H H Seydewitz

University of Freiburg, Freiburg, Baden-Württemberg, Germany

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Publications (43)211.15 Total impact

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    ABSTRACT: The identification of strategies to improve mutant CFTR function remains a key priority in the development of new treatments for cystic fibrosis (CF). Previous studies demonstrated that the K⁺ channel opener 1-ethyl-2-benzimidazolone (1-EBIO) potentiates CFTR-mediated Cl⁻ secretion in cultured cells and mouse colon. However, the effects of 1-EBIO on wild-type and mutant CFTR function in native human colonic tissues remain unknown. We studied the effects of 1-EBIO on CFTR-mediated Cl⁻ secretion in rectal biopsies from 47 CF patients carrying a wide spectrum of CFTR mutations and 57 age-matched controls. Rectal tissues were mounted in perfused micro-Ussing chambers and the effects of 1-EBIO were compared in control tissues, CF tissues expressing residual CFTR function and CF tissues with no detectable Cl⁻ secretion. Studies in control tissues demonstrate that 1-EBIO activated CFTR-mediated Cl⁻ secretion in the absence of cAMP-mediated stimulation and potentiated cAMP-induced Cl⁻ secretion by 39.2±6.7% (P<0.001) via activation of basolateral Ca²⁺-activated and clotrimazole-sensitive KCNN4 K⁺ channels. In CF specimens, 1-EBIO potentiated cAMP-induced Cl⁻ secretion in tissues with residual CFTR function by 44.4±11.5% (P<0.001), but had no effect on tissues lacking CFTR-mediated Cl⁻ conductance. We conclude that 1-EBIO potentiates Cl⁻secretion in native CF tissues expressing CFTR mutants with residual Cl⁻ channel function by activation of basolateral KCNN4 K⁺ channels that increase the driving force for luminal Cl⁻ exit. This mechanism may augment effects of CFTR correctors and potentiators that increase the number and/or activity of mutant CFTR channels at the cell surface and suggests KCNN4 as a therapeutic target for CF.
    PLoS ONE 01/2011; 6(8):e24445. · 3.53 Impact Factor
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    ABSTRACT: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype-phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl- channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)-mediated Cl- secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non-DeltaF508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR-mediated Cl- secretion with patients in whom Cl- secretion was absent. Residual anion secretion was detected in 40% of CF patients, and was associated with later disease onset (P < 0.0001), higher frequency of PS (P < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of approximately 12%-54% of controls. Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR-mediated Cl- secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.
    Gastroenterology 11/2004; 127(4):1085-95. · 12.82 Impact Factor
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    ABSTRACT: Deletion of the codon for phenylalanine at position 508 (DeltaF508) is the most frequent disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In heterologous cells, defective processing of the DeltaF508 protein results in endoplasmic reticulum retention, proteolytic degradation, and absence of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent plasma membrane Cl(-) conductance. However, data with respect to the processing block of DeltaF508 protein in native epithelia are limited and conflicting. To characterize both the fate and function of DeltaF508 protein in a native epithelium, we measured CFTR-mediated Cl(-) secretion, localization of the CFTR protein, and CFTR maturation in rectal biopsy specimens from normal individuals and DeltaF508 homozygous patients with cystic fibrosis (CF). Ussing chamber studies showed that cAMP-dependent and cholinergic Cl(-) secretion was absent from rectal tissues freshly excised from DeltaF508 homozygous patients with CF. By immunohistochemistry, we detected wild-type but not DeltaF508 CFTR at the luminal membrane of crypt colonocytes. By sequential immunoprecipitation and immunoblotting analyses, mature CFTR protein was detected in normal but not in DeltaF508 homozygous tissues. Collectively, these data show that there is insufficient maturation and transport of DeltaF508 CFTR from the endoplasmic reticulum to the apical membrane to support CFTR-mediated Cl(-) secretion in the CF colon.
