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Biomedical subjects

F Ratjen

Publications and source records attributed to F Ratjen.

At least 55 records · Page 3Linked to original sources
PubMed1999

Cystic fibrosis lung disease: the role of nitric oxide.

This review summarizes current knowledge about the role of nitric oxide (NO) in cystic fibrosis (CF) lung disease. NO is endogenously produced by a group of enzymes, the NO synthases (NOSs). There are three isoforms of NOS, each encoded by different genes: neuronal (nNOS), immune or inducible (iNOS), and endothelial (eNOS) nitric oxide synthase.(1) They all form NO and L-citrulline by enzymatic oxidation of L-arginine. This reaction requires a number of cosubstrates, including molecular oxygen and tetrahydrobiopterin. It is now known whether all three isoenzymes are constitutively expressed in cells of the respiratory tract and that their gene expression is inducible.(2,3) NO production by iNOS, the "high-output" NOS, is stimulated by bacterial lipopolysaccharide (LPS) as well as proinflammatory cytokines such as interleukin (IL)-1gamma, IL-2, interferon (IFN)-gamma, and tumor necrosis factor (TNF). In contrast to nNOS and eNOS, activation of iNOS does not require an increase in intracellular Ca(2+) concentration.

Adolescent↗
PubMed1999

Decreased levels of nitrosothiols in the lower airways of patients with cystic fibrosis and normal pulmonary function.

Airway S-nitrosothiols (SNOs) are naturally occurring bronchodilators. SNOs, nitrate, and nitrite were measured in bronchoalveolar lavage fluid of 23 patients with cystic fibrosis (CF) and mild pulmonary disease (aged 6-16 years) and 13 healthy children (aged 8-15 years). Concentrations of SNOs were decreased in the lower airways of patients with CF and mild pulmonary disease (median, range: 0, 0-320 nmol/L vs 80, 0-970 nmol/L) despite normal levels of the inert nitric oxide metabolites nitrate and nitrite (mean +/- SEM: 3.7 +/- 0.5 micromol/L vs 4.8 +/- 0.9 micromol/L). S-nitrosolation- mediated bioreactivities may be impaired by depletion of the CF airway SNO reservoir.

Adolescent↗
PubMed1999

Tuberculoma of the pons.

A case of a pontine tuberculoma in a 12-year-old male from Somalia is presented. Cranial magnetic resonance imaging, performed in Abu Dhabi 1 month before admission in Germany revealed a tumorous lesion in the pons with surrounding edema; a presumptive diagnosis of a pontine glioma was made. Chest radiograph disclosed a pulmonary infiltrate with cavitation, as well as hilar and left mediastinal lymphadenopathy, suggestive of active tuberculosis. Tuberculostatic therapy led to an improvement of the patient's clinical status and a significant reduction in the size of the pontine tuberculoma. Intracranial tuberculomas rarely are seen in industrialized countries. They should, however, be considered as an important part of the differential diagnosis of intracranial space-occupying lesions. In most cases, as in this patient, conservative therapy provides good or excellent results.

Antitubercular Agents↗
PubMed1999

Effect of inhaled nitric oxide on pulmonary function in cystic fibrosis.

Concentrations of nitric oxide (NO) have been found to be reduced in both the upper and lower airway of patients with cystic fibrosis (CF). As NO modulates bronchomuscular tone, low NO levels may contribute to the obstructive lung disease in these patients. To assess whether increasing inspiratory NO concentrations has any impact on lung function, we have studied 13 CF patients aged 14-38 years in a clinically stable condition and nine healthy controls. NO was applied via a mixing chamber for 5 min with NO concentrations of 100 parts per billion, 1 and 40 parts per million. Spirometry was performed at baseline and after inhalation on each occasion. There were no clinical side-effects at any NO concentration and no changes in oxygen saturation were observed. Lung function remained unchanged in all subjects throughout the study period. Sputum nitrate and nitrite concentrations before and after inhalation of high NO concentrations (40 ppm) in eight CF patients did not show any significant changes, even though a tendency to higher nitrate levels was observed (399 +/- 231 vs. 556 +/- 474 mumol l-1). Therefore, inhaled NO at either the physiological levels present in the upper airway of normal individuals or those used therapeutically to treat pulmonary hypertension has no immediate effect on bronchomuscular tone in patients with cystic fibrosis.

