Role of NADPH oxidase-2 and oxidative stress in children exposed to passive smoking.

This study explored oxidative stress, nicotinamide adenine dinucleotide phosphate oxidase-2 (Nox2) activity and endothelial function in children exposed or not to passive smoking. Compared with controls (n=57), Nox2 activity and isoprostanes were higher in children exposed to passive smoking (n=57); conversely, nitric oxide (NO) bioavailability and flow-mediated dilation were lower in children exposed to passive smoking. A bivariate analysis showed that Nox2 activity correlated with flow-mediated dilation, NO bioavailability and isoprostanes. A multivariate analysis showed that Nox2 activity was significantly associated with serum isoprostanes and cotinine levels; flow-mediated dilation was associated with isoprostanes and carotid intima-media thickness.In children exposed to passive smoking, Nox2-derived oxidative stress is upregulated and inversely associated with impaired artery dilation.

Passive Smoking Exacerbates Nicotinamide-Adenine Dinucleotide Phosphate Oxidase Isoform 2-Induced Oxidative Stress and Arterial Dysfunction in Children with Persistent Allergic Rhinitis.

OBJECTIVE: To characterize nicotinamide-adenine dinucleotide phosphate oxidase isoform 2 (NOX2), oxidative stress, and endothelial function in children with and without allergic rhinitis and to ascertain the effect of passive smoke exposure on these factors, because there is an established association between allergic rhinitis and increased cardiovascular risk in adults. METHODS: We recruited 130 children-65 with persistent allergic rhinitis and 65 healthy controls. A cross-sectional study was performed to compare endothelial function by flow-mediated dilation, blood levels of isoprostanes, serum activity of soluble NOX2-dp (sNOX2-dp), and nitric oxide bioavailability, in these 2 groups of children. Serum cotinine levels were assessed to measure exposure to passive smoking. RESULTS: Compared with healthy controls, children with persistent allergic rhinitis had significantly higher sNOX2-dp and isoprostanes levels, lower flow-mediated dilation, and reduced nitric oxide bioavailability. Multivariable linear regression analysis showed that flow-mediated dilation, isoprostanes, and cotinine were independently associated with sNOX2-dp levels. Of note, sNOX2-dp serum levels were significantly higher in children with allergic rhinitis exposed to smoke, as compared with unexposed children with allergic rhinitis. CONCLUSION: NOX2 is activated in children with persistent allergic rhinitis and passive smoke exposure exacerbates this effect. We further demonstrate an association between higher sNOX2-dp and oxidative stress and endothelial dysfunction.

Primary school children often underestimate their nasal obstruction.

BACKGROUND: No consensus has ever been reached about the correlation between nasal resistance and the subjective sensation of nasal patency. The aim of the present study was to better de ne whether primary school and secondary school aged children correctly estimate their nasal obstruction. MATERIALS AND METHODS: Two hundred eighty four children (168 males and 116 female) aged between 6 and 14 years (9.5+2.9 years) affected by Pediatric Allergic Rhinitis underwent Rhinomanometry and they were considered as correctly estimating their nasal obstruction when the grade of nasal patency corresponded to the severity of the NOSE score, overestimating when the grade of nasal patency was <1 when compared to the severity of the score, underestimating when the grade of nasal patency was >1 when compared to the severity of the score. RESULTS: Correlation between NOSE score and nasal patency was statistically significant (r -0.74; p<0.001). Children between 6 and 9 years of age underestimate (43.7%) and children >12 overestimate (34.7%) their symptoms more frequently than children among other age ranges (p<0.001). CONCLUSION: Although NOSE score approximately allow to quantify nasal obstruction, in children, especially between 6 and 9 years of age, an objective measurement of nasal patency should be performed to better define the therapeutic approach.

High-mobility group box-1 (HMGB-1) and serum soluble receptor for advanced glycation end products (sRAGE) in children affected by vernal keratoconjunctivitis.