    Gastroenterology 02/2004; 126(1):32-41. · 12.82 Impact Factor
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    ABSTRACT: Background & Aims: Deletion of the codon for phenylalanine at position 508 (ΔF508) is the most frequent disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In heterologous cells, defective processing of the ΔF508 protein results in endoplasmic reticulum retention, proteolytic degradation, and absence of adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent plasma membrane Cl− conductance. However, data with respect to the processing block of ΔF508 protein in native epithelia are limited and conflicting. Methods: To characterize both the fate and function of ΔF508 protein in a native epithelium, we measured CFTR-mediated Cl− secretion, localization of the CFTR protein, and CFTR maturation in rectal biopsy specimens from normal individuals and ΔF508 homozygous patients with cystic fibrosis (CF). Results: Ussing chamber studies showed that cAMP-dependent and cholinergic Cl− secretion was absent from rectal tissues freshly excised from ΔF508 homozygous patients with CF. By immunohistochemistry, we detected wild-type but not ΔF508 CFTR at the luminal membrane of crypt colonocytes. By sequential immunoprecipitation and immunoblotting analyses, mature CFTR protein was detected in normal but not in ΔF508 homozygous tissues. Conclusions: Collectively, these data show that there is insufficient maturation and transport of ΔF508 CFTR from the endoplasmic reticulum to the apical membrane to support CFTR-mediated Cl− secretion in the CF colon.
    Gastroenterology 01/2004; 126(1):32-41. · 12.82 Impact Factor
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    Journal of Medical Genetics 08/2003; 40(7):e88. · 5.70 Impact Factor
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    ABSTRACT: Human airway epithelia express Ca2+-activated Cl- channels (CaCC) that are activated by extracellular nucleotides (ATP and UTP). CaCC is preserved and seems to be up-regulated in the airways of cystic fibrosis (CF) patients. In the present study, we examined the role of basolateral K+ channels in CaCC-mediated Cl- secretion in native nasal tissues from normal individuals and CF patients by measuring ion transport in perfused micro Ussing chambers. In the presence of amiloride, UTP-mediated peak secretory responses were increased in CF compared with normal nasal tissues. Activation of the cAMP pathway further increased CaCC-mediated secretion in CF but not in normal nasal mucosa. CaCC-dependent ion transport was inhibited by the chromanol 293B, an inhibitor of cAMP-activated hKvLQT1 K+ channels, and by clotrimazole, an inhibitor of Ca2+-activated hSK4 K+ channels. The K+ channel opener 1-ethyl-2-benzimidazolinone further increased CaCC-mediated Cl- secretion in normal and CF tissues. Expression of hSK4 as well as hCACC-2 and hCACC-3 but not hCACC-1 was demonstrated by reverse transcriptase PCR on native nasal tissues. We conclude that Ca2+-activated Cl- secretion in native human airway epithelia requires activation of Ca2+-dependent basolateral K+ channels (hSK4). Co-activation of hKvLQT1 improves CaCC-mediated Cl- secretion in native CF airway epithelia, and may have a therapeutic effect in the treatment of CF lung disease.
    Pediatric Research 05/2003; 53(4):608-18. · 2.67 Impact Factor
  • H H Seydewitz, J Gram, H D Bruhn, I Witt
    Hamostaseologie 06/2002; 22(2):7-10. · 1.59 Impact Factor
  • H H Seydewitz, M Henschen, W Kühnel, M Brandis
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    ABSTRACT: Pediatric reference ranges for osteocalcin measured by a new, fully automated, chemiluminescent immunometric assay on the Immulite immunoanalyzer are presented. Samples from 627 children, ranging from newborns to 18 years of age, were measured. Osteocalcin values are generally higher in children than in adults, highest levels being reached during the puberty growth spurt at about 12 years in girls and 14 years in boys, thereafter rapidly declining towards adult levels.