Administration, Inhalation↗
PubMed1999

Intrapulmonary protein leakage in immunocompromised children and adults with pneumonia.

BACKGROUND: Pulmonary infections are associated with an increase in capillary permeability but information regarding age related differences in the local inflammatory response is lacking. To quantify the degree of capillary leakage during inflammation, the concentrations of the plasma proteins albumin, alpha1-antitrypsin, alpha2-macroglobulin and the locally produced proteins elastase, myeloperoxidase, lactoferrin and fibronectin were studied in the bronchoalveolar lavage (BAL) fluid of immunosuppressed children and adults with pneumonia. METHODS: Sixteen children aged 2-16 years and 15 adults who developed pneumonia while receiving immunosuppressive therapy for haematological malignancies were included in the study. Bronchoalveolar lavage was performed via a flexible bronchoscope with three aliquots of 1 ml/kg body weight in children and 200 ml in adults. Protein concentrations in BAL fluid were determined using highly sensitive immunoluminometric assays. RESULTS: Despite considerable variability, the median concentrations of all proteins in BAL fluid were significantly higher in both patient populations than in previously collected age adjusted reference values. The concentrations of serum derived proteins were significantly higher in children with pneumonia than in adult patients. In contrast, no differences were observed between the two groups for locally produced proteins. CONCLUSIONS: These data suggest that the degree of protein exudation is more pronounced in immunosuppressed children with pneumonia than in adults in a similar clinical situation. This is in agreement with our studies in healthy individuals and may reflect a greater permeability of the alveolar-capillary membrane in children, regardless of disease status.

Adolescent↗
PubMed1999

Effect of L-arginine infusion on airway NO in cystic fibrosis and primary ciliary dyskinesia syndrome.

Airway nitric oxide concentrations in patients with cystic fibrosis or primary ciliary dyskinesia syndrome have been shown to be lower than in healthy subjects. Decreased NO concentrations may contribute to impaired ciliary clearance, respiratory tract infections, or obstructive lung disease in these conditions. Nasal and exhaled NO concentrations were compared before and after infusion of 500 mg x kg(-1) L-arginine, the substrate of NO synthases, in 11 cystic fibrosis (CF) patients, seven primary ciliary dyskinesia (PCD) syndrome patients, and 11 control subjects. Baseline nasal and exhaled NO concentrations were significantly lower in both CF and PCD syndrome patients than in controls (p<0.01). In controls, the maximum increase of NO was seen immediately after L-arginine infusion in the upper airways (1.8-fold) and 3 h after the infusion in the lower airways (1.4-fold). Although NO concentrations also increased significantly in both CF (1.9-fold and 1.6-fold, respectively) and PCD syndrome patients (1.4-fold and 1.8-fold, respectively), concentrations remained subnormal compared with baseline values of controls. Pulmonary function remained unchanged in both patient groups. In conclusion, the low airway nitric oxide formation in both cystic fibrosis and primary ciliary dyskinesia syndrome patients can be augmented by L-arginine administration. The finding that pulmonary function remained unchanged in both conditions may be due to the fact that normalization of airway nitric oxide concentrations could not be achieved.

Adolescent↗
PubMed1998

Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis.

In chronic Pseudomonas aeruginosa pulmonary infection of patients with cystic fibrosis (CF), antibiotic therapy generally fails to eradicate the bacterial pathogen. The mucoid bacterial phenotype, high sputum production by the host, and low airway levels of antibiotics seem to be responsible for the observed decrease in antibiotic efficacy. We hypothesized that early antibiotic treatment by inhalation in CF patients may be able to prevent or at least delay airway infection. In a prospective placebo-controlled, double-blind, randomized multicenter study, 22 CF patients received either 80 mg b.i.d. of aerosolized tobramycin or placebo for a period of 12 months shortly after the onset of P. aeruginosa pulmonary colonization. Two patients in the tobramycin and six patients in the placebo group stopped inhalation before the 12 month treatment period. Using life table analysis, the time to conversion from a P. aeruginosa-positive to a P. aeruginosa-negative respiratory culture was significantly shorter in the tobramycin-treated group than in the placebo group (P < 0.05, log rank test). Lung function parameters and markers of inflammation did not change in either group during treatment. The results of this study suggest that early tobramycin inhalation may prevent and/or delay P. aeruginosa pulmonary infection in CF patients.

