Vitamin D status in internationally adopted children: the northwest Italy experience.

BACKGROUND: The majority of internationally adopted children, before adoption, might have experienced malnutrition, exposure to infectious diseases, environmental deprivation, and neglect; they could also develop medical problems such as vitamin D deficiency. Scantly data are available about vitamin D status in internationally adopted children and, to our knowledge, no report exists on Italian adoptees. METHODS: We carried out a prospective multicenter study, involving three Pediatric Centers in Piedmont, Italy, to collect information about 25-hydroxyvitamin D (25[OH]D) profile in adoptees, shortly after their arrival in Italy. RESULTS: In 142/158 internationally adopted children 25(OH)D was measured: 75 males and 67 females, with a mean age of 4.22±2.2 years. Fifty-three (37.3%) of them came from Asia, 48 (33.8%) from Africa, 24 (16.9%) from Eastern Europe, and 17 (12%) from Latin America. The median level of 25(OH)D in serum was 21.5 ng/mL (IQR range 14.3-29.7 ng/mL): 26 (18.2%) of the examined children had an insufficiency of 25-OHD, whereas 36 (25.2%) had a deficiency. Adoptees with longer time of institution stay had a significant risk to develop 25(OH)D deficiency. The Asian origin proved to be a risk factor to develop 25(OH)D deficiency, whereas the age >1 year was significantly associated with 25(OH)D insufficiency. CONCLUSIONS: Our survey showed that vitamin D deficiency and insufficiency, in internationally adoptees, are frequent and relevant health problems.

Weaning in neurally adjusted ventilatory assist: a prospective interventional study in neonates.

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) is a respiratory support triggered by the electrical activity of the diaphragm (EAdi). Only few studies evaluated NAVA short-term efficacy and safety in newborns. Aim of this study was to assess efficacy and safety of NAVA in a cohort of newborns and to analyze ventilation parameters helpful to guide weaning. METHODS: Thirty-four newborns with respiratory failure were ventilated with synchronized intermittent mandatory ventilation plus pressure-regulated volume control plus pressure support (SIMV(PRVC)+PS) for 12 hours and switched to NAVA until extubation. Ventilator and vital parameters, oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) ratio (S/F), arterialized capillary blood gases (aCBG), and sedatives dose were recorded. The occurrence of reintubation within the first 72 hours, pneumothorax and mortality were evaluated. RESULTS: After 6 hours of NAVA, a significant reduction of FiO2 (0.25 versus 0.32), and peak inspiratory pressure (13 versus 18 mmHg), and a significant increase of S/F (383 versus 316) were found, compared to SIMV(PRVC)+PS. Other ventilation, vital and aCBG parameters were similar in both ventilation modes. During NAVA a significant reduction of sedation was shown. All subjects were successfully extubated guided by EAdi peak during weaning. No reintubation, pneumothorax, or death were recorded. CONCLUSIONS: NAVA can be effectively and safely used in neonates. The EAdi peak could be a reliable index to guide the physicians during weaning and extubation.

Information Survey on the Use of Complementary and Alternative Medicine.

Background and Objectives: Complementary and alternative medicines (CAMs) are generally considered non-scientific and poor effective therapies. Nevertheless, CAMs are extensively used in common clinical practice in Western countries. We decided to promote a Delphi consensus to intercept the opinion of Italian physicians on CAM use in clinical practice. Materials and Methods: We run a Delphi-based consensus, interviewing anonymously 97 physicians. Of these, only 78 participate to the questionnaire. Results: Consensus about agreement and disagreement have been reached in several topics, including indication, as well as safety issues concerning CAMs. Conclusions: The use of CAMs in clinical practice still lacks evidence. Experts agree about the possibility to safely use CAMs in combination with conventional medicines to treat non-critical medical conditions.

Supplementation with Bifidobacterium breve BR03 and B632 strains improved insulin sensitivity in children and adolescents with obesity in a cross-over, randomized double-blind placebo-controlled trial.