BACKGROUND: Vernal keratoconjunctivitis (VKC) is a chronic disease affecting conjunctiva even though the immunopathogenetic mechanisms underlying this inflammation are unclear. The aim of our study is to investigate serum levels of HMGB1 and circulating sRAGE in children affected by VKC before and after treatment with cyclosporine A (CsA) eye drops and in a group of healthy children. METHODS: Twenty-four children affected by VKC aged between 5 and 12 yrs of life were enrolled at the Department of Pediatrics, Division of Allergy and Immunology, 'Sapienza' University of Rome. Twenty-four healthy children without atopy, ocular, and systemic disease, cross-matched for sex and age to patients affected by VKC, represented the controls. All children affected by VKC were treated with CsA 1% eye drops for 4 wks, and blood samples were collected before and 2 wks after the end of treatment while the controls underwent to a single blood sample at the time of enrollment. RESULTS: Serum basal levels of HMGB1 and sRAGE were higher in children with VKC when compared with controls while, in patients affected by VKC, no difference was detected between atopic and non-atopic, and between ANA-positive and ANA-negative children. A significant reduction in serum HMGB1 and sRAGE levels was detected after the therapy while CsA serum levels were negative. CONCLUSIONS: Our study gives a support to the definition of VKC as a systemic inflammation in which HMGB1 and its soluble receptors could play a role.

Malocclusion and rhinitis in children: an easy-going relationship or a yet to be resolved paradox? A systematic literature revision.

OBJECTIVE: The relation between nasal flow and malocclusion represents a practical concern to pediatricians, otorhinolaryngologists, orthodontists, allergists and speech therapists. If naso-respiratory function may influence craniofacial growth is still debated. Chronic mouth-breathing is reported to be associated also with a characteristic pattern of dental occlusion. On the other hand, also malocclusion may reduce nasal air flows promoting nasal obstruction. Hereby, the aim of this review was to describe the relationship between rhinitis and malocclusion in children. METHODS: An electronic search was conducted using online database including Pubmed, Web of Science, Google Scholar and Embase. All studies published through to January 30, 2017 investigating the prevalence of malocclusion in children and adolescents (aged 0-20 years) affected by rhinitis and the prevalence of rhinitis in children with malocclusion were included. The protocol was registered at PROSPERO - International prospective register of systematic reviews under CRD42016053619. RESULTS: Ten studies with 2733 patients were included in the analysis. The prevalence of malocclusion in children with rhinitis was specified in four of the studies ranging from as high as 78.2% to as low as 3%. Two out of the studies reported the prevalence of rhinitis in children with malocclusion with a rate ranging from 59.2 to 76.4%. CONCLUSION: The results of this review underline the importance of the diagnosis and treatment of the nasal obstruction at an early age to prevent an altered facial growth, but the data currently available on this topic do not allow to establish a possible causal relationship between rhinitis and malocclusion.

Rapid Maxillary Expansion and Upper Airway Morphology: A Systematic Review on the Role of Cone Beam Computed Tomography.

OBJECTIVE: This study aimed to investigate the quality of cone beam computed tomography (CBCT) studies evaluating the effects of rapid maxillary expansion on upper airway morphology. MATERIALS AND METHODS: A database search was conducted using PubMed, Ovid, and Cochrane Library up to December 2016. Studies in which CBCT was adopted to visualize the upper airway before and after rapid maxillary expansion were included. The population target was growing patients. Methodological quality assessment was performed. RESULTS: The screening process resulted in the exclusion of 1079 references, resulting in only 9 remaining papers that fulfilled the inclusion criteria. No randomized clinical trials were found. The quality scores ranged from 36% to 68% of the maximum achievable, and the mean quality score of the studies was 50%. No good quality studies were detected in our sample. CONCLUSIONS: Inconsistencies in the CBCT protocols utilized were detected between studies. Head posture, tongue position, and segmentation protocols were not consistent. These discrepancies were reflected in the different results obtained in the studies. A valid and consistent protocol with regard to head and tongue positioning, as well as nasal cavity volume segmentation, is required.

Vitamin D levels in children affected by vernal keratoconjunctivitis.