    Clinical Chemistry and Laboratory Medicine 11/2001; 39(10):980-2. · 3.01 Impact Factor
  • H H Seydewitz, T Gonska, M Mall, J Kueh
    Human Mutation 10/2000; 16(3):277. · 5.21 Impact Factor
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    ABSTRACT: Glycogen storage disease type 1a (GSD 1a) is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase). A variant (GSD 1b) is caused by a defect in the transport of glucose-6-phosphate (G6P) into the microsome and is associated with chronic neutropenia and neutrophil dysfunction. Mutually exclusive mutations in the G6Pase gene and the G6P transport gene establish GSD la and GSD 1b as independent molecular processes and are consistent with a multicomponent translocase catalytic model. A modified translocase/catalytic unit model based on biochemical data in a G6Pase knockout mouse has also been proposed for G6Pase catalysis. This model suggests coupling of G6Pase activity and G6P transport. A 5-mo-old girl with hypoglycemia, hepatomegaly, and lactic acidemia was diagnosed with GSD 1a. She also developed neutropenia, neutrophil dysfunction, and recurrent infections characteristic of GSD 1b. Homozygous G188R mutations of the G6Pase gene were identified, but no mutations in the G6P translocase gene were found. We have subsequently identified a sibling and two unrelated patients with similar genotypic/phenotypic characteristics. The unusual association of neutrophil abnormalities in patients with homozygous G188R mutations in the G6Pase gene supports a modified translocase/catalytic unit model.
    Pediatric Research 10/2000; 48(3):329-34. · 2.67 Impact Factor
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    ABSTRACT: Ion transport defects underlying cystic fibrosis (CF) lung disease are characterized by impaired cyclic adenosine monophosphate (cAMP)-dependent Cl(-) conductance. Activation of Cl(-) secretion in airways depends on simultaneous activation of luminal Cl(-) channels and basolateral K(+) channels. We determined the role of basolateral K(+) conductance in cAMP- dependent Cl(-) secretion in native human airway epithelium obtained from non-CF and CF patients. CF tissues showed typical alterations of short-circuit currents with enhanced amiloride-sensitive Na(+) conductance and defective cAMP-mediated Cl(-) conductance. In non-CF tissues, Cl(-) secretion was significantly inhibited by the chromanol 293B (10 micromol/liter), a specific inhibitor of K(V)LQT1 K(+) channels. Inhibition was increased after cAMP-dependent stimulation. Similar effects were obtained with Ba(2+) (5 mmol/liter). In patch-clamp experiments with a human bronchial epithelial cell line, stimulation with forskolin (10 micromol/liter) simultaneously activated Cl(-) and K(+) conductance. The K(+) conductance was reversibly inhibited by Ba(2+) and 293B. Analysis of reverse-transcribed messenger RNA from non-CF and CF airways showed expression of human K(V)LQT1. We conclude that the K(+) channel K(V)LQT1 is important in maintaining cAMP-dependent Cl(-) secretion in human airways. Activation of K(V)LQT1 in CF airways in parallel with stimulation of residual CF transmembrane conductance regulator Cl(-) channel activity or alternative Cl(-) channels could help to circumvent the secretory defect.
