverted in CF subjects (n = 12) for ICM parameters with carbachol response of -3.0 (0.5) μA/cm, histamine -1.0 (0.8) μA/cm and a forskolin response of 0.5 (0.3) and also for NPD parameters; basal NPD of -42.2 (4.3) and response to Cl free + isoproterenol of 4.3 (0.7). Pearson correlation test showed the comparability of ICM and NPD in assessing CFTR function.. ICM is equivalent to NPD in the ability to distinguish patients with CF from controls and could be used as surrogate markers of CFTR activity in treatment protocols.

Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Infant; Intestines; Male; Middle Aged; Nose; Young Adult

Bordetella bronchiseptica is a Gram-negative bacterium that infects and causes disease in a wide variety of animals. B. bronchiseptica also infects humans, thereby demonstrating zoonotic transmission. An extensive characterization of human B. bronchiseptica isolates is needed to better understand the distinct genetic and phenotypic traits associated with these zoonotic transmission events. Using whole-genome transcriptome and CGH analysis, we report that a B. bronchiseptica cystic fibrosis isolate, T44625, contains a distinct genomic content of virulence-associated genes and differentially expresses these genes compared to the sequenced model laboratory strain RB50, a rabbit isolate. The differential gene expression pattern correlated with unique phenotypes exhibited by T44625, which included lower motility, increased aggregation, hyperbiofilm formation, and an increased in vitro capacity to adhere to respiratory epithelial cells. Using a mouse intranasal infection model, we found that although defective in establishing high bacterial burdens early during the infection process, T44625 persisted efficiently in the mouse nose. By documenting the unique genomic and phenotypic attributes of T44625, this report provides a blueprint for understanding the successful zoonotic potential of B. bronchiseptica and other zoonotic bacteria.

Topics: Animals; Bacterial Adhesion; Bacterial Proteins; Biofilms; Bordetella bronchiseptica; Bordetella Infections; Comparative Genomic Hybridization; Cystic Fibrosis; Disease Models, Animal; Female; Genome, Bacterial; Mice; Mice, Inbred C57BL; Microarray Analysis; Nose; Phenotype; Sequence Analysis, DNA; Virulence

Nasal potential difference (NPD) and intestinal current measurement (ICM) are functional CFTR tests that are used as adjunctive diagnostic tools for cystic fibrosis (CF). Smoking has a systemic negative impact on CFTR function. A diagnostic comparison between NPD and ICM and the impact of smoking on both CFTR tests has not been done.. The sweat chloride test, NPD, and ICM were performed in 18 patients with CF (sweat chloride >60 mmol/l), including 6 pancreatic sufficient (PS) patients, and 13 healthy controls, including 8 smokers. The NPD CFTR response to Cl-free and isoproterenol perfusion (Δ0Cl- + Iso) was compared to the ICM CFTR response to forskolin/IBMX, carbachol, and histamine (ΔIsc, forskolin/IBMX+ carbachol+histamine).. The mean NPD CFTR response and ICM CFTR response between patients with CF and healthy controls was significantly different (p <0.001), but not between patients with CF who were PS and those who were pancreatic insufficient (PI). Smokers have a decreased CFTR response measured by NPD (p = 0.049). For ICM there is a trend towards decreased CFTR response (NS). Three healthy control smokers had NPD responses within the CF-range. In contrast to NPD, there was no overlap of the ICM response between patients with CF and controls.. ICM is superior to NPD in distinguishing between patients with CF who have a sweat chloride > 60 mmol/l and healthy controls, including smokers. Neither NPD nor ICM differentiated between patients with CF who were PS from those who were PI. Smoking has a negative impact on CFTR function in healthy controls measured by NPD and challenges the diagnostic interpretation of NPD, but not ICM.

Topics: Adolescent; Adult; Case-Control Studies; Child; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Intestinal Mucosa; Male; Nose; Rectum; Respiratory Mucosa; Smoking; Sweat; Young Adult

Hydrogen cyanide (HCN) in exhaled breath has been proposed as a biomarker for airway inflammation, and also a marker of the presence in the airways of specific organisms, especially Pseudomonas aeruginosa. However the production of HCN by salivary peroxidase in the oral cavity increases orally exhaled concentrations, and may not reflect the condition of the lower airways. Using SIFT-MS we aimed to determine an appropriate single-exhalation breathing maneuver which avoids the interference of HCN produced in the oral cavity. We have established that the SIFT-MS Voice200™ is suitable for the online measurement of HCN in exhaled breath. In healthy volunteers a significantly higher end exhaled HCN concentration was measured in oral exhalations compared to nasal exhalations (mean ± SD) 4.5 ± 0.6 ppb versus 2.4 ± 0.3 ppb, p < 0.01. For the accurate and reproducible quantification of end exhaled HCN in breath a nasal inhalation to full vital capacity and nasal exhalation at controlled flow is recommended. This technique was subsequently used to measure exhaled HCN in a group of patients with chronic suppurative lung disease (CSLD) and known microbiological colonization status to determine utility of HCN measurement to detect P. aeruginosa. Median nasal end exhaled HCN concentrations were higher in patients with CSLD (3.7 ppb) than normal subjects (2.0 ppb). However no differences between exhaled HCN concentrations of subjects colonized with P. aeruginosa and other organisms were identified, indicating that breath HCN is not a suitable biomarker of P. aeruginosa colonization.