BACKGROUND: Vernal keratoconjunctivitis (VKC) is a chronic and often severe bilateral conjunctivitis. VKC etiology still remains unclear although endocrine, genetic, neurogenic and environmental factors have been implicated. Vitamin D is a fat-soluble prohormone whose main function is the regulation of calcium and phosphate metabolism. The aim of this study was to evaluate serum vitamin D in children affected by VKC compared to the healthy children and investigate the relationship between its levels and disease severity. METHODS: A total of 110 children, 47 affected by VKC, aged between 5 and 12 years were enrolled at the Department of Pediatrics, Division of Allergy and Immunology, "Sapienza" University of Rome. Used as controls were 63 healthy children with negative skin prick test (SPT), without allergic, ocular and systemic disease. Serum samples were obtained in April from all the children included in the study. Vitamin D dosage was repeated in October in 20 patients after therapy and in 20 controls. A conjunctival scraping was performed in all children affected by VKC. RESULTS: Children affected by VKC had lower vitamin D levels compared to healthy controls and we found an increase in vitamin D levels after therapy with cyclosporine eye drops 1% although this increase was lower than that of healthy controls. Moreover we found significant correlations between vitamin D level and the severity of the disease. CONCLUSIONS: The study shows that children affected by VKC have lower vitamin D levels when compared to healthy controls and highlights a significant correlation between its levels and disease severity.

Stroke and migraine is there a possible comorbidity?

The association between migraine and stroke is still a dilemma for neurologists. Migraine is associated with an increased stroke risk and it is considered an independent risk factor for ischaemic stroke in a particular subgroup of patients. The pathogenesis is still unknown even if several studies report some common biochemical mechanisms between these two diseases. A classification of migraine-related stroke that encompasses the full spectrum of the possible relationship between migraine and stroke includes three main entities: coexisting stroke and migraine, stroke with clinical features of migraine, and migraine-induced stroke. The concept of migraine-induced stroke is well represented by migrainous infarction and it is described in the revised classification of the International Headache Society (IHS), representing the strongest demonstration of the relationship between ischaemic stroke and migraine. A very interesting common condition in stroke and migraine is patent foramen ovale (PFO) which could play a pathogenetic role in both disorders. The neuroradiological evidence of subclinical lesions most typical in the white matter and in the posterior artery territories in patients with migraine, opens a new field of research. In conclusion the association between migraine and stroke remains an open question. Solving the above mentioned issues is fundamental to understand the epidemiologic, pathogenetic and clinical aspects of migraine-related stroke.

Mean Platelet Volume, Vitamin D and C Reactive Protein Levels in Normal Weight Children with Primary Snoring and Obstructive Sleep Apnea Syndrome.

INTRODUCTION: Studies on Mean Platelet Volume (MPV) in children with Sleep Disordered Breathing (SDB) report conflicting results and the hypothesis of an intermittent hypoxemia leading to a systemic inflammation is reaching consensus. Vitamin D exerts anti-inflammatory properties and its deficiency has been supposed to play a role in sleep disorders. Emerging interest is rising about Primary Snoring (PS) since it is reasonable that also undetectable alteration of hypoxia might predispose to an increased production of inflammatory mediators. In this perspective, in a group of children affected by SDB, our aim was to investigate MPV, vitamin D and C Reactive Protein (CRP) levels, which had been previously evaluated separately in different studies focused only on Obstructive Sleep Apnea Syndrome (OSAS). MATERIALS AND METHODS: We enrolled 137 children: 70 healthy controls (HC), 67 affected by SDB undergoing a polysomnographic evaluation, 22 with a diagnosis of PS and 45 with a diagnosis of OSAS. All patients underwent routine biochemical evaluations including blood cell counts, CRP and vitamin D. RESULTS: Children affected by SDB had a mean age of 8.49±2.19 and were prevalently males (23 females, 34%; 44 males, 66%). MPV levels were higher in OSAS and PS when compared to HC; platelet count (PLT) and CRP levels were higher while Vitamin D levels were lower in children with SDB when compared to HC. MPV levels were correlated with PLT (r = -0.54; p<0.001), vitamin D (r = -0.39; p<0.001) and CRP (r = 0.21; p<0.01). A multiple regression was run to predict MPV levels from vitamin D, CRP and PLT and these variables significantly predicted MPV (F = 17.42, p<0.0001; adjusted R2 = 0.37). Only platelet count and vitamin D added statistically significantly to the prediction (p<0.05). CONCLUSION: The present study provides evidence of higher MPV and lower vitamin D levels in children with PS as well as in children with OSAS, and supports the underlying inflammation, hence, highlighting the importance of an early diagnosis of this previously considered benign form of SDB.