    American Journal of Respiratory Cell and Molecular Biology 10/2000; 23(3):283-9. · 4.15 Impact Factor
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    ABSTRACT: The flavonoid genistein has been shown to activate a Cl(-) conductance in various cell types expressing CFTR. We examined if similar effects can be observed when genistein is applied to native ex vivo tissues from human respiratory tract and rectum. We further compared the effects when genistein was applied to oocytes of Xenopus laevis expressing CFTR. In oocytes, both wtCFTR and DeltaF508-CFTR were activated by genistein while both cyclic AMP (K(v)LQT1) and Ca(2+) (SK4) activated K(+) channels were inhibited at high concentrations of genistein. Biopsies from nasal polyps and rectal mucosa were obtained from normal individuals (non-CF) and CF patients and in the presence of amiloride (10 micromol l(-1); mucosal side) the effects of genistein were assessed using a perfused Ussing chamber. In non-CF airway epithelia, genistein (50 micromol l(-1); mucosal side) increased lumen negative I(sc) but had no additional effects on tissues pre-stimulated with IBMX and forskolin (100 micromol l(-1) and 1 micromol l(-1); both sides). In non-CF rectal biopsies, in the presence of amiloride (10 micromol l(-1); mucosal side) and indomethacin (10 micromol l(-1); basolateral side), genistein increased lumen negative I(sc) and enabled cholinergic (carbachol; CCH, 100 micromol l(-1); basolateral side) stimulation of Cl(-) secretion indicating activation of luminal CFTR Cl(-) channels. However, after stimulation with IBMX/forskolin, genistein induced opposite effects and significantly inhibited CCH activated I(sc). In CF airway and intestinal tissues genistein failed to induce Cl(-) secretion. Thus, genistein is able to activate luminal CFTR Cl(-) conductance in non-CF tissues and mutant CFTR in oocytes. However, additional inhibitory effects on basolateral K(+) conductance and missing effects in native CF tissues do not support the use for pharmacological intervention in CF.
    British Journal of Pharmacology 09/2000; 130(8):1884-92. · 5.07 Impact Factor
  • H H Seydewitz, M Mall, J Kuehr
    Human Mutation 05/2000; 15(4):390. · 5.21 Impact Factor
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    ABSTRACT: Rectal biopsies from cystic fibrosis (CF) patients show defective cAMP-activated Cl(-) secretion and an inverse response of the short-circuit current (I(sc)) toward stimulation with carbachol (CCh). Alternative Cl(-) channels are found in airway epithelia and have been attributed to residual Cl(-) secretion in CF colon. The aim of the present study was to investigate ion conductances causing reversed I(sc) upon cholinergic stimulation. Furthermore, the putative role of an alternative Ca(2+)-dependent Cl(-) conductance in human distal colon was examined. Cholinergic ion secretion was assessed in the absence and presence of cAMP-dependent stimulation. Transepithelial voltage and I(sc) were measured in rectal biopsies from non-CF and CF individuals by means of a perfused micro-Ussing chamber. Under baseline conditions, CCh induced a positive I(sc) in CF rectal biopsies but caused a negative I(sc) in non-CF subjects. The CCh-induced negative I(sc) in non-CF biopsies was gradually reversed to a positive response by incubating the biopsies in indomethacin. The positive I(sc) was significantly enhanced in CF and was caused by activation of a luminal K(+) conductance, as shown by the use of the K(+) channel blockers Ba(2+) and tetraethylammonium. Moreover, a cAMP-dependent luminal K(+) conductance was detected in CF individuals. We conclude that the cystic fibrosis transmembrane conductance regulator is the predominant Cl(-) channel in human distal colon. Unlike human airways, no evidence was found for an alternative Cl(-) conductance in native tissues from CF patients. Furthermore, we demonstrated that both Ca(2+)- and cAMP-dependent K(+) secretion are present in human distal colon, which are unmasked in rectal biopsies from CF patients.
    AJP Gastrointestinal and Liver Physiology 05/2000; 278(4):G617-24. · 3.65 Impact Factor
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    ABSTRACT: We report a large genomic deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, viz., a deletion that is frequently observed in Central and Eastern Europe. The mutation, termed CFTRdele2,3(21 kb), deletes 21,080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of European and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course of our study. Clinical evaluation of CFTRdele2,3(21 kb) homozygotes and a comparison of compound heterozygotes for deltaF508/CFTRdele2,3(21 kb) with pairwise-matched deltaF508 homozygotes indicate that this deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common in Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%), Austrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian (1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Latvia, Macedonia and Greece and has sporadically been observed in Canada, USA, France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croatia, Romania or Serbia. Haplotype analysis has identified the same extragenic CF-haplotype XV-2c/KM. 19 "A" and the same infrequent intragenic microsatellite haplotype 16-33-13 (IVS8CA-IVS 17bTA-IVS 17bCA) in all examined CFTRdele2,3(21 kb) chromosomes, suggesting a common origin for this deletion. We conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent.