BACKGROUND & AIMS: Variations in gut microbiota might impact metabolism leading to body weight excess. We assessed the impact of a probiotic supplementation in pediatric obesity on weight, metabolic alterations, selected gut microbial groups, and functionality. METHODS: Cross-over, double-blind, randomized control trial (BIFI-OBESE trial; NCT03261466). 101 youths (6-18 years, Tanner stage ≥2) with obesity and insulin-resistance on diet were randomized to 2 × 109 CFU/AFU/day of Bifidobacterium breve BR03 (DSM 16604) and B. breve B632 (DSM 24706) (51) or placebo (50) for 8 weeks with a 4-weeks wash-out period. RESULTS: All subjects (M/F 54/47) completed the first 8 weeks, and 82 (M/F 43/39) the last part without adverse events. Mixed-effects models revealed a carry-over effect on many variables in the entire study, narrowing the analysis to the first 8 weeks before the wash-out periods. All subjects improved metabolic parameters, and decreased weight and Escherichia coli counts. Probiotics improved insulin sensitivity at fasting (QUICKI, 0.013 CI95%0.0-0.03) and during OGTT (ISI, 0.654 CI95%-0.11-1.41). Cytokines, GLP1, and target microbial counts did not vary. Of 25 SCFAs, acetic acid and acetic acid pentyl-ester relative abundance remained stable in the probiotics, while increased in the placebo (p < 0.02). A signature of five butanoic esters identified three clusters, one of them had better glucose responses during probiotics. CONCLUSION: An 8 weeks treatment with B. breve BR03 and B632 had beneficial effects on insulin sensitivity in youths with obesity. Microbiota functionality could influence metabolic answers to probiotics. Long-term studies to confirm and enrich our findings are justified. Tailored probiotic treatments could be an additional strategy for obesity. TRIAL REGISTRATION: NCT03261466.

Probiotics Supplements Reduce ER Stress and Gut Inflammation Associated with Gliadin Intake in a Mouse Model of Gluten Sensitivity.

Exposure to gluten, a protein present in wheat rye and barley, is the major inducer for human Celiac Disease (CD), a chronic autoimmune enteropathy. CD occurs in about 1% worldwide population, in genetically predisposed individuals bearing human leukocyte antigen (HLA) DQ2/DQ8. Gut epithelial cell stress and the innate immune activation are responsible for the breaking oral tolerance to gliadin, a gluten component. To date, the only treatment available for CD is a long-term gluten-free diet. Several studies have shown that an altered composition of the intestinal microbiota (dysbiosis) could play a key role in the pathogenesis of CD through the modulation of intestinal permeability and the regulation of the immune system. Here, we show that gliadin induces a chronic endoplasmic reticulum (ER) stress condition in the small intestine of a gluten-sensitive mouse model and that the coadministration of probiotics efficiently attenuates both the unfolded protein response (UPR) and gut inflammation. Moreover, the composition of probiotics formulations might differ in their activity at molecular level, especially toward the three axes of the UPR. Therefore, probiotics administration might potentially represent a new valuable strategy to treat gluten-sensitive patients, such as those affected by CD.

The Prevalence of Thyroid Autoimmunity in Children with Developmental Dyslexia.

METHODS: We enrolled pediatric subjects with developmental dyslexia and, as a control group, healthy age- and sex-matched subjects without developmental dyslexia. Thyroid function was evaluated in subjects with developmental dyslexia measuring serum concentrations of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4). Thyroid autoimmunity was evaluated in all subjects measuring antithyroid peroxidase (TPO-Ab) and antithyroglobulin (TG-Ab) antibodies. In subjects with developmental dyslexia, thyroid ultrasonography (US) was also performed. RESULTS: We enrolled 51 subjects with developmental dyslexia (M : F = 39 : 12, mean age 12.4 ± 9 years) and 34 controls (M : F = 24 : 10, mean age 10.8 ± 4 years). TPO-Ab positivity was significantly higher in subjects with developmental dyslexia compared to controls (60.8% vs. 2.9%, p < 0.001), while no significant difference was found in TG-Ab positivity (16% vs. 5.8%). Thyroid US performed in 49 subjects with developmental dyslexia revealed a thyroiditis pattern in 60%. CONCLUSIONS: We found an extremely high prevalence of thyroid autoimmunity in children with developmental dyslexia. Further studies are needed to confirm our observations, but our findings may change the approach to this disorder and eventually lead to a systematic determination of thyroid autoimmunity in children with developmental dyslexia.

