Why does airway inflammation persist? Is it failure to treat early?
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Administration, Inhalation↗
Biomedical subjects
S Pedersen
Publications and source records attributed to S Pedersen.
Measurement of airway inflammation in children. Introduction.
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Asthma↗
Inflammatory markers in clinical practice.
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Adult↗
Dust in pig buildings.
It is well documented in the international scientific literature that airborne dust in pig houses can cause serious health problems for humans as well as for animals. Extensive research has been carried out in different countries during the last few decades to improve the scientific understanding of air quality issues related to intensive animal production. Research and review papers were presented at the international symposium on Dust Control in Animal Production Facilities, held in Denmark in 1999. Different techniques have been used in order to reduce dust burdens in pig confinement buildings, but up to date only the procedure of spraying oil or a mixture of oil and water has contributed to reducing the indoor dust concentrations significantly. This article summarizes the current level of understanding of dust issues in intensive animal production buildings, mainly on the basis of papers presented at the above-mentioned symposium.
Air Pollutants, Occupational↗
Breath-synchronized nebulization diminishes the impact of patient-device interfaces (face mask or mouthpiece) on the inhaled mass of nebulized budesonide.
The choice of patient-device interface (face mask or mouthpiece) influences the inhaled mass and the lung deposition of nebulized drugs. The use of a mouthpiece has been shown to double the lung deposition compared with use of a face mask. We have determined the inhaled mass of budesonide using a jet nebulizer with mouthpiece in either a constant output or breath-synchronized mode in children. We have also determined the inhaled mass when the jet nebulizer is used with a nonsealing face mask in a constant output mode. The study was a 1-day, randomized, crossover, single-center study involving 158 asthmatic children (age range 5.1-15.7 years). Nebulized budesonide was administered in three single nominal doses of 1.0 mg by means of a jet nebulizer. The inhaled mass of budesonide was defined as the amount of drug deposited on filters positioned between the nebulizer and the mouthpiece or face mask. The mean inhaled mass of budesonide from different age groups ranged from 1 7.1% to 21.6% of the nominal dose with breath-synchronized nebulization with a mouthpiece. With constant output nebulization with a mouthpiece, the mean inhaled mass ranged from 8.9% to 12.2%, and with a nonsealed face mask the mean inhaled mass ranged from 5.0% to 6.9%. For children using jet nebulizers with mouthpiece, breath-synchronized nebulization appears to be superior to conventional constant output nebulization. The use of jet nebulizers with nonsealing face masks should be avoided.
Administration, Inhalation↗
Assessing and treating the depressed child.
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Adolescent↗
Localization of a human nucleoporin 155 gene (NUP155) to the 5p13 region and cloning of its cDNA.
Nucleoporins are the main components of nuclear pore complexes (NPCs) involved in nucleo-cytoplasmic transport. Starting with an expressed DNA fragment retrieved by exon trapping from pooled human BAC clones mapped to the short arm of chromosome 5, we identified a human nucleoporin cDNA sequence by PCR from a human testis cDNA library. The coding sequence showed high homology to that of the rat nucleoporin 155 (Nup155) cDNA. FISH analysis with the human BAC clone as probe localized the human NUP155 gene to chromosome band 5p13. Northern analysis showed that the human NUP155 gene was expressed at different levels in all tissues tested. Two species of transcripts were observed with estimated lengths of 5.4 and 4.7 kb, respectively, in concordance with the finding of two alternative polyadenylation sites in the cDNA. The genomic location of the human NUP155 gene suggests a possible role in the mental and developmental retardation associated with hemizygous deletions of the 5p13 region.
Amino Acid Sequence↗
Chemical modification of lysine side chains of cyclodextrin glycosyltransferase from Thermoanaerobacter causes a shift from cyclodextrin glycosyltransferase to alpha-amylase specificity.
Cyclodextrin glycosyltransferases and alpha-amylases are two groups of enzymes with related secondary structures. However, cyclodextrin glycosyltransferases display transferase activities not present in alpha-amylases, probably derived from the existence of two more domains and different amino acid sequences. The hydrolytic activity of cyclodextrin glycosyltransferases is generally quite low, except for two cyclodextrin glycosyltransferases from termophiles. In this work, we have carried out the chemical modification (with acetic anhydride) of the amino groups of cyclodextrin glycosyltransferase from Thermoanaerobacter to assess their contributions to protein function. The acetylated cyclodextrin glycosyltransferase showed a significant reduction of its cyclization, coupling and disproportionation activities. Surprisingly, the hydrolytic (saccharifying) activity was slightly enhanced. These results suggest the participation of one or more lysine side chains in the interactions contributing to the transferase activity, either in any of the S11 subsites or in the acceptor binding site.
Acetic Anhydrides↗
Mechanical stress induces release of ATP from Ehrlich ascites tumor cells.
The supernatant from a suspension of Ehrlich cells exposed to centrifugation at 700xg for 45 s induced a transient increase in the intracellular concentration of free, cytosolic Ca2+, [Ca2+]i, as well as activation of an outwardly rectifying whole-cell current when added to a suspension of non-stimulated cells. These effects were inhibited by suramin, a non-specific P2 receptor antagonist, and mimicked by ATP. Reversed phase HPLC analysis revealed that the supernatant from Ehrlich cells exposed to centrifugation contained 2. 6+/-0.2 microM ATP, and that the mechanical stress-induced release of ATP was inhibited by glibenclamide and verapamil, non-specific inhibitors of the cystic fibrosis transmembrane conductance regulator and P-glycoprotein, respectively. After trypan blue staining, less than 0.5% of the cells were unable to extrude the dye. Addition of extracellular ATP induced a suramin-sensitive, transient, concentration-dependent increase in [Ca2+]i, activation of an outwardly rectifying whole-cell current and a hyperpolarization of the plasma membrane. The ATP-induced hyperpolarization of the plasma membrane was strongly inhibited in the presence of charybdotoxin (ChTX), an inhibitor of several Ca2+-activated K+ channels, suggesting that stimulation of P2 receptors in Ehrlich cells evokes a Ca2+-activated K+ current. The relative potencies of several nucleotides (ATP, UTP, ADP, 2-MeSATP, alpha,beta-MeATP, bzATP) in eliciting an increase in [Ca2+]i, as well as the effect of repetitive addition of nucleotides were investigated. The results lead us to conclude that mechanical stimulation of Ehrlich cells leads to release of ATP, which in turn stimulates both P2Y1 and P2Y2 receptors, resulting in Ca2+ influx as well as release and activation of an outwardly rectifying whole-cell current.
Adenosine Triphosphate↗
Short-term lower leg growth rate in children with rhinitis treated with intranasal mometasone furoate and budesonide.
BACKGROUND: Mometasone furoate (MF) aqueous nasal spray is a potent intranasal glucocorticoid with low systemic bioavailability. Knemometry has been shown to be a sensitive method of detecting systemic effects of exogenous steroids in children. OBJECTIVE: We sought to assess whether MF (100 or 200 microg) or budesonide intranasal aqueous spray (400 microg) influences the short-term lower leg growth rate in children with seasonal or perennial allergic rhinitis. METHODS: MF, budesonide, and placebo were administered once daily for 2 weeks to 22 children aged 7 to 12 years (mean, 10 years) in a randomized, double-blind, crossover study. Lower leg measurements were done before and after each 2-week treatment period. Two-week washout intervals separated each treatment period. RESULTS: There were no significant differences in lower leg growth rates among the MF 200 microg (0.95 +/- 0.79 mm; mean +/- SD), budesonide 400 microg (0.73 +/- 0.61 mm), or placebo (0.69 +/- 0.70 mm) groups. The growth rate of the group receiving a 100-microg dose of MF (1.16 +/- 0.67 mm) was greater than that for the group receiving placebo (P =.024) or budesonide (P =.033). No statistically significant sequence effect (P =.11), carry-over effect (P =.24), overall treatment effect (P =.086), or period effect (P =.065) was detected. CONCLUSION: No short-term adverse effects on linear lower leg growth rates were detected after once daily MF or budesonide at clinically relevant doses.
Administration, Intranasal↗
Drug delivery from the Turbuhaler and Nebuhaler pressurized metered dose inhaler to various age groups of children with asthma.
A total of 198 children aged 3 to 15 years inhaled a single dose of 200 micrograms budesonide from a Nebuhaler pressurized metered dose inhaler (pMDI) and a Turbuhaler dry powder inhaler in a randomized crossover study. The budesonide dose delivered to a patient was assessed by measuring the amount of drug deposited on a filter inserted between the inhaler outlet and the patient's mouth. The dose of budesonide deposited on the filter and the estimated dose of particles with a mass median aerodynamic diameter (MMAD) of 5 microns or less after inhalation from the Turbuhaler were both approximately twice the values inhaled from the pMDI Nebuhaler in children less than 5 years of age (P < 0.01). The variation in the dose delivered to the patient was similar for the two inhalers in children over 5 years old. In 3- to 4-year-old children, dose delivery to the patient was higher and/or more consistent from the pMDI Nebuhaler than from the Turbuhaler. Filter dose after Turbuhaler treatment varied significantly from peak inspiratory flow rate through the Turbuhaler (PIFTbh) (P < 0.01). The percentage of children producing a PIFTbh greater than 50 L/min decreased with age (89%, 45%, and 14% in 5-, 4-, and 3-year-old children, respectively). It is concluded that drug delivery to a child with asthma varies with age and inhalation device. Further studies are needed to assess the clinical importance of this finding.