    Human Genetics 04/2000; 106(3):259-68. · 4.63 Impact Factor
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    ABSTRACT: We report a large genomic deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, viz., a deletion that is frequently observed in Central and Eastern Europe. The mutation, termed CFTRdele2,3(21 kb), deletes 21,080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of European and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course of our study. Clinical evaluation of CFTRdele2,3(21 kb) homozygotes and a comparison of compound heterozygotes for &#40F508/CFTRdele2,3(21 kb) with pairwise-matched &#40F508 homozygotes indicate that this deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common in Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%), Austrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian (1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Latvia, Macedonia and Greece and has sporadically been observed in Canada, USA, France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croatia, Romania or Serbia. Haplotype analysis has identified the same extragenic CF-haplotype XV-2c/KM.19 "A" and the same infrequent intragenic microsatellite haplotype 16-33-13 (IVS8CA-IVS17bTA-IVS17bCA) in all examined CFTRdele2,3(21 kb) chromosomes, suggesting a common origin for this deletion. We conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent.
    Human Genetics 02/2000; 106(3):259-268. · 4.63 Impact Factor
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    H H Seydewitz, D Matern
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    ABSTRACT: Molecular genetic analysis of 40 patients with glycogen storage disease type Ia (GSD Ia) revealed mutations on all 80 alleles and verified the diagnosis in all patients. At least 7 patients were diagnosed with GSD Ia solely on the basis of clinical findings prior to our analysis. Five mutations, Q20R, W50X, G81R, W156L, and G188D have not been reported so far. This study underscores that molecular genetic analysis is a reliable and convenient alternative to the enzyme assay in a fresh liver biopsy specimen to diagnose GSD Ia.
    Human Mutation 01/2000; 15(1):115-6. · 5.21 Impact Factor
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    ABSTRACT: It is suggested that urinary eosinophil protein X (EPX) is a noninvasive tool to monitor bronchial inflammation in asthmatic children. However, circadian variation of the number and activation of eosinophils might possibly influence urinary EPX excretion. Measurements of urinary EPX (radioimmunoassay) were used to investigate circadian variation of eosinophilic activation and to monitor bronchial inflammation in children with asthma before and after treatment with corticosteroids. Urinary EPX excretion (microg/mmol creatinine) was measured in the morning and afternoon in 22 stable asthmatics and in 16 nonatopic, nonasthmatic controls to investigate circadian variation. Additionally, EPX excretion in the afternoon was analysed in 21 children with chronic asthma before and after 6 weeks of treatment with inhaled corticosteroids, and in seven children within 24 h of admission due to an asthma exacerbation and again 3 months after discharge. EPX excretion in the first morning urine sample of the day compared with the afternoon urine sample was significantly higher both in children with asthma (n = 22; mean +/- standard deviation: 179.7 +/- 97.3 vs 60.9 +/- 40.7 microg/mmol creatinine, P = 0.0001) and in nonatopic nonasthmatic controls (n = 16; 114.5 +/- 57.1 vs 53.4 +/- 29.0 microg/mmol creatinine, P = 0.0001). EPX excretion decreased significantly after 6 weeks of anti-inflammatory treatment in the group of children with chronic asthma (n = 21; 124.7 +/- 84.6 vs 87. 5 +/- 61.9 microg/mmol creatinine, P = 0.02) and in the group of children with an acute asthma exacerbation 3 months after discharge (n = 7; 233.2 +/- 174.5 vs 75.8 +/- 59.5 microg/mmol creatinine, P = 0.02). This study suggests a circadian variation of EPX excretion in children with asthma and in nonatopic, nonasthmatic controls. Measurement of EPX excretion is helpful monitoring therapy in asthmatic children if circadian variation is considered.