Topics: Adult; Biomarkers; Breath Tests; Bronchiectasis; Case-Control Studies; Cystic Fibrosis; Exhalation; Female; Humans; Hydrogen Cyanide; Inhalation; Male; Mass Spectrometry; Middle Aged; Mouth; Nose; Pseudomonas aeruginosa; Pseudomonas Infections; Reproducibility of Results

OBJECTIVE. The aim of this study was to estimate the significance of nasal potential difference (NPD) in the diagnosis of cystic fibrosis (CF) in children with clinical symptoms suggestive of the disease, positive sweat test results, and/or genetically confirmed diagnosis. MATERIAL AND METHODS. NPD measurements according to the modifications by Alton were performed in 50 children with clinical CF symptoms supported by positive sweat test results, 50 children with other obstructive lung diseases, and 50 healthy children. A subgroup of 17 children with the diagnosis confirmed by 2 identified mutations in the CF transmembrane regulatory gene was analyzed individually. RESULTS. The mean NPD value recorded in 50 children with clinical symptoms of CF supported by positive sweat test results and/or genetic analysis was -28.0 mV [SD, 10.2]. The mean NPD value in the subgroup of children with 2 identified mutations in the CF gene (n=17) was more negative than in the subgroup of children with unrecognized mutations (n=33) (-37.1 mV [SD, 7.0] vs. -23.4 mV [SD, 8.3], P<0.001). The mean NPD value in patients with other obstructive lung diseases and healthy children was significantly more positive than in the group of CF children with positive sweat test results and/or identified mutations (-18.1 mV [SD, 3.6] and -15.5 mV [SD, 4.3] vs. -28.0 mV [SD, 10.2], P<0.001). The NPD cut point value for the genetically confirmed diagnosis of CF was -35.0 mV (sensitivity, 93.9%; specificity, 88.2%), while in general, the NPD prognostic value was -24.0 mV (sensitivity, 58.0%; specificity, 98.0%). CONCLUSIONS. The NPD measurement is a valuable tool for the diagnosis of CF in children, but further studies are necessary to establish NPD values related to the CF genotype and to reduce the intrasubject variability of this test.

Topics: Adolescent; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diagnostic Techniques, Respiratory System; Female; Humans; Infant; Male; Nose; Respiratory Mucosa; Sodium Chloride Symporters; Sweat

When ventilating large volumes of air during exercise, airway fluid secretion is essential for airway function. Since these are impaired in cystic fibrosis and exercise-induced asthma, it was the aim of this study to determine how exercise affects airway Na(+) and Cl(-) transport and whether changes depend on exercise intensity. Nasal potential was measured in Ringer's solution, with amiloride to block Na(+) transport, and in low chloride-containing isoproterenol to assess Cl(-) channels. Nasal potential was measured at rest and during submaximal and maximal bicycle ergometer exercise in individuals with cystic fibrosis, exercise-induced asthma and controls. At rest, nasal potential was significantly higher in cystic fibroses than in the others. Maximal exercise decreased nasal potentials in cystic fibrosis and controls but not in exercise asthma. Submaximal exercise decreased nasal potentials only in cystic fibrosis. Cl(-) transport was not affected. Our results indicate that nasal potentials and Na(+) transport were decreased by maximal exercise in healthy and cystic fibrosis, whereas submaximal exercise decreased potentials in cystic fibrosis only. Exercise did not affect nasal potentials in asthmatics. Decreased reabsorption during exercise might favour airway fluid secretion during hyperpnoea. This protective effect appears blunted in patients with exercise-induced asthma.

Topics: Adult; Amiloride; Asthma, Exercise-Induced; Chloride Channels; Cystic Fibrosis; Exercise; Exercise Test; Female; Humans; Ion Transport; Isoproterenol; Male; Membrane Potentials; Nose; Sodium; Sodium Channel Blockers; Treatment Outcome; Young Adult

A clinical program to assess whether lipid GL67A-mediated gene transfer can ameliorate cystic fibrosis (CF) lung disease is currently being undertaken by the UK CF Gene Therapy Consortium. We have evaluated GL67A gene transfer to the murine nasal epithelium of wild-type and CF knockout mice to assess this tissue as a test site for gene transfer agents. The plasmids used were regulated by either (1) the commonly used short-acting cytomegalovirus promoter/enhancer or (2) the ubiquitin C promoter. In a study of approximately 400 mice with CF, vector-specific CF transmembrane conductance regulator (CFTR) mRNA was detected in nasal epithelial cells of 82% of mice treated with a cytomegalovirus-plasmid (pCF1-CFTR), and 62% of mice treated with an ubiquitin C-plasmid. We then assessed whether CFTR gene transfer corrected a panel of CFTR-specific endpoint assays in the murine nose, including ion transport, periciliary liquid height, and ex vivo bacterial adherence. Importantly, even with the comparatively large number of animals assessed, the CFTR function studies were only powered to detect changes of more than 50% toward wild-type values. Within this limitation, no significant correction of the CF phenotype was detected. At the current levels of gene transfer efficiency achievable with nonviral vectors, the murine nose is of limited value as a stepping stone to human trials.