Growth hormone receptor polymorphisms and growth hormone response to stimulation test: a pilot study.

BACKGROUND: No gold standard pharmacological stimulation test exists for the diagnosis of growth hormone deficiency (GHD). In addition, the genetic factors that influence growth hormone (GH) responses remain unclear. This study aimed to determine whether polymorphisms in exon 6 of the GH receptor gene influence responses to the L-arginine GH stimulation test. METHODS: This study included 27 prepubertal patients with confirmed GHD. GHD was defined as a peak GH level <8 ng/mL in response to pharmacological stimulation. The mean GH peak after L-arginine stimulation was 2.9±2.9 ng/mL. RESULTS: The included patients had the following genotypes at the third position of codon 168: AA (N.=1), AG (N.=15) and GG (N.=11). Patients carrying the AA and AG genotypes exhibited stronger responses to arginine than patients with the GG genotype (3.1±2.7 vs. 1.5±1.3 ng/mL, P=0.01). CONCLUSIONS: The approach employed in this study could elucidate GH profiles under physiological and pathological conditions, facilitating improved interpretation of pharmacological stimulation tests.

Developmental and behavioral profile in a domestic adoptees sample: a new challenge for the pediatrician.

BACKGROUND: The aim of this study is to investigate the changes of developmental and behavioral profile in a domestic adoptees sample. METHODS: Thirty-six domestic adoptive families were recruited, resulting in a sample of 39 children. Families were sent a general questionnaire for collecting data related to the children demographic variables, infant's background (time spent in institutional care, age at adoption), children's health status and anthropometric measures at T0, T1, T2, and T3. Moreover, the Infant Behavior Questionnaire-Revised Very Short Form and a modified version of parent-report of Child Behavior Checklist were used to assess temperament and to detect behavioral problems. RESULTS: As regards the psychopathological evaluation, behavior problems were more common in older children, especially among girls. In particular they exhibited a higher frequency of internalizing problems versus externalizing. CONCLUSIONS: Children in foster care suffer discontinuity of care that negatively affects their emotional and physical development. It is important for pediatricians to be aware of the special needs of adopted children, providing adequate support to adoptive families.

Vitamin D Supplementation Modulates ICOS+ and ICOS- Regulatory T Cell in Siblings of Children With Type 1 Diabetes.

OBJECTIVES: Vitamin D plays an immunoregulatory activity. The aim of this study was to assess the correlation between blood serum 25(OH)D levels and Th17 and Treg circulating subsets, mainly Treg/inducible costimulatory-positive (ICOS+), which seems to have a protective role in autoimmunity, in children with type 1 diabetes mellitus (T1D) and their healthy siblings (S). The secondary aim was to evaluate the impact of vitamin D supplementation on these subsets. PATIENTS AND METHODS: 22 T1D and 33 S were enrolled. Glucose, hemoglobin A1c, 25 OH vitamin D (25[OH]D), T helper type 17 (Th17; CD4+CCR6+), regulatory T cells (Treg; CD4+CD25+Foxp3+), and Treg/ICOS+ cells were evaluated. According to human leukocyte antigen (HLA) haplotypes, subjects were classified as "at risk" (HLA+), "protective haplotypes" (HLA-; "nested controls"), and "undetermined" (HLAUND). T1D and S subjects were supplemented with cholecalciferol 1000 IU/die and evaluated after 6 months. RESULTS: Vitamin D insufficiency (74.4%) and deficiency (43%) were frequent. S subjects with 25(OH)D levels <25 nmol/L had Th17, Treg (p < 0.01), and Treg/ICOS+ (P < 0.05) percentages higher than subjects with 25(OH)D >75 nmol/L. Treg/ICOS+ percentages (P < 0.05) were higher in HLA- S subjects compared to percentages observed in S with T1D. At baseline, in S subjects, a decreasing trend in Th17 and Treg/ICOS+ values (P < 0.05) from vitamin D deficiency to sufficiency was observed; 25(OH)D levels were negative predictors of Treg/ICOS+ (R2 = 0.301) and Th17 percentages (R2 = 0.138). After 6 months, supplemented S subjects showed higher 25(OH)D levels (P < 0.0001), and lower Th17 (P < 0.0001) and Treg/ICOS+ (P < 0.05) percentages than at baseline; supplemented T1D patients only had a decrease in Th17 levels (P < 0.05). CONCLUSION: Serum 25(OH)D levels seem to affect Th17 and Treg cell subsets in S subjects, consistent with its immunomodulating role. HLA role should be investigated in a larger population.

