Julio Ardura

Emergence and evolution of the circadian rhythm of melatonin in children.

Objective: To assess the age at which the circadian rhythm of melatonin begins. Methods: 55 children, divided into groups from the neonatal period to 24 months of life, were studied. Urine samples were taken from 28 newborn babies to measure 6-sulfatoxymelatonin (aMT6s). Salivary samples were collected from infants (27 cases), to measure melatonin (aMT). aMT was measured by RIA and aMT6s by ELISA using commercial kits. Changes in the levels of aMT6s and aMT were evaluated using the Friedman test and Wilcoxon matched pair test. Results: The group aged 27–41 days showed statistically significant differences in daily aMT6s and aMT concentrations. The highest values were always found between 24.00 and 8.00 h. This day/night difference persisted from 2–3 to 13–24 months of age. Conclusion: The data indicate that the circadian melatonin rhythm appears at the end of the neonatal period and persists thereafter.

Development of sleep–wakefulness rhythm in premature babies

The aims of this study were: (1) to investigate the evolution of the sleep pattern in preterm newborns during their first month of life; (2) to assess the influence of light–dark on the sleep pattern; and (3) to compare this pattern with that of full–term newborns. The population consisted of 60 healthy, preterm newborns and 63 full–term newborns, divided into four age groups, 1 week apart, throughout the first month of life. Preterm newborns were further divided into five groups according to conceptional (corrected) age. An observer took note every 30 min, for 24 h, of sleep or wakefulness in every case. The average sleeping time in preterm groups according to postnatal age remained unchanged during the first month of life: 17.57 honday 1 and 17.15h on day 28. When the preterm infants were re–grouped according to conceptional age, average daily sleep was 17.86 h at 32 weeks and 15.22 h at 37 weeks. The full–term newborns had an average daily sleep of 14.78 h on day 1 and 11.94 h on day 28, with a decrease throughout week 4 of life (p < 0.001). The decrease in daily sleeping time in the full–term groups, took place at the expense of the daylight span, where there was a decrease througout the first month of life (p < 0.01). There were no differences in preterm newborns during the light and dark phases. A progressive synchronization of sleep to the light–dark was seen in the control group. Therefore, the sleeping pattern could be taken as an indication of the degree of biological immaturity of preterm newborns.

Melatonin in epilepsy and febrile seizures.

A study on melatonin rhythm in children with generalized idiopathic epilepsy and simple fever is presented in this article. A population of 40 children was divided into 4 groups, namely, epilepsy, febrile seizure, and 2 control groups. Salivary melatonin was measured by means of radioimmunoassay. Friedman 2-way analysis of variance (ANOVA) and Wilcoxon tests were employed to assess the existence of melatonin rhythm. Comparison across groups was performed by means of ANOVA and Mann-Whitney tests. Higher melatonin levels were found at night, with a peak at 04:00 h in all groups. Significant diurnal rhythm was also detected for these levels. No significant overall differences between case and control groups were found for melatonin levels, though patients showed lower peak melatonin values than controls at 04:00 h with a significant difference in the febrile seizure group (10.70 vs 19.5 pg/mL respectively; P<.04). Our data support the presence of diurnal rhythm in blood melatonin concentrations in children with epileptic and febrile seizures. Comparison between case and control groups showed lower peak concentrations in the febrile seizure group with respect to healthy controls.

Bronchiolitis due to respiratory syncytial virus in hospitalized children: a study of seasonal rhythm

Aim: The objective of this study was to describe the rhythm of respiratory syncytial virus (RSV) bronchiolitis seasonal outbreaks in hospitalized children.

Host and environmental factors influencing respiratory secretion of pro-wheezing biomarkers in preterm children.