    Clinical & Experimental Allergy 12/1999; 29(11):1497-501. · 4.79 Impact Factor
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    ABSTRACT: In order to investigate nasal inflammation and subsequent adaptation after ambient ozone exposure, nasal lavage (NL) fluid was collected from 170 schoolchildren on 11 occasions (time points) between March and October. Eosinophil cationic protein (ECP), albumin and leukocytes were quantified as markers of nasal inflammation. The highest half-hour outdoor O3 concentration for each individual on the day prior to the NL was used as a measure of exposure (O3indiv). To avoid confounding with exposure to common environmental allergens, the study population was restricted to children without sensitization to inhalant allergens. In the initial period of increased O3 levels in May (time point 4), with a median O3indiv of 135 microg x m(-3) (5th-95th percentile 100-184 microg x m(-3)), the highest medians of all 11 leukocyte and ECP measurements were observed. The highest O3indiv were observed in June at time point 7 (O3indiv 173 microg x m(-3), 5th-95th percentile 120-203 microg x m(-3)). Cross-sectional analysis of all 11 time points revealed no significant association of O3indiv on the one hand and ECP, albumin and leukocyte levels on the other. A multivariable model estimated using generalized estimating equations showed a statistically significant association of O3indiv and leukocytes and ECP as the dependent variable, when time points 1-4 were analysed (p<0.05). In the same model, this association diminished continuously when time points 5-11 were added stepwise, in spite of high O3 exposure. Not even a tendency towards an O3 effect could be recognized when time points 1-8 were considered. The results indicate: 1) acute inflammation of the nasal mucosa after the first increase in ambient ozone levels, with 2) a significant dose-dependent increase in leukocyte and eosinophil cationic protein levels, and 3) possible adaptation of the nasal mucosa in spite of constant high levels of ozone exposure in children during the summer season.
    European Respiratory Journal 10/1999; 14(4):854-61. · 6.36 Impact Factor
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    ABSTRACT: In order to investigate nasal inflammation and subsequent adaptation after ambient ozone exposure, nasal lavage (NL) fluid was collected from 170 schoolchildren on 11 occasions (time points) between March and October.Eosinophil cationic protein (ECP), albumin and leukocytes were quantified as markers of nasal inflammation. The highest half-hour outdoor O3 concentration for each individual on the day prior to the NL was used as a measure of exposure (O3indiv). To avoid confounding with exposure to common environmental allergens, the study population was restricted to children without sensitization to inhalant allergens.In the initial period of increased O3 levels in May (time point 4), with a median O3indiv of 135 µg·m-3 (5th –95th percentile 100–184 µg·m-3), the highest medians of all 11 leukocyte and ECP measurements were observed. The highest O3indiv were observed in June at time point 7 (O3indiv 173 µg·m-3, 5th–95th percentile 120–203 µg·m-3). Cross-sectional analysis of all 11 time points revealed no significant association of O3indiv on the one hand and ECP, albumin and leukocyte levels on the other. A multivariable model estimated using generalized estimating equations showed a statistically significant association of O3indiv and leukocytes and ECP as the dependent variable, when time points 1–4 were analysed (p<0.05). In the same model, this association diminished continuously when time points 5–11 were added stepwise, in spite of high O3 exposure. Not even a tendency towards an O3 effect could be recognized when time points 1–8 were considered.The results indicate: 1) acute inflammation of the nasal mucosa after the first increase in ambient ozone levels, with 2) a significant dose-dependent increase in leukocyte and eosinophil cationic protein levels, and 3) possible adaptation of the nasal mucosa in spite of constant high levels of ozone exposure in children during the summer season.
    European Respiratory Journal 09/1999; 14(4):854 - 861. · 6.36 Impact Factor

Publication Stats

823 Citations
211.15 Total Impact Points

Institutions

  • 1984–2011
    • University of Freiburg
      • • Institute of Physiology
      • • Department of Pediatrics
      • • Institute of Biology I
      Freiburg, Baden-Württemberg, Germany
  • 1999–2000
    • University Children's Hospital Basel
      Bâle, Basel-City, Switzerland
  • 1987
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany