Gender-specific disease modification by NOS3.
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Anemia, Sickle Cell↗
Biomedical subjects
Felix Ratjen
Publications and source records attributed to Felix Ratjen.
Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis.
Recombinant human deoxyribonuclease (rhDNase) has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis (CF), but its long-term effect on airway inflammation remains unknown. In this study, we used bronchoalveolar lavage (BAL) to investigate the long-term effect of rhDNase on inflammation in patients with CF having mild lung disease. A total of 105 patients with CF (> or =5 years of age) having normal lung function were randomized to receive rhDNase (2.5 mg/day) or no rhDNase. Patients with a normal percentage of neutrophils in BAL fluid at baseline were not randomized and served as the control group. The percentage of neutrophils in the pooled BAL sample was similar in both randomized groups at baseline. A significant increase in neutrophils was observed over the 3-year study period in both untreated patients and control subjects, whereas neutrophils remained unchanged in patients treated with rhDNase. Elastase activities and interleukin-8 concentrations also increased in untreated patients and remained stable in patients on rhDNase. We conclude that in patients with CF, an increase in neutrophilic airway inflammation is found that is positively influenced by rhDNase treatment.
Adolescent↗
Cystic fibrosis.
Cystic fibrosis is the most common autosomal recessive disorder in white people, with a frequency of about 1 in 2500 livebirths. Discovery of the mutated gene encoding a defective chloride channel in epithelial cells--named cystic fibrosis transmembrane conductance regulator (CFTR)--has improved our understanding of the disorder's pathophysiology and has aided diagnosis, but has shown the disease's complexity. Gene replacement therapy is still far from being used in patients with cystic fibrosis, mostly because of difficulties of targeting the appropriate cells. Life expectancy of patients with the disorder has been greatly increased over past decades because of better notions of symptomatic treatment strategies. Here, we summarise advances in understanding and treatment of cystic fibrosis, focusing on pulmonary disease, which accounts for most morbidity and deaths.
Adolescent↗
Effects of sex and of gene variants in constitutive nitric oxide synthases on exhaled nitric oxide.
Genetic factors may contribute to the variability of exhaled nitric oxide in healthy individuals. We studied exhaled nitric oxide and genetic variants in both neuronal and endothelial nitric oxide synthases in 105 healthy nonsmoking and smoking subjects. Genomic DNA was screened for a repeat polymorphism in intron 20 of the neuronal nitric oxide synthase gene and for the 894G/T mutation of the endothelial nitric oxide synthase gene. Exhaled nitric oxide was significantly higher in males than females among both nonsmokers (p < 0.0001) and smokers (p = 0.003). No association was found between exhaled nitric oxide and the endothelial nitric oxide synthase gene variant. However, healthy nonsmoking females with greater numbers of repeats (i.e., both alleles with 12 or more repeats) in neuronal nitric oxide synthase had significantly lower nitric oxide levels than did females with fewer numbers of repeats (i.e., at least one allele with fewer than 12 repeats) (13.6 +/- 1.6 versus 19.4 +/- 1.6 ppb, p = 0.02). No association was found between exhaled nitric oxide and neuronal nitric oxide synthase genotype in males. These data suggest that variants in the neuronal nitric oxide synthase gene contribute to the variability of airway nitric oxide concentrations in healthy females.
Adolescent↗
Endothelial nitric oxide synthase variants in cystic fibrosis lung disease.
Variants in the genes encoding for the nitric oxide synthases may act as disease modifier loci in cystic fibrosis, affecting both an individual's nitric oxide level and pulmonary function. In this study, the 894G/T variant in exon 7 of the endothelial nitric oxide synthase gene was related to exhaled nitric oxide and pulmonary function in 70 cystic fibrosis patients who were aged 14.8 +/- 6.9 years (mean +/- SD), with a FEV1 of 69.4 +/- 24.8% predicted. Although there was no association between endothelial nitric oxide synthase genotypes and exhaled nitric oxide in males, nitric oxide levels were significantly higher in female cystic fibrosis patients with an 894T mutant allele, compared with female patients homozygous for the 894G wild-type allele (7.0 +/- 4.4 versus 3.6 +/- 1.9 parts per billion, p = 0.02). Furthermore, in female patients, colonization of airways with Pseudomonas aeruginosa was significantly (p < 0.05) less frequent when carrying an 894T mutant allele as compared with wild type. These data suggest that the 894T variant in the endothelial nitric oxide synthase gene is associated with increased airway nitric oxide formation in female cystic fibrosis patients, possibly affecting colonization of airways with P. aeruginosa.
Adolescent↗
Nitrogen redox balance in the cystic fibrosis airway: effects of antipseudomonal therapy.