To cite this article: Matías V, San Feliciano L, Fernández JE, Lapeña S, Garrido E, Ardura J, Soga MJ, Aragón MP, Remesal A, Benito F, Andrés J, Centeno F, Marugán V, Bachiller R, Bermejo‐Martin JF. Host and environmental factors influencing respiratory secretion of pro‐wheezing biomarkers in preterm children. Pediatric Allergy Immunology 2012: 23: 441–447.

Nasopharyngeal aspirate cytokine levels 1 yr after severe respiratory syncytial virus infection

Respiratory syncytial virus (RSV) infection is an important cause of recurrent wheezing in infants. Nevertheless, the link between RSV infection and wheezing has yet to be elucidated at the molecular level. Here, we present a preliminary study on the evolution of the immune response in the respiratory tract at long‐term after RSV infection. Twenty‐seven immune mediators were profiled in nasopharyngeal aspirates (NPAs) obtained from 20 children hospitalized due to a severe infection by RSV at discharge from hospital and again 1 yr later. The same mediators were profiled in parallel in NPAs from 12 healthy controls. In the year following discharge, 85% (17/20) of children of the RSV group suffered at least one episode of wheezing documented by the pediatrician. On the contrary, wheezing episodes were observed only in 25% (3/12) of children in the control group. While most of the mediators profiled returned to normal levels by 1 yr after discharge from hospital, RSV children showed a persistent nasal hyper‐secretion of VEGF, G‐CSF, IL‐10, IL‐6, IFN‐γ, IL‐7 and IL‐13. In previous works VEGF, IL‐10 and IFN‐γ have been put in relation with the pathogenesis of post‐virus induced asthma. G‐CSF, IL‐6, IL‐7 and IL‐13 are increased in respiratory and plasma samples of asthmatic patients. Here, we evidence for the first time a persistent elevation of these mediators as late as 1 yr after severe RSV disease resolution, reinforcing their possible implication in the pathogenesis of wheezing.

Similar Cytokine Profiles in Response to Infection with Respiratory Syncytial Virus Type A and Type B in the Upper Respiratory Tract in Infants

Human respiratory syncytial virus (RSV) is the leading viral cause of severe respiratory illness in infants and young children worldwide. RSV isolates can be divided into 2 subgroups, type A and type B. Here, we compare for the first time the nasal profiles of 27 immune mediators in response to both viral subtypes in 14 children infected with RSV/A, 8 children infected with RSV/B, 11 children coinfected with RSV/A plus other respiratory viruses, and finally, 27 control children, all <2 years old. Our results evidence that children’s infection with both RSV subtypes induces very similar profiles of immune mediators in the upper respiratory tract, characterized by the elevation of Th1 and Th2 cytokines, chemokines and growth factors. Interestingly, no major differences in the profiles of the immune mediators were found between the children infected exclusively with RSV/A and those infected with RSV/A plus other respiratory viruses.