Local allergic rhinitis in children: Novel diagnostic features and potential biomarkers.

BACKGROUND: Local allergic rhinitis (LAR) is a phenotype of rhinitis that has been poorly studied in children. It is characterized by the same symptoms of allergic rhinitis but with the absence of markers of systemic atopy. OBJECTIVE: To identify children affected by LAR and to analyze the pathogenesis of this disease. We chose to focus our attention on interleukin (IL) and thymic stromal lymphopoietin (TSLP). METHODS: We enrolled 20 children affected by nonallergic rhinitis (negative skin-prick test results and serum specific immunoglobulin E [sIgE] values). Each patient underwent a nasal allergen provocation test (NAPT) with dust mite and grass pollen. Before and after NAPT, nasal lavage was performed to detect sIgE, IL-5, and TSLP; anterior active rhinomanometry was used to evaluate changes in nasal obstruction. RESULTS: Two patients were positive to a nonspecific NAPT and, thus, were excluded from the study. Of the remaining 18 children, 12 (66.7%) had positive results to at least one NAPT. Among these 12 patients, nasal sIgE levels for Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Lolium perenne increased significantly after NAPT (D. pteronyssinus, p < 0.005; D. farinae, p < 0.05; L. perenne, p < 0.05). Nasal IL-5 levels showed a significant increase after NAPT (p ≤ 0.006), and this increase was significantly higher in children who had positive NAPT results than in those patients with negative NAPT results (p ≤ 0.03). Among the 12 children who had a positive NAPT result, nasal TSLP was detected in 4 patients (33.3%) and its levels showed a relevant increase after NAPT, even though the difference did not reach statistical significance (p ≤ 0.061). CONCLUSION: Observed results raise the importance of better refining the diagnostic protocol for LAR in children. Nasal TSLP and IL-5 levels offer new insights concerning localized allergic inflammation, although the role of nasal sIgE has still to be clarified.

Sublingual immunotherapy in children and its potential beneficial collateral effect on respiratory tract infections.

Although directed to the control of allergic symptoms, a possible effect of sublingual immunotherapy (SLIT) on susceptibility to infections has been hypothesized. Two hundred sixty-five children aged between 3 and 4 years of age affected by allergic rhinitis completed a 6 year prospective case-control study. One hundred forty-three children after 2 years of SLIT reported a lower prevalence of respiratory tract infections when compared to children not undergoing SLIT.

Intranasal budesonide in children affected by persistent allergic rhinitis and its effect on nasal patency and Nasal Obstruction Symptom Evaluation (NOSE) score.

BACKGROUND: Intranasal steroids are recognized as an effective treatment for allergic rhinitis (AR) although their effect on nasal patency has never been evaluated with an objective instrument such as anterior rhinomanometry in children. Moreover this effect has been widely assessed with total Nasal Symptom Scores (NSS) including all symptoms of allergic rhinitis and not with scores specifically focused on nasal obstruction such as the Nasal Obstruction Symptom Evaluation score (NOSE). MATERIALS AND METHODS: Sixty children (42 males and 18 female) aged 6-10 years, affected by persistent AR, were randomized and divided in two groups of 30 children to be included in an unblinded trial: one group treated with intranasal budesonide and isotonic nasal saline for 2 weeks and the other group treated only with isotonic nasal saline for 2 weeks. Each child underwent rhinomanometry and completed the NSS and the NOSE scores before and after treatment. RESULTS: At the baseline nasal patency and NSS total score, NOSE total scores were correlated (r=-0.29, p<0.001; r=-60, p<0.001). After 2 weeks of treatment improvements in nasal patency, NSS and NOSE were seen (Δ NSS 4.13 ± 1.38 vs 1.33 ± 1.93, p<0.001; Δ NOSE 34 ± 17.97 vs 9 ± 18.21, p<0.001; Δ nasal patency -26.13 ± 25.25 vs -11.83 ± 11.31, p<0.001). Correlations were found between rhinitis duration and Δ nasal patency and Δ NOSE (r=-0.84, p<0.001; r=0.43, p<0.01). CONCLUSION: Intranasal budesonide is effective in increasing nasal patency in children. Moreover the NOSE score was strongly correlated with nasal flow and, hence, this score should be regarded as a valid and reliable instrument in children.

Endothelial dysfunction and oxidative stress in children with sleep disordered breathing: role of NADPH oxidase.

OBJECTIVE: Oxidative stress plays a crucial role in impairing endothelial function in sleep disordered breathing (SDB) but the underlying mechanism is still undefined. The objective of this study was to evaluate the interplay between oxidative stress, assessed by serum isoprostanes (8-iso-PGF2α) and soluble NOX2-dp (sNOX2-dp), and endothelial function, assessed by flow-mediated dilation (FMD), in children with SDB and healthy controls (HC). METHODS: One-hundred forty-four children including 45 with primary snoring (PS), 22 with obstructive sleep apnea (OSA) and 67 HC were recruited in this study; in 15 out of 22 OSA children FMD, serum 8-iso-PGF2α and sNOX2-dp were assessed before and after one month post adeno-tonsillectomy (AT). RESULTS: Compared with HC, OSA and PS children had significantly higher sNOX2-dp and serum 8-iso-PGF2α levels and lower FMD; compared with PS, FMD was significantly lower in OSA children. No significant difference for sNOX2-dp and serum 8-iso-PGF2α was observed between OSA and PS children. FMD was inversely correlated with sNOX2-dp levels (p<0.001) and with serum 8-iso-PGF2α (p<0.001). In multiple linear regression analysis, sNOX2-dp (p<0.001) and serum 8-iso-PGF2α (p<0.001) were the only independent predictive variables associated with FMD. AT significantly decreased sNOX2-dp and serum 8-iso-PGF2α levels (from 38.2±8.8 to 22.4±11.1 pg/ml, p<0.001, and from 281.4±69.7 to 226.0±66.4 pg/ml, p<0.001, respectively); conversely, FMD significantly increased after AT in OSA children (from 3.0±1.5 to 8.0±2.8%, p<0.001). CONCLUSION: This study suggests that NOX2-derived oxidative stress is involved in artery dysfunction in SDB children. Such hypothesis is reinforced by FMD improvement after AT coincidentally with oxidative stress lowering. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02247167.

Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF-1/NKX2.1 gene.

NK2 homeobox-1 (NKX2.1) gene encoding the thyroid transcription factor-1 (TTF-1) plays a critical role in lung, thyroid, and central nervous system morphogenesis and function; mutations cause a rare form of progressive respiratory failure associated with alterations of surfactant synthesis, composition, and homeostasis. Molecular mechanisms are heterogeneous and poorly explored. A 28 days old male, soon after birth, presented respiratory failure requiring oxygen treatment at FiO2 27%, prolonged for 2 weeks. Routine neonatal screenings detected a high thyroid stimulating hormone concentration. On day 27 congenital hypothyroidism was confirmed and substitutive treatment was begun. Since the persistence of respiratory symptoms sweat test, CFTR mutation, lymphocyte subpopulations, and sputum cultures were tested, resulting negative. Brain and cardiac defects were also ruled out. Bronchoscopy and BAL analysis were normal. Computed tomography showed bilateral multiple ground glass attenuation, consolidative areas and diffuse bronchial wall thickening. Based on the severity of symptoms, the exclusion of other causes of respiratory disease and the CT findings of interstitial lung disease, we investigated genes affecting the surfactant homeostasis. Sequencing analysis of the three exons of the TTF1 revealed a heterozygous mutation c.334G > T that results in the replacement of glycine in position 112 with a stop codon, generating a nonsense protein that lacks the correct transactivation domain in the C-terminal region. Genetic analysis of the family showed that the father, who was asymptomatic, carried the mutation. Screening for TTF-1 deletions or mutations should always be considered in children with congenital hypothyroidism and an unexplained neonatal respiratory distress or neurodevelopmental deficits.

Human milk and breastfeeding in surgical infants.

Human milk and breastfeeding represent the nutritional normative standards for term and preterm newborns. With the term "surgical infants" we refer to all newborns who undergo surgery during the first days of life and who are assisted in the neonatal intensive care unit during the postoperative period and then in the neonatal surgery unit. There are many obstacles to breastfeeding these newborns. The "barriers" include the unstable clinical conditions before and after surgery, the period of separation between the mother and child, and often the lack of attention to breastfeeding. Few studies have assessed if newborns with surgical diseases are breastfeed and if human milk is beneficial for their outcome. We believe that the best option is to offer them their own mother's milk through the promotion and support of breastfeeding. A specific program focused on the needs of these vulnerable children should be created. Furthermore the surgical and pediatric staff of the neonatal surgery unit should be informed and trained to increase such a program's feasibility.

Cephalometric pattern and nasal patency in children with primary snoring: the evidence of a direct correlation.

INTRODUCTION: Sleep disordered breathing (SDB) might affect craniofacial growth and children with obstructive sleep apnea syndrome present an increase in total and lower anterior heights of the face and a more anterior and inferior position of the hyoid bone when compared to nasal breathers. OBJECTIVE: To investigate the correlation between rhinomanometric and cephalometric parameters in children with primary snoring (PS), without apnea or gas exchange abnormalities. MATERIALS AND METHODS: Thirty children with habitual snoring (16 females and 14 males) aged 4-8 years (mean age 6.85±1.51 years) were selected by a SDB validate questionnaire. All subjects underwent lateral cephalometric, panoramic radiographies. RESULTS: In our sample 10 children (33%) had snoring 3 nights/week, 11 (37%) 4-6 nights/week and 9 (30%) every night/week. Overall 7 patients (23.3%) were affected by adenoid hypertrophy (AH), 4 (13.3%) by tonsillar hypertrophy (TH) and 13 (43.3%) by AH and TH. We found a more vertical position of the hyoid bone to the mandibular plane (H⊥VT) in patients with a higher frequency (7.3±2.7 vs 7.6±3.7 vs 10.9±2.5 in children snoring 3 nights/week, 4-6 nights/week and every night/week respectively; p = 0.032). Concerning nasal patency significant correlations were found with ANB (maxillary and jaw position with respect to the cranial base), NS∧Ar (growth predictor), sumangle, FMA (total divergence), SnaSnp∧GoMe (inferior divergence), BaN∧PtGn (facial growth pattern), Phw1_PsP (posterosuperior airway space), AHC3H (the horizontal distance between the most anterosuperior point of the hyoid bone and the third cervical vertebra). CONCLUSION: The present study supports the relationship between nasal obstruction and specific craniofacial characteristics in children with primary snoring and lead us to hypothesize that nasal obstruction might explain the indirect link between snoring and cephalometric alterations.

Assessing the relationship between serum resistin and nasal obstruction in children with allergic rhinitis.

BACKGROUND: Nasal obstruction has been reported as a "key symptom" of allergic rhinitis (AR) because it is deeply associated with impaired quality of life and it reflects more directly the allergic inflammation in the nasal mucosa. Resistin is known to be involved in inflammatory processes exerting an important role in the regulation of cytokine production even though its effective proinflammatory activity at nasal level has never been fully established. This study investigates the relationship between resistin levels and nasal obstruction assessed by an objective method such as active anterior rhinomanometry. METHODS: Fifty-three children between 4 and 10 years of age affected by persistent allergic rhinitis (PAR) were enrolled and subdivided in two groups. Serum resistin levels were detected in all children. The same day patients underwent rhinomanometry, which was considered negative (no nasal obstruction) when the fraction of predicted values (p.v.'s) was between 71 and 100% and it was considered positive when the fraction of p.v. was ≤70%. RESULTS: The serum resistin levels were significantly higher in children with moderate-severe PAR than in patients with mild PAR (p < 0.03). Furthermore, serum resistin levels were significantly higher in children with positive rhinomanometry compared with negative rhinomanometry (p < 0.03). The fraction of p.v.'s of nasal flows in patients with nasal obstruction had a significant negative correlation with serum resistin levels (p < 0.001). CONCLUSION: This study provides evidence that resistin levels are increased in children with severe nasal obstruction measured by an objective and quantitative approach.