Administration, Inhalation↗
Comparing inhaled glucocorticosteroids.
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Administration, Inhalation↗
Systemic availability and pharmacokinetics of nebulised budesonide in preschool children.
AIM: To evaluate the systemic availability and basic pharmacokinetic parameters of budesonide after nebulisation and intravenous administration in preschool children with chronic asthma. METHODS: Plasma concentrations of budesonide were measured for three hours after an intravenous infusion of 125 micrograms budesonide. The children then inhaled a nominal dose of 1 mg budesonide through the mouthpiece of a Pari LC Jet Plus nebuliser connected to a Pari Master compressor, and the plasma concentrations of budesonide were measured for another six hours. The amount of budesonide inhaled by the patient ("dose to subject") was determined by subtracting from the amount of budesonide put into the nebuliser, the amount remaining in the nebuliser after nebulisation, the amount emitted to the ambient air (filter), and the amount found in the mouth rinsing water. RESULTS: Ten patients aged 3 to 6 years completed both the intravenous and the inhaled treatment. The mean dose to subject was 23% of the nominal dose. The systemic availability of budesonide was estimated to be 6.1% of the nominal dose (95% confidence intervals (CI), 4.6% to 8.1%) or 26.3% of the dose to subject (95% CI, 20.3% to 34.1%). Budesonide clearance was 0.54 l/min (95% CI, 0.46 to 0.62), steady state volume of distribution 55 litres (95% CI, 45 to 68), and the terminal half life was 2.3 hours (95% CI, 2.0 to 2.6). CONCLUSIONS: Approximately 6% of the nominal dose (26% of the dose to subject) reached the systemic circulation of young children after inhalation of nebulised budesonide. This is about half the systemic availability found in healthy adults using the same nebuliser.
Anti-Inflammatory Agents↗
The modification of the wobble base of tRNAGlu modulates the translation rate of glutamic acid codons in vivo.
In Escherichia coli, uridine in the wobble position of tRNAGlu and tRNALys is modified to mnm5s2U34. This modification is believed to restrict the base-pairing capability, i.e. to prevent misreading of near-cognate codons and reduce the efficiency of cognate codon reading, especially of codons ending in G. We have determined the influence of the 5-methylaminomethyl and the 2-thio modifications of mnm5s2U34 in tRNAGlu on the translation rate of the glutamate codons GAA and GAG in vivo. In wild-type cells, GAG is translated slower (7. 7 codons/second) and GAA faster (18 codons/second) than the average codon (13 codons/second). Surprisingly, tRNAGlu lacking the 5-methylaminomethyl group, thus containing s2U34, translated GAA twofold faster (47 codons/second) and GAG fourfold slower (1.9 codons/second) than fully modified tRNAGlu. In contrast, tRNAGlu that contains mnm5U34 instead of mnm5s2U34 translated GAA fourfold slower (4.5 codons/second) and GAG only 20% slower (6.2 codons/second). Clearly, the 5-methylaminomethyl group of mnm5s2U34 facilitates base-pairing with G while decreasing base-pairing with A, resulting in rates of translation of GAG and GAA that approach that of the average codon. The 2-thio group increases the recognition of GAA and has only a minor effect on the decoding of GAG. Furthermore, the 2-thio group is important for aminoacylation (see the accompanying paper). These data imply that the function of mnm5s2U34 may be different from what has been suggested previously.
Codon↗
P2 receptor-mediated signal transduction in Ehrlich ascites tumor cells.