Topics: Animals; Bacterial Adhesion; Cystic Fibrosis; Cytomegalovirus; Enhancer Elements, Genetic; Female; Gene Transfer Techniques; Genetic Therapy; Liposomes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Nose; Plasmids; Promoter Regions, Genetic

It is not known whether the progressive airway changes in cystic fibrosis (CF) are all secondary to infection and inflammation. The CF mouse nose shares electrophysiologic and cellular properties with human CF airway epithelium. In the present work, we tested the hypothesis that structural abnormalities in the nasal mucosa of CF mice develop independent of infection and inflammation. We performed nasal lavage and subsequent serial coronal section through the nasal tissue of adult CF (mutations Cftr(TgHm1G551D) and Cftr(tm1Unc)-TgN((FABPCFTR))) and wild-type mice raised under normal housing conditions. Nasal tissue was also obtained from Day 17 embryos and newborn pups. Detailed histologic examination of the respiratory and olfactory epithelium within the nasal cavity was performed. Bacterial culture, cell count, and macrophage inflammatory protein-2 (MIP-2) concentration were assessed in nasal lavage fluid. Significantly thickened respiratory epithelium and increased mucous cell density was found in adult CF mice of both mutations compared with wild-type animals. In contrast, the olfactory epithelium was thinner, with a decreased cell density. Areas of lymphoid aggregates were found in CF mice but not in non-CF mice. There were no differences in bacterial growth, cell count, or MIP-2 concentrations. No genotype differences were observed in the embryonic or newborn periods. There are significant histologic changes in the nasal mucosa of adult CF mice, not associated with increased lumenal inflammation or bacterial content, and which are not present perinatally. These may be novel therapeutic targets.

Topics: Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Genotype; Homozygote; Humans; Infections; Inflammation; Mice; Mice, Mutant Strains; Mice, Transgenic; Nose; Olfactory Mucosa; Polymorphism, Single Nucleotide; Respiratory Mucosa

Staphylococcus aureus is one of the first pathogens which often persistently infect the airways of cystic fibrosis (CF) patients. Nasal S. aureus carriage is a risk factor for S. aureus infections in non-CF patients. Topical treatment strategies successfully eradicate nasal S. aureus carriage, thereby decreasing S. aureus infection. A prospective longitudinal multicenter study was conducted to assess whether nasal carriage represents a risk factor for S. aureus colonization of the oropharynx in young CF patients. Cross-sectional analysis revealed a significantly higher prevalence of S. aureus-positive nasal (28/80 [35%] versus 20/109 [18%]; P < 0.01) and oropharyngeal (35/80 [44%] versus 20/109 [18%]; P < 0.001) cultures in children with CF compared to a control group. The first site of S. aureus detection was the nose in 6 patients and the oropharynx in 14 patients, respectively. Longitudinal analysis demonstrated a significantly higher S. aureus prevalence (61/62 [98%] versus 47/62 [76%]; P < 0.001) and persistence (46/62 [74%] versus 31/62 [50%]; P < 0.01) in the oropharynx than in the nose. In CF patients, the oropharynx, and not the nose, was the predominant site of S. aureus infection and persistence. Hence, it is unlikely that CF patients will benefit from topical treatment strategies to eradicate nasal carriage.

Topics: Antigens, Bacterial; Carrier State; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Infant; Longitudinal Studies; Male; Nose; Oropharynx; Prevalence; Prospective Studies; Receptors, Cell Surface; Respiratory Tract Infections; Risk Factors; Staphylococcal Infections; Staphylococcus aureus

