Exhaled nitric oxide in healthy children: Variability and a lack of correlation with atopy

Nitric oxide (NO) is a free radical produced by several lung cells via the enzyme nitric oxide synthetase (NOS) and can be easily measured in exhaled air by chemiluminescence analysis. As the iso-enzyme iNOS may be induced by cytokines and endotoxin, NO is elevated in several chronic inflammatory airway diseases. Prior to using exhaled nitric oxide (eNO) as a non-invasive marker of airway inflammation in daily routine, the role of possibly influencing factors such as age, time of the day, smoking exposure and intra-individual variability have to be clarified. NO concentrations were measured in 107 healthy children aged 4–18 years at an expiratory flow of 184 ml/s. Spirometry and a skin-prick test were performed and a questionnaire on family history of atopy, personal symptoms of atopic disease and smoke exposure was completed. For intra-individual variability nitric oxide was measured in six children three times daily on 6 consecutive days. Median eNO concentration was 5.7 p.p.b., and increased significantly with age but did not vary with gender. No correlation was found between eNO and smoke exposure, positive skin-prick test, FEV ₁, MEF₂₅ and time of the day. There was no circadian rhythm found in the six children measured on 6 consecutive days, but the eNO showed an intra-individual coefficient of variation of 25.9%. With the help of a two-compartment model of the lung the alveolar NO concentration was estimated to be 4.1 p.p.b and was shown to be constant with age, whereas the airway part of NO steadily increased with age. When comparing eNO values with standardized measurement techniques, the age of the children and the large intra-subject coefficient of variation have to be taken into account, whereas in healthy children subject-specific factors such as atopic history, gender and skin test reactivity did not affect eNO measurement.     

Cibacron blue stimulation of surfactant secretion in rat type II pneumocytes.

1. The effect of cibacron blue, a selective P2y-purinoceptor antagonist in some systems, on the stimulatory effect of adenosine 5'-triphosphate (ATP) on [3H]-phosphatidylcholine secretion was examined in primary cultures of rat type II pneumocytes prelabelled by overnight culture with [3H]-choline. 2. Cibacron blue alone stimulated phosphatidylcholine secretion in a concentration-dependent manner in the range 10(-4)-10(-3) M. At a concentration of 10(-4) or lower, cibacron blue had no effect on ATP-induced phosphatidylcholine secretion but at 10(-4)-10(-3) M it increased the effect of ATP. Enhancement of the ATP effect was apparent whether cibacron blue was added before or together with ATP. Cibacron blue also increased ATP-induced secretion in the presence of the P1-purinoceptor antagonist, xanthine amine congener (10(-5) M). 3. The stimulatory effect of cibacron blue on phosphatidylcholine secretion was additive to those of 5' (N-ethylcarboxyamido) adenosine (NECA) and terbutaline but less than additive to that of ATP. 4. Cibacron blue alone had no effect on formation of cyclic AMP or inositol phosphate and when added simultaneously with ATP it did not affect the ATP-induced increase in these second messengers. Preincubation of the cells with cibacron blue before addition of ATP, however, resulted in antagonism of the ATP-induced increase in cyclic AMP and inositol phosphates. Preincubation with ATP had the same effect. The stimulatory effects of NECA and terbutaline on cyclic AMP formation were enhanced by preincubation with cibacron blue. 5. Thus, ATP-induced phosphatidylcholine secretion in type II cells is not diminished by the P2y-antagonist, cibacron blue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial hypertrophy and enhanced left ventricular contractility in Zucker diabetic fatty rats.

Heart failure is known to be a complication of insulin-dependent (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) even in the absence of coronary heart disease or hypertension. The mechanisms leading to diabetic cardiomyopathy are unknown. The aim of the study was to characterize structural and functional alterations in hyperinsulinemic Zucker diabetic fatty (ZDF) rats treated with or without insulin. Diabetic animals showed a twofold increase in cardiomyocyte volume with increased left ventricular ANP but not BNP mRNA levels in spite of a reduced plasma renin activity (PRA) 2 months after onset of diabetes compared to nondiabetic littermates. These changes were associated with an increase in left ventricular performance as assessed by echocardiography. Insulin treatment led to a significant increase in body weight (BW), total heart weight, myocardial protein content, and left ventricular mass (LVM). Perivascular fibrosis and laminin thickness were significantly augmented in diabetic rat myocardium irrespective of insulin treatment, whereas interstitial collagen I and fibronectin were similarly found in diabetic and control myocardium. Initial stages of diabetic cardiomyopathy in hyperinsulinemic rats are characterized by cardiomyocyte hypertrophy and enhanced cardiac contractility. It is suggested that hyperinsulinemia may be involved in cardiac hypertrophy.     

Lung ultrasound—a new diagnostic modality in persistent tachypnea of infancy

Lung ultrasound (LUS) has been increasingly used in diagnosing and monitoring of various pulmonary diseases in children. The aim of the current study was to evaluate its usefulness in children with persistent tachypnea of infancy (PTI). This was a controlled, prospective, cross‐sectional study that included children with PTI and healthy subjects. In patients with PTI, LUS was performed at baseline and then after 6 and 12 months of follow‐up. Baseline results of LUS were compared to (a) baseline high‐resolution computed tomography (HRCT) images, (b) LUS examinations in control group, and (c) follow‐up LUS examinations. Twenty children with PTI were enrolled. B‐lines were found in all children with PTI and in 11 (55%) control subjects (P < .001). The total number of B‐lines, the maximal number of B lines in any intercostal space, the distance between B‐lines, and pleural thickness were significantly increased in children with PTI compared to controls. An irregularity of the pleural line was found in all patients with PTI and in none of the healthy children. There were no significant changes in LUS findings in patients with PTI during the study period. The comparison of HRCT indices and LUS findings revealed significant correlations between the mean lung attenuation, skewness, kurtosis and fraction of interstitial pulmonary involvement, and the number of B‐lines as well as the pleural line thickness. LUS seems to be a promising diagnostic tool in children with PTI. Its inclusion in the diagnostic work‐up may enable to reduce the number of costly, hazardous, and ionizing radiation‐based imaging procedures.     