Breast feeding and early life immunomodulation

To the Editor, We have read with interest the article from Belderbos et al. (1) suggesting the ability of breastfeeding to down-modulate the secretion of TNF-a and IL-10 by white blood cells in term children during the first month of life. Also very recently, we have reported the existence of an inverse association between duration of breastfeeding and levels of IL-10 and RANTES secreted by the upper respiratory tract 1 year after birth in preterm children (2). A total of 77 children were recruited in our study. Gestational age (weeks) was (mean, SD) 31.9 (2.9). Sex composition was (women/men): 35/38. Weight at birth (kg) was 1.8 (0.5). Length at birth (cm) was 42.5 (4.2). Eight children had broncho-pulmonary dysplasia at birth. The most frequent accompanying condition was the presence of personal (n = 16) or familiar antecedents (n = 32) of atopic dermatitis. The majority of the children received breastfeeding (60%) for an average of 5.4 months after birth. Cytokines were measured using the 27-plex Bio-Rad assay (Hercules, CA, USA) on a Luminex platform (Austin, TX, USA), including IL-1 receptor antagonist (IL-1RA), IL-9, IL-15, Eotaxin, human fibroblast growth factor–basic (FGF-b): IFN-inducible protein 10 (IP-10), macrophage inflammatory protein 1a (MIP1a), platelet-derived growth factor (PDGF-BB), regulated upon activation, normal T cell expressed, and secreted protein (RANTES), vascular endothelial growth factor (VEGF), IL1b, IL-6, IL-8, IL-7, IL-17, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1b (MIP-1b), IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte macrophage colonystimulating factor (GM-CSF), IFN-c and tumor necrosis factor alpha (TNF-a). Interestingly, duration of breastfeeding (in months) inversely correlated with levels in nasopharyngeal aspirates of IL-1b (Spearman correlation coefficient, p): ( 0.254, 0,035), G-CSF ( 0.236, 0.050), MIP-1b ( 0.250, 0.039), IL-10 ( 0.323, 0,007), and TNF-a ( 0.254, 0,035) (Fig. 1), and also with RANTES, IL-6, IL-17 at the level (p < 0.1). Belderbos et al. normalized cytokines by means of logarithmic transformation. Reproducing this approach, we now used logarithmic values for cytokines. Univariate linear regression analysis was performed again to evaluate the relationship between breastfeeding and cytokine levels 1 year after birth. Potential confounding variables were also evaluated in the univariate analysis: gestational age, sex, weight at birth, height at birth, [breastfeeding (duration in months)], bronchopulmonary dysplasia, atopic dermatitis, smoking habit at home, assistance to daycare, siblings at daycare or at school, number of people living at home, sibilances needing of treatment in the first year of life, [prophylaxis with PVZ (three or more doses)], symptoms of respiratory infection in the first year of life observed by the pediatrician, and necessity of hospitalization in the first year of life. Those variables yielding p values <0.2 in the univariate analysis were entered into a further multivariate analysis. After adjusting for potential confounding variables, duration of breastfeeding was inversely associated with levels of RANTES and IL-10 (Table 1) In turn, the variable (siblings at daycare or at school) was directly associated with IL-10 levels and the variable (prophylaxis with PVZ) was inversely associated with levels of this cytokine. Both RANTES and IL-10 are involved in allergy/asthma pathogenesis. In conclusion, these works are pioneer in providing biological evidence on the immuno-modulatory ability of breastfeeding in early life. This activity could be explained by the protective effect of breastfeeding against infections (3, 4). Alternatively, breastfeeding-induced protection might rely on tolerance induction to common environmental and dietary antigens because of antigen transfer across mammary epithelium or to the presence of factors in breast milk influencing neonatal immune system maturation, including immunoglobulins, oligosaccharides, and antimicrobial proteins/peptides (5). These results could explain thus the potential protective effect of breastfeeding against asthma/allergy.

Automatic diagnosis of ADHD based on nonlinear analysis of actimetry registries

Attention-Deficit Hyperactivity Disorder (ADHD) is the most common mental health problem in childhood and adolescence. Its diagnosis is commonly performed in a subjective manner since current objective measurements are either expensive or time-consuming. However, subjective methods tend to overestimate the severity of the pathology. In this paper, we propose a novel methodology for automatic diagnosis of ADHD based on signal processing methods. The method is constructed in two stages: 1) An automatic activity/rest detection filter which allows for a separate analysis of both types of periods and 2) A feature extraction module based on nonlinear regularity quantification of either the global signal or the detected epochs. Results on real data show that the proposed methodology can discriminate between patients and controls with sensibility and specificity values approaching 80%.

Congenital anophthalmia: a circadian rhythm study.

A circadian rhythm of heart rate and respiratory rate was seen at 1, 8, and 12 months of age in an infant born without ocular tissue, which supports the possibility that the time cues were nonphotic. No melatonin circadian rhythm was detected at any age up to 9 years of age, and this is most likely associated with the anophthalmia and lack of photic input to the suprachiasmatic nucleus. Usually circadian organization is present after the neonatal period and approaches adult levels with development.