The mechanisms, by which the P2 receptor agonists adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) evoke an increase in the free cytosolic calcium concentration ([Ca2+]i) and in intracellular pH (pHi), have been investigated in Ehrlich ascites tumor cells. The increase in [Ca2+]i evoked by ATP or UTP is abolished after depletion of intracellular Ca2+ stores with thapsigargin in Ca2+-free medium, and is inhibited by U73122, an inhibitor of phospholipase C (PLC), indicating that the increase in [Ca2+]i is primarily due to release from intracellular, Ins(1,4,5)P3-sensitive Ca2+ stores. ATP also activates a capacitative Ca2+-entry pathway. ATP as well as UTP evokes a biphasic change in pHi, consisting of an initial acidification followed by alkalinization. Suramin and 4,4'-diisothiocyano-2,2'-stilbene-disulfonic acid (DIDS) inhibit the biphasic change in pHi, apparently by acting as antagonists at P2 receptors. The alkalinization evoked by the P2 receptor agonists is found to be due to activation of a 5'-(N-ethyl-N-isopropyl)amiloride (EIPA)-sensitive Na+/H+ exchanger. ATP and UTP elicit rapid cell shrinkage, presumably due to activation of Ca2+ sensitive K+ and Cl- efflux pathways. Preventing cell shrinkage, either by incubating the cells at high extracellular K+ concentration, or by adding the K+-channel blocker, charybdotoxin, does not affect the increase in [Ca2+]i, but abolishes the activation of the Na+/H+ exchanger, indicating that activation of the Na+/H+ exchanger is secondary to the Ca2+-induced cell shrinkage.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Ribosomal protein S1 is required for translation of most, if not all, natural mRNAs in Escherichia coli in vivo.
We have deleted the chromosomal rpsA gene, encoding ribosomal protein S1, from an Escherichia coli strain carrying a plasmid where rpsA was controlled by the lac promoter and operator. This exogenous source of protein S1 was essential for growth. Thus we have verified the absolute requirement for protein S1. To see if translation of individual mRNAs differed in the requirements for protein S1, we removed the inducer and followed the time-course of the synthesis of several individual proteins and of total RNA, DNA and protein. Growth immediately shifted from being exponential to being linear, with a rate of protein synthesis defined by the pre-existing amount of protein S1. The expression pattern of the individual proteins indicated that the translation of all mRNAs was dependent on protein S1. Unexpectedly, we found that depletion for protein S1 for extended periods introduced a starvation for amino acids. Such starvation was indicated by an increased synthesis of ppGpp and could be reversed by addition of a mixture of all 20 amino acids. Measurements of the peptide chain elongation rate in vivo showed that ribosomes without protein S1 were unable to interfere with the peptide chain elongation rate of the active ribosomes and that, therefore, protein S1 was unable to diffuse from one ribosome to another during translation. We conclude that protein S1-deficient ribosomes are totally inactive in peptide chain elongation on most, if not all, naturally occurring E. coli mRNAs.
Bacterial Proteins↗
Swelling-activated potassium currents of Ehrlich ascites tumour cells.
The K+ and Cl- currents activated by Ca2+-ionophore treatment or by hypotonic cell swelling have been studied in Ehrlich ascites tumour cells by the patch-clamp technique. A charybdotoxin-inhibitable K+ current was activated by increasing intracellular Ca2+ concentration. In contrast, the K+ current activated by cell swelling was insensitive to charybdotoxin as well as to apamin, suggesting that channels different from those sensitive to Ca2+ are responsible for regulatory volume adjustments in these cells. The magnitude of the K+ and Cl- currents activated by hypotonic challenge was markedly temperature-dependent, possibly reflecting the temperature-dependence of enzymes involved in the intracellular signalling of cell volume regulation.
Animals↗
Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-response to terbutaline in children with mild asthma.
The aim of this study was to investigate whether regular treatment with inhaled salmeterol modifies the dose-response curve to the inhaled short-acting beta2-agonist terbutaline or affects the concentration of nitric oxide (NO) in exhaled air of children with asthma. Twenty-two children aged 7 to 15 years (mean = 11.6 years) with mild asthma were treated with inhaled 50 microg salmeterol twice daily or placebo for 3 weeks in a randomized double-blind cross-over study. These treatments were followed by treatment with inhaled 200 microg budesonide twice daily for 3 weeks. On the last day of each period, NO level was measured in exhaled air and a cumulative dose-response experiment with terbutaline (cumulative dose: 1,475 microg) was performed. Baseline lung functions after salmeterol treatment were significantly higher than baseline after placebo (P + 0.05). Salmeterol treatment flattened out the dose-response curve to terbutaline such that higher doses of terbutaline were required to produce the same degree of bronchodilation (ED50 for FEV1 was increased by an estimated factor of 70 (95% CI: 0.8-6307) and ED50 for FEF25-75 by a factor of 41 (95% CI: 6.7-254); P < 0.05). NO levels were unaffected by salmeterol treatment (12.7 ppb; placebo = 10.7 ppb), but were significantly reduced during budesonide therapy (5.2 ppb; P < 0.001). The corresponding maximal NO levels were 19.5 (placebo), 22.9 (salmeterol), and 9.4 ppb (budesonide). We conclude that 3 weeks treatment with salmeterol does not affect NO levels in exhaled air, but it significantly changes the dose-response curve to terbutaline.
Adolescent↗