Denitrifying bacteria metabolize nitrogen oxides through assimilatory and dissimilatory pathways. These redox reactions may affect lung physiology. We hypothesized that airway colonization with denitrifying bacteria could alter nitrogen balance in the cystic fibrosis (CF) airway. We measured airway nitrogen redox species before and after antimicrobial therapy for Pseudomonas aeruginosa in patients with CF. We also studied ammonium (NH(4)(+)) and nitric oxide (NO) metabolism in clinical strains of P. aeruginosa in vitro and in CF sputum ex vivo. Ammonium concentrations in both sputum and tracheal aspirates decreased with therapy. Nitric oxide reductase (NOR) was present in clinical strains of P. aeruginosa, which both produced NH(4)(+) and consumed NO. Further, NO consumption by CF sputum was inhibited by tobramycin ex vivo. We conclude that treatment of pseudomonal lung infections is associated with decreased NH(4)(+) concentrations in the CF airways. In epithelial cells, NH(4)(+) inhibits chloride transport, and nitrogen oxides inhibit amiloride-sensitive sodium transport and augment chloride transport. We speculate that normalization of airway nitrogen redox balance could contribute to the beneficial effects of antipseudomonal therapy on lung function in CF.
Ammonia↗
Bronchoalveolar lavage protein patterns in children with malignancies, immunosuppression, fever and pulmonary infiltrates.
Severe respiratory infections are a major cause of morbidity and mortality in children receiving immunosuppressive therapy for malignancies. The goal of this study was to assess the major changes in the protein patterns in these children. Bronchoalveolar lavage (BAL) fluids of seven control children and of ten children with malignancies and fever not responding to broad spectrum antibiotic treatment was separated by horizontal two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the isoelectric point range 3-9. We observed a large increase of alpha(1)-antitrypsin (p = 0.0004) and decreases of the immunoglobulin (Ig) binding factor, transthyretin and cystatin S. Significant changes occurred also in the small acidic proteins. The relative abundance of the IgG heavy and light chains may hinder the separation and identification of many minor protein spots located in the basic area of the gel, suggesting that their removal during sample preparation may be warranted. This study demonstrated significant alterations in BAL fluid proteome in immunosuppressed children with persistent fever and pulmonary infiltrates. Future target regions of interest were identified. Sample prefractionation and the selection of suitable narrow isoelectric point ranges will be necessary for optimized detection and separating conditions.
Adolescent↗
Airway nitric oxide in Duchenne muscular dystrophy.
The expression of muscle membrane-associated neuronal nitric oxide synthase (NOS1) is significantly impaired in Duchenne muscular dystrophy. Mean (+/- SEM) exhaled NO in 13 male patients with Duchenne muscular dystrophy was significantly lower than in 11 healthy age-matched male control subjects (7.5 +/- 1.4 vs 16.6 +/- 3.2 parts per billion, P <.02) or 17 adult male control subjects (18.5 +/- 1.8 parts per billion, P <.001). These findings provide indirect evidence that NOS1 contributes significantly to fractional exhaled nitric oxide in healthy children.
Adolescent↗
beta2 adrenoceptor gene polymorphisms in cystic fibrosis lung disease.
The cystic fibrosis membrane conductance regulator can be activated through beta2-adrenoceptor (beta2AR) stimulation. We tested the hypothesis that coding sequence polymorphisms in the beta2AR gene contribute to the disease state in patients with cystic fibrosis. The Arg16Gly, Gln27Glu, and Thr164Ile beta2AR polymorphisms were studied by specific polymerase chain reaction and restriction fragment length polymorphism analysis in 126 cystic fibrosis patients. Forced expiratory volume in 1 s was significantly (P < 0.05) reduced in cystic fibrosis patients carrying the Gly16 allele in either homozygous or heterozygous form (Gly16Gly + Arg16Gly) compared to patients homozygous for the Arg16 allele (60.3 +/- 3.5% versus 75.7 +/- 4.9% predicted). Similarly, forced vital capacity and flows at lower lung volumes were significantly (P < 0.05 and P < 0.01) lower in cystic fibrosis patients carrying the Gly16 allele. In addition, the Gly16 allele was associated with a greater 5 year decline in pulmonary function (P < 0.01). Bronchodilator responses to albuterol were not significantly different between the groups. The Thr164Ile variant was found in four patients; these patients had markedly reduced pulmonary function. Isoproterenol-stimulated cyclic AMP formation was significantly blunted in cystic fibrosis patients carrying either the Gly16 allele or Thr164Ile genotype compared to cystic fibrosis patients homozygous for the respective Arg16 alleles. These data provide the first evidence suggesting that polymorphisms of the beta2AR gene contribute to clinical severity and disease progression in cystic fibrosis.
Adolescent↗
Beta2-agonists for asthma: the pediatric perspective.
Inhaled beta-agonists are commonly prescribed for the treatment of wheezing disorders in infants and children. Despite this, there are concerns that these medications have potentially detrimental effects on lung health and symptoms. We will review the ontogeny of beta-agonist receptor and smooth muscle development from fetal life through infancy and childhood as well as the evidence supporting the clinical utility of beta-agonists in wheezing infants and asthmatic children. Finally, the potential detrimental effects of long- and short-acting beta-agonists in infants and children are discussed.
Adrenergic beta-2 Receptor Agonists↗