In hostile environments diversity within a bacterial population may be beneficial for the fitness of the microbial community as a whole. Here we analysed the population diversity of Staphylococcus aureus in infecting and colonizing situations. In the study, performed independently in two German centres, the heterogeneity of the S. aureus population was determined by quantifying the occurrence of phenotypic variants (differences in haemolysis, pigmentation, colony morphology) in primary cultures from nose, oropharyngeal and sputum specimens from cystic fibrosis (CF) patients and in nose swabs from healthy S. aureus carriers. The proportion of heterogeneous samples, the number of clearly distinguishable isolates per sample and the qualitative differences between phenotypes was significantly higher in CF sputum specimens than in the other samples. The heterogeneity of the S. aureus population could be correlated with high bacterial densities in the sputum samples. In patients co-infected with Pseudomonas aeruginosa lower S. aureus bacterial loads and less heterogeneity in the S. aureus population were observed. Typing of all S. aureus isolates from heterogeneous samples by pulsed-field gel electrophoresis or spa typing revealed that the bacteria were polyclonal in 30%, monoclonal with minor genetic alterations in 25% or not distinguishable in 69% of the specimens. Some specimens harboured monoclonal and polyclonal variants simultaneously. Importantly, differences in antibiotic susceptibility were detected in phenotypic S. aureus variants within a single specimen. Diversification of a S. aureus population is highly favoured during chronic CF lung infection, supporting the general hypothesis that maintenance of intrahost diversity can be of adaptive value, increasing the fitness of the bacterial community.

Topics: Adolescent; Adult; Bacterial Typing Techniques; Carrier State; Child; Child, Preschool; Cystic Fibrosis; Electrophoresis, Gel, Pulsed-Field; Female; Hemolysis; Humans; Infant; Male; Microbial Sensitivity Tests; Nose; Oropharynx; Phenotype; Sputum; Staphylococcal Infections; Staphylococcus aureus

Cystic fibrosis is usually diagnosed based on suspicion arising from a typical clinical picture and must be confirmed by either a finding of high chloride concentrations in sweat tests on 2 separate days or detection of 2 gene mutations. The nasal potential difference (NPD) test has been proposed to provide evidence of abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR), a receptor that forms a chloride ion channel. The test is especially useful for patients who have normal chloride concentrations in sweat tests and in whom 2 gene mutations related to cystic fibrosis have not been detected. The NPD test requires 2 electrodes connected to a voltmeter (a Tholy-Medicap device). One is placed on the nasal mucosa of the inferior turbinate and the other is placed subcutaneously on the forearm. A reading less than -40 mV is considered abnormal, as values under that cut point are never found in healthy individuals. Two abnormal NPD findings on separate days are required for a diagnosis of CFTR dysfunction. False negatives arise when the integrity of the epithelium is altered. After application of amiloride, NPD decreases more markedly in cystic fibrosis patients than in healthy individuals and applying isoproterenol or fenoterol after amiloride provokes no response in patients with the genetic defect that prevents chloride ion channel activation.

Topics: Action Potentials; Cystic Fibrosis; Electrodes; Electrophysiology; Epithelium; Equipment Design; Humans; Nose

To examine the relationship between cystic fibrosis transmembrane regulator gene mutations (CFTR) and in vivo transepithelial potentials.. We prospectively evaluated 162 men including 31 healthy subjects, 21 obligate heterozygotes, 60 with congenital bilateral absence of the vas deferens (CBAVD) and 50 with CF by extensive CFTR genotyping, sweat chloride and nasal potential difference testing.. Six (10%) men with CBAVD carried no CFTR mutations, 18 (30%) carried one mutation, including the 5T variant, and 36 (60%) carried mutations on both alleles, for a significantly higher rate carrying one or more mutations than healthy controls (90% versus 19%, p < 0.001). There was an overlapping spectrum of ion channel measurements among the men with CBAVD, ranging from values in the control and obligate heterozygote range at one extreme, to values in the CF range at the other. All pancreatic-sufficient patients with CF and 34 of 36 patients with CBAVD with mutations on both alleles carried at least one mild mutation. However, the distribution of mild mutations in the two groups differed greatly. Genotyping, sweat chloride and nasal potential difference (alone or in combination) excluded CF in all CBAVD men with no mutations. CF was confirmed in 56% and 67% of CBAVD men carrying 1 and 2 CFTR mutations, respectively.. Abnormalities of CFTR transepithelial function correlate with the number and severity of CFTR gene mutations.

Topics: Alleles; Amiloride; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Mutational Analysis; Epithelial Cells; Genotype; Humans; Male; Nose; Prospective Studies; Sodium Channel Blockers; Sweat; Vas Deferens

It has been proposed that defective submucosal gland function in CF airways is a major determinant of CF airway disease. We tested the hypothesis that submucosal gland function is defective early in CF subjects with minimal clinical disease. Functional assays of gland fluid secretion rate and viscosity were performed on freshly obtained nasal biopsies from 6 CF subjects and 5 non-CF controls (age range 2-22 years). Secretions from individual submucosal glands were visualized by light/fluorescence microscopy after orienting and immobilizing biopsy specimens in a custom chamber. The viscosity of freshly secreted gland fluid after pilocarpine, measured by fluorescence recovery after photobleaching of microinjected FITC-dextran, was 4.9 +/- 0.2- vs. 2.2 +/- 0.2-fold greater than water viscosity in CF vs. non-CF specimens, respectively (SE, P<10(-4)). Gland fluid secretion rate in CF specimens, measured by video imaging (4.5+/-0.5 nL/min/gland, n=6), was 2.7-fold reduced compared to non-CF specimens (n=3, P<0.05). Quantitative histology revealed similar size and morphology of submucosal glands in CF and non-CF specimens. Our results suggest that defective airway submucosal gland function is an early, primary defect in CF. Therapies directed at normalizing gland fluid secretion early in CF may thus reduce lung disease.

Topics: Adolescent; Adult; Biopsy; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dextrans; Exocrine Glands; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Humans; Kinetics; Microscopy, Fluorescence; Nose; Photobleaching; Pilocarpine; Respiratory Mucosa; Viscosity

Most patients with cystic fibrosis (CF) have a DeltaF508 mutation resulting in abnormal retention of mutant gene protein (DeltaF508-CFTR) within the cell. This study was undertaken to investigate DeltaF508-CFTR trafficking in native cells from patients with CF with the aim of discovering pharmacological agents that can move DeltaF508-CFTR to its correct location in the apical cell membrane.. Nasal epithelial cells were obtained by brushing from individuals with CF. CFTR location was determined using immunofluorescence and confocal imaging in untreated cells and cells treated with sildenafil. The effect of sildenafil treatment on CFTR chloride transport function was measured in CF15 cells using an iodide efflux assay.. In most untreated CF cells DeltaF508-CFTR was mislocalised within the cell at a site close to the nucleus. Exposure of cells to sildenafil (2 hours at 37 degrees C) resulted in recruitment of DeltaF508-CFTR to the apical membrane and the appearance of chloride transport activity. Sildenafil also increased DeltaF508-CFTR trafficking in cells from individuals with CF with a single copy DeltaF508 (DeltaF508/4016ins) or with a newly described CF trafficking mutation (R1283M).. The findings provide proof of principle for sildenafil as a DeltaF508-CFTR trafficking drug and give encouragement for future testing of sildenafil and related PDE5 inhibitors in patients with CF.

Topics: Adolescent; Adult; Biological Transport; Child; Child, Preschool; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Fluorescent Antibody Technique; Humans; Infant; Mutation; Nose; Phosphodiesterase Inhibitors; Piperazines; Purines; Respiratory Mucosa; Sildenafil Citrate; Sulfones

Nitric oxide (NO) plays an important role in a number of physiological processes in the airways, including host defense. Although the exact cellular and molecular source of the NO formation in airways is unknown, there is recent evidence that neuronal NO synthase (NOS1) contributes significantly to NO in the lower airways of cystic fibrosis (CF) patients. NOS1 protein has been shown to be expressed in nasal epithelium, suggesting an involvement of NOS1-derived NO in upper airway biology. We here hypothesized that nasal NO concentrations in CF patients are related to genotype variants in the NOS1 gene. Measurements of nasal NO concentration and pulmonary function were performed in 40 clinically stable CF patients. Genomic DNA from all patients was screened for an intronic AAT-repeat polymorphism in the NOS1 gene using polymerase chain reaction and simple sequence length polymorphism (SSLP) analysis. The allele size at that locus was significantly (P = 0.001) associated with upper airway NO. Mean (+/- SD) nasal NO concentrations were 40.5 +/- 5.2 ppb in CF patients (n = 12) with high repeat numbers (i.e., both alleles > or =12 repeats) and 72.6 +/- 7.4 ppb in patients (n = 28) with low repeat numbers (i.e., at least one allele <12 repeats). Furthermore, in the group of CF patients harboring NOS1 genotypes associated with low nasal NO, colonization of airways with P. aeruginosa was significantly more frequent than in patients with NOS1 genotypes associated high nasal NO concentrations (P = 0.0022). We conclude that (1) the variability in CF nasal NO levels are related to naturally occurring variants in the NOS1 gene, and (2) that nasal NOS1-derived NO affects the susceptibility of CF airways to infection with P. aeruginosa.

Topics: Adolescent; Adult; Alleles; Child; Cystic Fibrosis; Female; Genotype; Humans; Male; Nasal Mucosa; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nose; Phenotype; Polymorphism, Genetic; Pseudomonas Infections

