Local interleukin-10 production during respiratory syncytial virus bronchiolitis is associated with post-bronchiolitis wheeze

Background

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Following RSV bronchiolitis, 50% of children develop post-bronchiolitis wheeze (PBW). Animal studies have suggested that interleukin (IL)-10 plays a critical role in the pathogenesis of RSV bronchiolitis and subsequent airway hyperresponsiveness. Previously, we showed that ex vivo monocyte IL-10 production is a predictor of PBW. Additionally, heterozygosity of the single-nucleotide polymorphism (SNP) rs1800872 in the IL10 promoter region was associated with protection against RSV bronchiolitis.

Methods

This study aimed to determine the in vivo role of IL-10 in RSV pathogenesis and recurrent wheeze in a new cohort of 235 infants hospitalized for RSV bronchiolitis. IL-10 levels in nasopharyngeal aspirates (NPAs) were measured at the time of hospitalization and the IL10 SNP rs1800872 genotype was determined. Follow-up data were available for 185 children (79%).

Results

Local IL-10 levels during RSV infection turned out to be higher in infants that later developed physician diagnosed PBW as compared to infants without PBW in the first year after RSV infection (958 vs 692 pg/ml, p = 0.02). The IL10 promoter SNP rs1800872 was not associated with IL-10 concentration in NPAs.

Conclusion

The relationship between high local IL-10 levels during the initial RSV infection and physician diagnosed PBW provides further evidence of the importance of the IL-10 response during RSV bronchiolitis.     

Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss

Developmental abnormalities, cancer, and premature aging each have been linked to defects in the DNA damage response (DDR). Mutations in the ATR checkpoint regulator cause developmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome). Here we show that eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance of age-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities. Histological and genetic analyses indicate that ATR deletion causes acute cellular loss in tissues in which continuous cell proliferation is required for maintenance. Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity. In aggregate, these studies suggest that reduced regenerative capacity in adults via deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance of age-related phenotypes.     

Superoxide dismutase-like activities of copper(II) complexes tested in serum

The superoxide dismutase-like activities of a series of coordination complexes of copper were evaluated and compared to the activities of bovine erythrocyte superoxide dismutase (superoxide: superoxide oxidoreductase, EC 1.15.1.1) in serum using the nitroblue tetrazolium chloride (NBT)-reduction assay and electron paramagnetic resonance (EPR) spectroscopy. A 40% inhibition was observed for the initial rate of the NBT reduction by superoxide dismutase in serum, but more than 40% inhibition was achieved with CuSO4, Cu(II)-dimethylglyoxime, Cu(II)-3,8-dimethyl-4,7-diazadeca-3,7-dienediamide, Cu2[N,N'-(2-(O-hydroxy-benzhydrylidene)amino)ethyl]2-1,2-ethane dia mine), Cu(II)-(diisopropylsalicylate)2, Cu(II)-(p-bromo-benzoate)2, Cu(II)-(nicotinate)2 and Cu(II)-(1,2-diamino-2-methylpropane)2. The electron paramagnetic resonance technique of spin trapping was used to detect the formation of superoxide (O2-.) and other free radicals in the xanthine-xanthine oxidase system under a variety of conditions. Addition of the spin trapping agent 5,5-dimethylpyrroline 1-oxide (DMPO) to the xanthine-xanthine oxidase system in fetal bovine serum produced the O2-.-spin adduct of DMPO (herein referred to as superoxide spin adduct, DMPO-OOH) as the well known short-lived nitroxyl whose characteristic EPR spectrum was recorded before its rapid decay to undetectable levels. The hydroxyl radical (HO.) adduct of the spin trap DMPO (herein referred to as DMPO-OH) was detected to a very small extent. When CuSO4, or the test complexes of copper, were added to the xanthine-xanthine oxidase system in serum containing the spin trap, the yield of DMPO-OOH was negligible. In addition to their superoxide dismutase-like activity, CuSO4 and the copper complexes also behaved as Fenton-type catalysts as seen by the accumulation of varying amounts of the hydroxyl spin adduct DMPO-OH. Both the Fenton-type catalysis and the superoxide dismutase-like action of these compounds were lost when a chelator such as EDTA was included in the xanthine-xanthine oxidase incubation mixture. Addition of superoxide dismutase instead of the copper compounds to this enzyme system abolished the formation of superoxide adduct DMPO-OOH, and no hydroxyl adduct DMPO-OH was detected. This effect of superoxide dismutase remained unaltered by EDTA.     

Kinetics of oral propylene glycol-induced acute hyperlactatemia

The kinetics of PD-induced HL in rat have been investigated. The data obtained indicated that PD was solely responsible for the elevation (1.83- to 4.01-fold) of blood lactate that was sustained long enough to affect considerably the normal physiological function of the system. The production of lactate increased as the dose of PD increased up to 38.66 mmole/kg, thereby obeying the Michaelis-Menten kinetics model that gave an apparent Km and Vmax as 7.14 mmole/kg and 7.50 mmole/liter/hr, respectively. The t1/2 elimination time ranged from 1.40 to 5.82 hr which followed apparent first-order kinetics. Pyrazole inhibited (Ki = 6 mumole/kg) the PD-induced HL competitively, suggesting that alcohol dehydrogenase might have played a regulatory role in the conversion of PD to lactate. The PD-induced HL in rat and the LA in human patients are two distinct biochemical entities; reasoning has been given to substantiate that HL is lower order LA. Evidence has been presented to show that PD is a suitable and effective potential agent for producing experimental HL in rat in preference to agents that are currently being used.     

Chemical composition of salt-marsh plants from Ynys Môn (Anglesey): the concept of physiotypes

Abstract The chemical compositions of a number of halophytes from salt marshes on Ynys Môn (Anglesey), Wales, and of some related mesophytes and sand dune plants have been determined. Analyses of the inorganic ions broadly confirmed the existence of a characteristic chemical composition of many monoco-tyledonous salt-marsh plants in that they contain high levels of potassium and relatively low levels of sodium. In contrast to most dicotyledonous halophytes, especially members of the Chenopodiacease, the monocots restrict the entry of inorganic ions and use high levels of soluble sugars to maintain an adequate solute potential. Low calcium levels were not found to be a feature of these plants, as was previously reported. The large amounts of sugars found in the monocotyle-donous plants suggested that they must be located mainly in the vacuoles, in contrast to glycinebetaine which is thought to accumulate principally in the cytoplasm of the salt accumulating Chenopodiaceae. The monocotyledonous halophytes which accumulate proline differ from the normal monocotyledonous physiotype in the accumulation of larger quantities of sodium. Triglochin maritima is one species of this type, and Puccinellia maritima a less extreme example. Spartina spp. accumulating glycinebetaine and β-dimethyl-sulphoniopropionate also have unusually high inorganic ion contents for monocots. Several salt marsh plants contained large quantities of amino acids other than proline. As with ionic composition, the nature of the organic solutes broadly followed taxonomic lines. The usefulness of the physiotype concept is discussed.     

Nature of the negative ellipticity of human fetal hemoglobin in the 280 nm region

The uv circular dichroism (CD) spectra of aquomet hemoglobins A and F were followed to monitor their R→T conformational change. Titration studies with inositol hexaphosphate (IHP) for both adult and fetal hemoglobin showed identical total ellipticity changes although HbF was found to possess an inherently negative ultraviolet CD spectrum. By monitoring changes in the protein portion of the molecule, a dissociation constant for IHP of 16 μM was obtained for HbF. Chemical modification of HbF was found to leave the negative ellipticity unperturbed relative to native HbF. The results suggest that the negative ellipticity seen for stripped aquomet HbF is not due to a T conformation, but rather to an amino acid substitution in the γ chain of HbF.     

The role of propylene glycol metabolism in lactatemia in the rabbit.

Propylene glycol (1,2-propanediol PD) has been reported to significantly alter the blood parameters when administered as a drug vehicle. In this study, experiments were performed to estimate the pH, levels of PD, and its metabolites to determine the acute effect of PD in blood. PD was administered to rabbits orally in a single dose of 1 ml 28.4% aqueous solution per 100 g body weight equivalent to 38.66 mmol/kg. Whole blood pH and the levels of PD and metabolites were estimated at fast (O.O h, before feeding PD) and at 0.25, 1, and 3 h after the dose. PD elevated the concentrations of blood PD to its maximum (41.04 +/- 9.98 mmol/liter, n = 4) at 1 h; whereas blood PD is normally absent during fasting. PD significantly increased (P less than 0.01) the concentration of L-lactate in blood, which reached its plateau (2.55 +/- 0.62 mmol/liter, n = 4) at 0.25 h and was 2.45-fold higher than the observed fasted values (1.04 +/- 0.22 mmol/liter, n = 4). Production of D-lactate in blood was similarly increased significantly from 5.1 +/- 5.0 mumols/liter at fast to 150.0 +/- 30.4 mumols/liter at 3 h after oral PD (P less than 0.001, n = 4). As was observed in the fasted blood of PD treated rabbits, D-lactate levels at fast and after saline ingestion in the control animals was found either absent or too low. Despite this increase in lactate, blood pH did not alter significantly when appropriate anticoagulant, i.e., heparin + 4-methylpyrazole, was employed.(ABSTRACT TRUNCATED AT 250 WORDS)