The levelling-off of the secular trend of age at menarche among Italian girls.

OBJECTIVE: The main aim of this study was to verify whether the secular trend stopped in Italy by comparing the results of a 1990-2000 birth cohort versus a 1980-1990 birth cohort of Italian young women. The results were used to speculate about age at menarche as adaptive response to non-genetic factors. METHODS: In 2016, a study was set on 413, 18-to-26 year-old women (1990-2000 birth cohort) attending two Italian Universities by web-based, self-reported questionnaires. Previously in 2000, a research including 3,783 high school female students (1980-1990 birth cohort) was led. The age at menarche distribution was performed by Kaplan-Meier analysis. The comparison between the findings of the two birth cohorts was performed by Wilcoxon sum-rank test. Mixed models analysis was applied to evaluate the effect of cohort and socio-economic status on age at menarche. RESULTS: 1990-2000 cohort's age at menarche median was 12.44y (95%CI 12.37; 12.59y). There was no significant difference with age at menarche of the previous cohort (p = 0.56). Consistently, the advance of age at menarche in comparison to the mothers' one was not significantly different between the two cohorts (-0.27y±0.10y vs -0.25y±0.03y, p = 0.33). The socio-economic level was not significantly associated with menarcheal age. CONCLUSIONS: The findings of this study confirm that, like in other developed countries, the advance of age at menarche has stopped in Italy, consistently with the stop of the improvement of socio-economic conditions. Further studies are needed to explore the differential effect of each non-genetic factor to outline future scenarios of human sexual maturation. TRIAL REGISTRATION: the Comitato Etico per la Sperimentazione Clinica (CESC) della Provincia di Padova of the Veneto Region (Italy), n°3993/U16/16.

Vitamin D effects and endocrine diseases.

A lack of vitamin D has been linked to autoimmune diseases including type 1 diabetes, autoimmune thyroiditis and to obesity. The prevalence of vitamin D deficiency is higher in diabetic or obese children and patients with thyroiditis compared to healthy controls. Moreover, low vitamin D values seem to be associated with major complications and poor glycemic control, in particular in obese children. Supplementation with vitamin D, which has immune-regulatory properties, may support our therapies and improve the outcomes in different diseases. Although some studies suggest a possible role of vitamin D in the etiology of autoimmune diseases and obesity, data on supplementation benefits are inconclusive and further studies are needed. In this paper, we focus on the current evidence regarding vitamin D function in endocrine diseases and possible benefits of its supplementation in pediatric age.

Vitamin D and Cardiovascular Risk: which Implications in Children?

Vitamin D (25OHD) pleiotropic effects are widely recognized and studied. Recently, vitamin D cardiovascular effects are gaining interest, especially in children, although the studies present conflicting data. Some randomized controlled trials (RCTs) have demonstrated that cardiovascular risk markers, such as lipid parameters, inflammation markers, blood pressure, and arterial stiffness, are unaffected by vitamin D supplementation. By contrast, other studies show that low vitamin D levels are associated with higher risk of cardiovascular disease (CVD) and mortality, and support that increased risk of these diseases occurs primarily in people with vitamin D deficiency. An update on these points in pediatric patients is certainly of interest to focus on possible benefits of its supplementation.