CXCR1 and CXCR2 haplotypes synergistically modulate cystic fibrosis lung disease

Cystic fibrosis (CF) lung disease severity is largely independent on the CF transmembrane conductance regulator (CFTR) genotype, indicating the contribution of genetic modifiers. The chemokine receptors CXCR1 and CXCR2 have been found to play essential roles in the pathogenesis of CF lung disease. Here, we determine whether genetic variation of CXCR1 and CXCR2 influences CF lung disease severity. Genomic DNA of CF patients in Germany (n = 442) was analysed for common variations in CXCR1 and CXCR2 using a single-nucleotide polymorphism (SNP) tagging approach. Associations of CXCR1 and CXCR2 SNPs and haplotypes with CF lung disease severity, CXCR1 and CXCR2 expression, and neutrophil effector functions were assessed. Four SNPs in CXCR1 and three in CXCR2 strongly correlated with age-adjusted lung function in CF patients. SNPs comprising haplotypes CXCR1_Ha and CXCR2_Ha were in high linkage disequilibrium and patients heterozygous for the CXCR1-2 haplotype cluster (CXCR1-2_Ha) had lower lung function compared with patients with homozygous wild-type alleles (forced expiratory volume in 1 s ≤ 70% predicted, OR 7.24; p = 2.30 × 10(-5)). CF patients carrying CXCR1-2_Ha showed decreased CXCR1 combined with increased CXCR2 mRNA and protein expression, and displayed disturbed antibacterial effector functions. CXCR1 and CXCR2 genotypes modulate lung function and antibacterial host defence in CF lung disease.     

Betreuung von Mukoviszidosepatienten beim übergang vom Jugendalter zum Erwachsenen

During the last 30 years, life expectancy in patients with cystic fibrosis has significantly improved. In Germany, almost half of the 8500 patients are 18 years or older. Older patients have increased rates of cystic fibrosis typical complications, In addition the characteristic complications of adulthood, including arterial hypertension, hyperlipidemia, and cardiovascular diseases, occur. Also crisis of marriage or loss of work place, as well as family planning measures including in-vitro-fertilization are problems merely of the adult cystic fibrosis patient. Therefore adult patients should be treated in a centre specialized on adults. At the moment, in Germany only one third of all adult patients are followed up in an adult center, many patients are treated in age-independent centers, and also a significant number is treated in small clinics. In this article models for transition currently established in Germany are described and occurring problems with their implementation are discussed     

Impaired formation of the second messenger cAMP in mononuclear blood cells of children with pertussis

To determine the pathophysiologic significance of pertussis toxin (PT) on the human beta-adrenergic system, beta-adrenoceptor (beta-R)-density and cyclic AMP response of peripheral mononuclear blood cells (MN leukocytes) were studied in children during the paroxysmal stage of natural pertussis infection, after vaccination with pertussis monovaccine, and in controls. Isoprenaline-induced cAMP accumulation, measured in a protein-binding assay, was significantly reduced to about 25-50% in children during the first week of paroxysmal pertussis, compared with controls. In contrast, cAMP accumulation after stimulation of the adenylyl cyclase by forskolin was unaffected. The density and affinity of beta-R, estimated by 125I-cyanopindolol-binding studies, were not significantly altered. The suggestion that PT might impair the coupling of the beta-R signals to the adenylyl cyclase was confirmed by parallel in vitro studies on MN leukocytes from adults. These cells, when incubated with purified PT, showed a significantly diminished cAMP response to isoprenaline, whereas that to forskolin remained unaffected. As cAMP accumulation in response to prostaglandin E1 and hydrocortisone was also reduced, it appears that PT may directly affect G-proteins serving as signal transducers for several stimulatory receptors. In contrast to the actual disease, in children treated with pertussis monovaccine, cAMP accumulation as well as the beta-R were unaffected. It is concluded that in MN leukocytes obtained from children during the natural course of pertussis, as well as after incubation of normal MN leukocytes with PT, the stimulatory signal-transducing system for cAMP generation is inhibited.     

Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone

In contrast to several authors who found hepatic cytochrome P 450 2D6 (CYP2D6) metabolising status to be clinically unimportant in treatment with the CYP2D6 substrate, risperidone, we report on a 17-year-old schizophrenic patient who suffered from severe extrapyramidal side effects (EPS) while being treated with risperidone at 4 mg per day. He was genotyped as a CYP2D6 poor metaboliser (PM). The active moiety of risperidone (sum of risperidone and 9-hydroxyrisperidone) was elevated and increased even further under co-medication with haloperidol and biperiden. We conclude that the PM phenotype for CYP2D6 of this patient had major clinical importance in treatment with risperidone. Most likely metabolic pathways other than CYP2D6 were also involved that are probably inhibited by haloperidol.