Previous studies have indicated that milrinone, a specific type III phosphodiesterase inhibitor, may be able to induce chloride secretion in cystic fibrosis (CF) tissues. We have now assessed the effect of this agent in vivo on the nasal epithelium of CF mutant mice and also in the nose and lungs of human subjects with CF. Wild-type mice showed a small hyperpolarization of the nasal potential difference (PD) in response to milrinone (100 microM, 1.6 +/- 0.6 mV, n = 8, P < 0.05). In contrast, CF mice carrying either the most common human mutation of the gene for the CF transmembrane regulator (CFTR), DeltaF508 (protein mislocalized), or the G551D mutation (protein normally localized) failed to demonstrate this response. Milrinone perfused alone had no significant effect on the baseline nasal PD of human subjects without CF (14.7 +/- 4.0 mV preperfusion; 15.3 +/- 4.6 mV postperfusion), but significantly (P < 0.05) augmented the hyperpolarization induced by a subsequently perfused low-chloride solution (with milrinone, 36.8 +/- 3.0 mV, n = 6; without milrinone, 18.1 +/- 2.2 mV, n = 19). In contrast, in human subjects with CF (n = 6), milrinone alone significantly (P < 0. 05) altered the nasal baseline PD (52.2 +/- 3.3 mV preperfusion; 57. 4 +/- 4.2 mV, postperfusion) but not the subsequent responses to the low-chloride solution (with milrinone, 1.1 +/- 2.2 mV, n = 4; without milrinone, 0.6 +/- 0.5 mV, n = 28) or to isoproterenol (100 microM). In a separate study in subjects (n = 6) with the DeltaF508 mutation, nasal coadministration of milrinone with isoproterenol produced no effect in the presence of amiloride and a low-chloride solution (-0.8 +/- 0.5 mV). This was also the case in the nasal epithelium of CF subjects (n = 4) carrying at least one G551D allele (-0.3 +/- 0.8 mV). Similarly, milrinone did not hyperpolarize the PD of either the tracheal (n = 6) or segmental (n = 6) airways of CF subjects (DeltaF508) when applied topically in vivo in the presence of amiloride, isoproterenol, or adenosine triphosphate (all 100 microM) in a low-chloride solution. These data do not support the use of milrinone to induce chloride secretion in CF airways in vivo.

Topics: Amiloride; Animals; Chlorides; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelium; Humans; Isoproterenol; Lung; Male; Membrane Potentials; Mice; Milrinone; Mutation; Nose; Phosphodiesterase Inhibitors; Respiratory System; Solutions

We have investigated the role in vivo of mineralocorticoid and glucocorticoid hormones in regulating the rate of electrogenic amiloride-sensitive Na+ absorption across murine airway tissue studied in vivo (nasal potential difference) and in vitro (Ussing chambers). We found that elevating the plasma aldosterone concentration 10-fold (low-Na+ diet) had no significant effect on amiloride-sensitive Na+ absorption across tracheal or nasal epithelia. High doses of dexamethasone for 1 wk likewise did not change the rate of amiloride-sensitive Na+ absorption across airway epithelia. In contrast, both hormonal manipulations elevated the rate of colonic Na+ absorption. Furthermore, adrenalectomy (both normal and cystic fibrosis mice) also failed to alter Na+ absorption across airway epithelia. We conclude that, in vivo, neither the mineralocorticoid nor the glucocorticoid hormones significantly regulate the rates of amiloride-sensitive electrogenic Na+ absorption across airway epithelia in the adult mouse.

Topics: Adrenal Cortex Hormones; Adrenalectomy; Aldosterone; Aminoglutethimide; Animals; Biological Transport; Colon; Corticosterone; Cystic Fibrosis; Dexamethasone; Diet, Sodium-Restricted; In Vitro Techniques; Intestinal Mucosa; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Mice, Mutant Strains; Mucous Membrane; Nose; Sodium; Trachea

The aim of this study is to show our experience in the surveillance of home mechanical ventilation in pediatric patients.. Between July 1992 and September 1996, 14 patients (20 months to 18 years of age) received home ventilation on 16 occasions. There were 10 boys and 4 girls. Home ventilation lasted from 7 days to 28 months. All patients had chronic respiratory failure secondary to neuromuscular disease, cystic fibrosis or sleep apnea syndrome.. Tolerance was good in 11 patients and bad in 3, 2 of which suffered from cystic fibrosis and died in terminal respiratory failure. The patients who benefited most were those with neuromuscular disease, cyphoscoliosis and sleep apnea syndrome. The technique also has been used for ventilator weaning and as a bridge to lung transplantation.. Home nasal mechanical ventilation is a useful technique for the treatment of chronic respiratory failure in adults and children.

Topics: Adolescent; Adult; Child; Child, Preschool; Chronic Disease; Cystic Fibrosis; Equipment Design; Female; Home Care Services; Humans; Infant; Male; Nose; Respiration, Artificial; Respiratory Insufficiency; Retrospective Studies; Ventilators, Mechanical

Nitric oxide (NO) is present in exhaled air of humans. This NO is mostly produced in the upper airways, whereas basal NO excretion in the lower airways is low. Children with Kartagener's syndrome have an almost total lack of NO in nasally derived air, whereas adult asthmatics have increased NO in orally exhaled air. NO excretion was measured in the nasal cavity and in orally exhaled air in 19 healthy children, in 36 age matched subjects with asthma, and in eight children with cystic fibrosis. NO levels in orally exhaled air were similar in controls and in children with cystic fibrosis, at 4.8 (SD 1.2) v 5.8 (0.8) parts per billion (ppb), but were increased in asthmatic children who were untreated or were being treated only with low doses of inhaled steroids (13.8 (2.5) ppb). Nasal NO levels were reduced by about 70% in children with cystic fibrosis compared to controls and asthmatics. Measurements of airway NO release in different parts of the airways may be useful in non-invasive diagnosis and monitoring of inflammatory airway diseases.