Administration, Inhalation↗
PubMed1998

Isovolume pressure/flow curves of rapid thoracoabdominal compressions in infants without respiratory disease.

To assess whether flow limitation can be achieved during rapid thoracoabdominal compressions (RTC), we performed esophageal pressure measurements in 11 healthy infants less than 3 months of age. Recordings of esophageal pressure were obtained with an esophageal balloon placed in the lower esophagus. RTCs were started at 20 cm H2O and increased to 140 cm H2O or until the infant responded with glottic closure to the compression. Flow limitation was assessed from isovolume pressure flow curves at peak flow and flow at FRC (V'max, FRC). The transmission of jacket pressure was higher at peak flow than at FRC for pressures below 60 cm H2O, due to active inspiration during the compression. Active inspiration was not observed at compression pressures above 80 cm H2O, as reflected by a plateau in the esophageal pressure tracing. Esophageal pressure increased parallel to the compression pressure at jacket pressures below 60 cm H2O. The relationship between jacket pressure and esophageal pressure became curvilinear at high compression pressures and plateaued at compressions above 100 cm H2O, so that further increases in jacket pressure did not increase esophageal pressure. Flow limitation was seen in all infants studied, as indicated by a lack of increase in flow with increasing esophageal pressures for V'max, FRC. Jacket compression pressures of 60 cm H2O and esophageal pressures of 20 cm H2O were sufficient to reach maximal expiratory flow. These data indicate that jacket pressure is a poor indicator of pleural pressure at high compression pressures in young healthy infants, and high pressures are not needed, as flow limitation is seen during RTCs at moderate compression pressures.

Esophagus↗
PubMed1998

Nitric oxide metabolites in cystic fibrosis lung disease.

Although the activity of nitric oxide (NO) synthases are increased in lung tissue of patients with cystic fibrosis, the concentrations of nasal and exhaled NO have recently been found to be decreased in cystic fibrosis. This could either be due to reduced NO formation or metabolism of NO within airway fluids. In this study, the stable NO metabolites, nitrate and nitrite, were determined in the saliva and sputum of 18 stable cystic fibrosis patients, 21 cystic fibrosis patients during a pulmonary exacerbation, and in saliva and endotracheal secretions of normal controls. Median saliva concentrations of NO metabolites (nitrate plus nitrite) were 704 mumol/l (95% confidence interval (CI) 419 to 1477) in stable cystic fibrosis patients, 629 mumol/l (95% CI 382 to 1392) in cystic fibrosis patients presenting with pulmonary exacerbation, and 313 mumol/l (95% CI 312 to 454) in controls. Median sputum NO metabolite concentration in stable cystic fibrosis was 346 mumol/l (95% CI 311 to 504). This was not significantly different from cystic fibrosis patients presenting with pulmonary exacerbation (median 184 mumol/l, 95% CI 249 to 572), but significantly higher than in endotracheal secretions of controls (median 144 mumol/l, 95% CI 96 to 260). Sputum NO metabolite concentration in cystic fibrosis pulmonary exacerbation significantly increased during antibiotic treatment. A positive correlation was observed between sputum NO metabolites and lung function in stable cystic fibrosis, suggesting less airway NO formation in cystic fibrosis patients with more severe lung disease. These data indicate that decreased exhaled NO concentrations in cystic fibrosis patients may be due to retention and metabolism of NO within the airway secretions. However, sputum NO metabolites are not a useful marker of airway inflammation in cystic fibrosis lung disease.

Adolescent↗
PubMed1997

Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis.

Nitric oxide (NO) is produced by various cell types in the human respiratory tract. Endogenously produced nitric oxide is detectable in the exhaled air of healthy individuals. Exhaled NO has been shown to be increased in airway inflammation, most probably due to cytokine-mediated activation of NO synthases. To assess whether NO can serve as a marker of inflammation in cystic fibrosis (CF) lung disease, we measured exhaled NO in CF patients with a chemiluminescence analyser. Single breath measurements were performed in 27 stable CF patients (age range, 6-40 years) and 30 non-smoking controls (age range, 6-37 years). Exhaled NO concentrations were 9.1 +/- 3.6 ppb in the controls and 5.9 +/- 2.6 ppb (P < 0.001) in CF patients. To account for room air NO concentrations on the measurement of exhaled NO, we also calculated the difference between exhaled NO and ambient NO concentrations. Difference values were also significantly lower in CF compared with controls (P < 0.0001). In CF patients there was a positive correlation between exhaled NO and forced vital capacity (r = 0.43, P = 0.033), suggesting that exhaled NO is lower in patients with severe lung disease than in those with mild disease. We conclude that measurements of exhaled NO in CF does not reflect activity of CF airway inflammation. The decreased concentrations of exhaled NO may be due to inhibitory effects of inflammatory cytokines on NO syntheses in the airways and alveolar epithelial cells or to increased retention in airway secretions.

Adolescent↗
PubMed1997

Metabolites of nitric oxide in the lower respiratory tract of children.

UNLABELLED: Nitric oxide (NO) is produced in the upper and lower respiratory tract and can be detected in exhaled air of both healthy individuals and subjects with pulmonary diseases. Recent studies have shown that exhaled NO is mainly derived from the upper airways. There is, however, evidence that in aqueous solutions NO is rapidly converted to distinct oxides of nitrogen. We therefore studied the stable NO metabolites nitrate and nitrite in broncho-alveolar lavage (BAL) fluid and serum as indicators of NO formation in the lower respiratory tract. The study population consisted of 31 healthy children undergoing elective surgery for non-pulmonary illnesses and 13 immunosuppressed children with pneumonia. Nitrate and nitrite were determined photometrically. Nitrate was found in BAL fluid of all children. In children with pneumonia, nitrate concentrations in BAL fluid were significantly higher than in healthy children. A significant correlation was observed between nitrate in BAL fluid and serum of immunosuppressed children with pneumonia. Nitrite was not detected in any of the BAL fluid or serum samples. CONCLUSIONS: Our results suggest that in the lower airways significant amounts of NO are metabolised to nitrate. Studies on NO in pulmonary diseases should therefore include determination of nitrate in lower airway fluids.

Bronchoalveolar Lavage Fluid↗
PubMed1997

Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens.

Congenital absence of the vas deferens (CAVD) is a frequent cause for obstructive azoospermia and accounts for 1%-2% of male infertility. A high incidence of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has recently been reported in males with CAVD. We have investigated a cohort of 106 German patients with congenital bilateral or unilateral absence of the vas deferens for mutations in the coding region, flanking intron regions and promotor sequences of the CFTR gene. Of the CAVD patients, 75% carried CFTR mutations or disease-associated CFTR variants, such as the "5T" allele, on both chromosomes. The distribution of mutation genotypes clearly differed from that observed in cystic fibrosis. None of the CAVD patients was homozygous for delta F508 and none was compound heterozygous for delta F508 and a nonsense or frameshift mutation. Instead, homozygosity was found for a few mild missense or splicing mutations, and the majority of CAVD mutations were missense substitutions. Twenty-one German CAVD patients were compound heterozygous for delta F508 and R117H, which was the most frequent CAVD genotype in our study group. Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the "5T allele" was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. We identified a total of 46 different mutations and variants, of which 15 mutations have not previously been reported. Thirteen novel missense mutations and one unique amino-acid insertion may be confined to the CAVD phenotype. A few splice or missense variants, such as F508C or 1716 G-->A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance. Clinical examination of patients with CFTR mutations on both chromosomes revealed elevated sweat chloride concentrations and discrete symptoms of respiratory disease in a subset of patients. Thus, our collaborative study shows that CAVD without renal malformation is a primary genital form of cystic fibrosis in the vast majority of German patients and links the particular expression of clinical symptoms in CAVD with a distinct subset of CFTR mutation genotypes.

Adult↗
PubMed1997

Single-lung transplantation in a patient with cystic fibrosis and an asymmetric thorax.

We report metachronous single-lung transplantation for cystic fibrosis after contralateral pneumonectomy. Kyphoscoliosis and mediastinal shift required careful donor-lung sizing with computed tomography and was not dependent on typical parameters. Severe reperfusion injury was treated with nitric oxide, C1-esterase inhibitor, and continuous venovenous hemodialysis. The patient was extubated on the fifth postoperative day and is alive and well. We conclude that single-lung transplantation after contralateral pneumonectomy for patients with cystic fibrosis and an asymmetric chest and evident lung volume mismatch may be an acceptable functional therapeutic option.