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Asthma; Breath Tests; Budesonide; Child; Child, Preschool; Cystic Fibrosis; Drug Administration Schedule; Humans; Kartagener Syndrome; Nitric Oxide; Nose; Pregnenediones

Nitric oxide (NO) produced within the respiratory tract is detectable in exhaled and nasal air. Its synthesis may be induced by inflammatory cytokines and reduced by glucocorticoids. Increased concentrations have been found in asthma and bronchiectasis. In this study, NO concentrations were determined in 63 children with cystic fibrosis, of whom 13 were on inhaled steroids (mean age 13.3 years) and 50 were not (mean age 12.3 years); 57 normal children (mean age 12.2 years) were also studied. NO was measured by chemiluminescence analyser, exhaled NO following a relaxed vital capacity manoeuvre, and nasal NO with the breath held following a full inspiration. Mean concentration of exhaled NO in cystic fibrosis patients (no steroids) was 4.7 parts per billion (ppb) (95% confidence interval (CI) 4.0 to 5.3); this did not differ from values in normal children (mean 4.8 ppb, 95% CI 3.8 to 5.8) or in cystic fibrosis patients on inhaled steroids (mean 3.6 ppb, 95% CI 2.5 to 4.8). Nasal concentrations were significantly lower in cystic fibrosis patients, with or without inhaled steroids, than in normal children (cystic fibrosis, no inhaled steroids: 460 ppb, 95% CI 399 to 520; cystic fibrosis, inhaled steroids: 522 ppb, 95% CI 313 to 730, v normal children: 1024 ppb, 95% CI 896 to 1152, p < 0.0001). Considering the inflammatory nature of cystic fibrosis, it is surprising exhaled NO levels were not increased, but this may have been due to alteration in NO diffusion through thick mucus. The low nasal NO concentrations, which are probably the result of impaired flow from the paranasal sinuses, may contribute to the recurrent respiratory infections typical of cystic fibrosis.

Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Breath Tests; Child; Cystic Fibrosis; Female; Humans; Male; Nitric Oxide; Nose

Topics: Adult; Child; Cystic Fibrosis; Diagnosis, Differential; Electrodes; Electrophysiology; Epithelium; Humans; Nose

We have made two retroviral vectors encoding the bacterial beta-galactosidase (lacZ) as a marker gene and a long terminal repeat (LTR) containing an enhancer of the polyoma F101 virus [symbol: see text]. One vector, [symbol: see text], can be used as a test vector in grafting, lineage analysis and gene therapy studies. The other, [symbol: see text] carries an additional unique cloning site in which a gene of interest can be cloned. Titration experiments showed that in human epithelial cell lines, [symbol: see text] produces a transcriptionally active integration more often than the commonly used BAG vector with the wild type LTR. Human epithelial cells in primary culture could be successfully infected. Our data suggest that gene therapy protocols requiring infection in situ, such as in the case of cystic fibrosis, will be hampered by the relatively low local titres that can be achieved at present.

Topics: beta-Galactosidase; Cell Line; Cystic Fibrosis; DNA Restriction Enzymes; Enhancer Elements, Genetic; Epithelium; Genetic Markers; Genetic Therapy; Genetic Vectors; HeLa Cells; Humans; Moloney murine leukemia virus; Nose; Repetitive Sequences, Nucleic Acid; Transfection

The case histories of six cystic fibrosis patients awaiting heart-lung transplantation are reviewed. They all deteriorated with severe hypoxia and hypercapnia before donor organs became available. Nasal intermittent positive pressure ventilation was used in preference to conventional ventilation with excellent results in four patients. There were no episodes of hypotension or toxaemia and the patients were in a stable condition at the time of surgery and made an excellent post-operative recovery. The patients who were transplanted and the patient who died, for whom suitable donor organs did not become available, probably had a more comfortable time than they would have done if treated with conventional ventilation. This method of ventilation appears to be a useful bridge to transplantation when a patient suddenly deteriorates. It gives them a chance of survival for a few more days or even weeks during which time an urgent search for donor organs can be made. This is also a very cost effective method of ventilation and does not encroach on conventional Intensive Care Unit (ICU) facilities.