Child↗
PubMed1997

Genetic diversity among isolates of Aspergillus fumigatus in patients with cystic fibrosis.

Strains of Aspergillus fumigatus (n = 24) were isolated from the sputa of six patients with cystic fibrosis during periods from 3 to 11 months. The genetic polymorphisms of the strains were studied using the random amplified polymorphic DNA (RAPD) assay with three single oligonucleotides and pairwise combined primers. The analysis of RAPD patterns resulted in 15 different RAPD types. In four patients, the colonizing type changed, whereas in two others the same types were detected over periods between 3 and 11 months. The genetic diversity as well as the shift of the colonizing strains found in some patients might be important for the epidemiology of Aspergillus infections in patients with cystic fibrosis.

Adult↗
PubMed1997

Different BALF protein composition in normal children and adults.

UNLABELLED: Quantification of proteins in bronchoalveolar lavage fluid (BALF) is being performed increasingly, because of their potency in elucidating pathophysiological processes and their possible clinical relevance. STUDY POPULATION: 37 normal children (12 female, 25 male, mean age +/- SD 7.9 +/- 3.5 years, range 3-16 years) undergoing elective surgery for nonpulmonary illnesses and 16 healthy adults (all male, mean age +/- SD 24.7 +/- 2.6 years, range 20-28 years, 8 smokers, 8 nonsmokers) have been studied after approval by the ethics committees of both institutions. METHODS: BAL was performed with normal saline in the right middle lobe or one of its segments. Lavage volume was 15 x 20 ml in adults and 3 x 1 ml/kg in children. In adults the first aliquot was processed separately, 2 aliquots of the following were pooled (resulting in 8 different fractions) so that different lavage protocols could be calculated. The concentrations of the plasma-proteins alpha 1-proteinase inhibitor (alpha-1PI), alpha 2-macroglobulin (alpha 2PI), albumin (Alb) and of the locally released proteins myeloperoxidase (MPO), lactoferrin (Lf), elastase (Ela) and fibronectin (Fib) were determined in BALF using chemiluminescence immunoassays. RESULTS: The BALF concentrations of the plasma proteins were higher in children compared to adults. In contrast, concentrations of the locally released proteins were similar in both groups. Protein concentrations in the first recovered aliquot were different from the following in healthy adults with higher values of MPO, Lf and Ela and lower concentrations of alpha 1PI, alpha 2PI and Alb. Subsequent aliquots did not show a progressive dilution of these proteins with increasing lavage volumes. In smokers, BALF concentrations of albumin, alpha 1PI and MPO were higher compared to nonsmokers. CONCLUSION: BALF protein concentrations are different in normal children and adults. These results underscore the necessity to establish independent reference values for children, as could be demonstrated earlier with regard to BAL cell composition.

Adult↗
PubMed1997

[Bronchoalveolar lavage in childhood: technical aspects and reference values].

(BAL) has been increasingly used in recent years also in children. In paediatric pulmonary diseases, however, interpretation has proved difficult in the absence of standard reference values for BAL in childhood. It is the purpose of the present publication to discuss the methodological aspects of BAL in childhood and to proviced criteria by means of standard reference values for the assessment of BAL in paediatric patients. In a group of 50 children aged 3 to 15 years with healthy lungs, who were subjected to BAL during an elective surgical intervention, we examined both cellular and non-cellular components of the BAL. Whereas the percentage of macrophages and lymphocytes in the total population did not differ significantly from the standard values in adults, the absolute and relative granulocyte count was found to be elevated in children under 8 years of age. The CD4/CD8 quotient of BAL was 0.7 on the average, and hence clearly below the standard reference values defined for adults. In the non-cellular components we found an increase in the level of all proteins from plasma, whereas locally produced proteins did not differ from the findings in healthy adults. The total phospholipid content of BAL was markedly enhanced in children below 8 years of age and decreased with increasing age. These differences between children and adults should be taken into account when interpreting pathological findings. They are the basis for better defining the ranking of BAL in paediatric pulmonary diseases.

Adolescent↗