Topics: Adolescent; Adult; Cystic Fibrosis; Female; Heart-Lung Transplantation; Humans; Intermittent Positive-Pressure Ventilation; Male; Nose; Preoperative Care

Previous work confirmed the abnormal potential difference between the undersurface of the inferior nasal turbinate and a reference electrode in cystic fibrosis, but the technique is difficult and the results show overlap between the cystic fibrosis and the control populations. In the present study the potential difference from the floor of the nose has therefore been assessed in normal subjects, as well as in adult patients with cystic fibrosis, bronchiectasis and Young's syndrome. Voltages existing along the floor of the nasal cavity were recorded. The mean potential difference was similar in controls (-18 (SD 5) mv) and in patients with bronchiectasis (-17 (6) mv) and Young's syndrome (-20 (6) mv). The potential difference in cystic fibrosis (-45 (8) mv) was significantly different from controls (p less than 0.002) and there was no overlap between the cystic fibrosis values and values obtained in normal and diseased controls. This simple technique therefore discriminates well between patients with cystic fibrosis and other populations, raising the possibility of its use to assist in diagnosis.

Topics: Adolescent; Adult; Amyotrophic Lateral Sclerosis; Bronchiectasis; Cystic Fibrosis; Female; Humans; Male; Membrane Potentials; Nose; Platybasia; Syndrome

The transepithelial potential difference (PD) is raised across cystic fibrosis (CF) respiratory epithelia. This raised voltage reflects active sodium absorption across a relatively chloride impermeable membrane. Because relatively little is known about the regulation of the rate of sodium absorption across mammalian airways, we assessed the possible contribution of aldosterone to the PD in normal and CF respiratory epithelia. Aldosterone excretion in five CF patients was 12.2 +/- 0.9 micrograms/24 h, a mean value not different from normal control subjects (13.6 +/- 1.5 micrograms/24 h, n = 5). Despite similar aldosterone excretion rates, nasal PD was more than 2-fold greater in the CF patients (-53.6 +/- 6.4 mV) than normal subjects (-21.3 +/- 1.4 mV). The effect of an aldosterone antagonist, spironolactone, on aldosterone excretion and nasal and rectal PD was evaluated in four CF patients and five normal subjects. During spironolactone administration, aldosterone excretion increased (2- to 4-fold) and rectal PD decreased in both groups. However, nasal PD was unchanged in each group (CF = -52.1 +/- 4.3 mV pre, -53.6 +/- 1.4 mV during; normal = -21.2 +/- 3.1 mV pre, -21.6 +/- 3.2 mV during). We conclude that neither increased aldosterone secretion rates nor organ sensitivity to aldosterone can account for the abnormally raised PD that characterizes the respiratory epithelium of subjects with CF.

Topics: Adult; Aldosterone; Canrenone; Cystic Fibrosis; Electrophysiology; Epithelium; Female; Humans; Male; Nose; Rectum; Reference Values; Spironolactone

In rhinology, electron microscopy has been a useful research tool for the past 15 years, but provided only a few direct clinical applications. In this review, the author's work on the human nasal mucosa and the studies of other investigators are discussed, with the emphasis on allergic reactions and disturbances of the autonomous nervous system as well as the immotile cilia syndrome.

Topics: Autonomic Nervous System; Ciliary Motility Disorders; Cystic Fibrosis; Epithelium; Humans; Microscopy, Electron; Nasal Mucosa; Nose; Nose Diseases; Nose Neoplasms; Otolaryngology; Papilloma; Rhinitis, Allergic, Perennial

The majority (86.6%) of patients with cystic fibrosis were found to be carriers of Pseudomonas aeruginosa. None of them, however, carried P. aeruginosa in their nares. In contrast, none of the non-CF family members of the patients with CF were carriers of P. aeruginosa. For example, only 4 of 468 cultures from skin, throat, and nares of the family members were positive for P. aeruginosa. Isolations of P. aeruginosa from the same CF patients were often of the same pyocine type. No specific pyocine type of P. aeruginosa was predominant in patients with CF. Isolations of P. aeruginosa from siblings with CF may or may not be of the same pyocine type as that of the family proband. Colonization of a patient with CF by P. aeruginosa is not a threat to the non-CF members of the family.

Topics: Adolescent; Anti-Bacterial Agents; Antibodies, Bacterial; Carrier State; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Infant; Male; Nose; Pseudomonas aeruginosa; Pseudomonas Infections; Pyocins; Serotyping; Skin

Topics: Autopsy; Cardiovascular System; Cystic Fibrosis; Ear; Female; Gallbladder; Genitalia, Female; Genitalia, Male; Humans; Intestines; Kidney; Liver; Lung; Malabsorption Syndromes; Male; Nose; Pancreas; Pharynx; Sweat Glands

Topics: Child; Child, Preschool; Chlorides; Cystic Fibrosis; Humans; Infant; Nasal Mucosa; Nose; Paranasal Sinuses; Proteins; Radiography; Sodium

Topics: Adolescent; Aerosols; Anti-Bacterial Agents; Cystic Fibrosis; Deoxyribonuclease I; Diagnosis, Differential; Drug Therapy; Humans; Lung Diseases; Nasal Polyps; Nose; Nose Deformities, Acquired; Sinusitis; Steroids; Streptodornase and Streptokinase; Streptokinase; Trypsin