How to Apply European and American Guidelines on High Blood Pressure in Children and Adolescents. A Position Paper Endorsed by the Italian Society of Hypertension and the Italian Society of Pediatrics.

Children are defined as hypertensive when their blood pressure values equal or exceed the 95th percentile of the blood pressure value distribution in a pediatric population, according to gender, age and height. The population on which reference tables are based is of fundamental importance to establish the threshold values for the diagnosis of hypertension in pediatric age. Before 2017, both American and European guidelines used nomograms created in the same reference population which included children of all weight classes. Given the close and well-known association between hypertension and excess weight in childhood, the 2017 American guidelines proposed new reference nomograms excluding subjects with overweight and obesity from the "historical" reference population. Furthermore, the new American guidelines suggested a fixed cut-off of 130/80 mmHg, starting from 13 years and regardless of gender and height, to make the diagnosis of hypertension. In this document, the Italian Hypertension Society (SIIA) and the Italian Pediatric Society (SIP) jointly discuss a number of issues raised by the new American guidelines that involve the entire medical community, and also address the definition of arterial hypertension in the transition phase between childhood and adulthood.

Food security and the nutritional status of children in foster care: new horizons in the protection of a fragile population.

BACKGROUND: The nutritional status of foster children, the quality of daily menus in group homes and the Food Security inside these organizations have been poorly studied and this study means to investigate them. METHODS: A sample of 125 children, ranging in age from 0-17 years, among seven group homes (group A) was compared with 121 children of the general population we (group B). To evaluate nutritional status, BMI percentiles were used. Mean percentiles of both groups were compared through statistical analysis. Both nutritional and caloric daily distributions in each organization were obtained using the 24-hour recall method. A specific questionnaire was administered to evaluate Food Security. RESULTS: From the analysis of mean BMI-for-age (or height-for-length) percentiles, did not observe statistically significant differences between group A and group B. The average daily nutrient and calorie distribution in group homes proves to be nearly optimal with the exception of a slight excess in proteins and a slight deficiency in PUFAs. Moreover, a low intake of iron and calcium was revealed. All organizations obtained a "High Food Security" profile. CONCLUSIONS: Nutritional conditions of foster children are no worse than that of children of the general population. Foster care provides the necessary conditions to support their growth.

Vitamin D and ω-3 Supplementations in Mediterranean Diet During the 1st Year of Overt Type 1 Diabetes: A Cohort Study.

Vitamin D and omega 3 fatty acid (ω-3) co-supplementation potentially improves type 1 diabetes (T1D) by attenuating autoimmunity and counteracting inflammation. This cohort study, preliminary to a randomized control trial (RCT), is aimed at evaluating, in a series of T1D children assuming Mediterranean diet and an intake of cholecalciferol of 1000U/day from T1D onset, if ω-3 co-supplementation preserves the residual endogen insulin secretion (REIS). Therefore, the cohort of 22 "new onsets" of 2017 received ω-3 (eicosapentenoic acid (EPA) plus docosahexaenoic acid (DHA), 60 mg/kg/day), and were compared retrospectively vs. the 37 "previous onsets" without ω-3 supplementation. Glicosilated hemoglobin (HbA1c%), the daily insulin demand (IU/Kg/day) and IDAA1c, a composite index (calculated as IU/Kg/day × 4 + HbA1c%), as surrogates of REIS, were evaluated at recruitment (T0) and 12 months later (T12). In the ω-3 supplemented group, dietary intakes were evaluated at T0 and T12. As an outcome, a decreased insulin demand (p < 0.01), particularly as pre-meal boluses (p < 0.01), and IDAA1c (p < 0.05), were found in the ω-3 supplemented group, while HbA1c% was not significantly different. Diet analysis in the ω-3 supplemented group, at T12 vs. T0, highlighted that the intake of arachidonic acid (AA) decreased (p < 0.01). At T0, the AA intake was inversely correlated with HbA1c% (p < 0.05; r;. 0.411). In conclusion, the results suggest that vitamin D plus ω-3 co-supplementation as well as AA reduction in the Mediterranean diet display benefits for T1D children at onset and deserve further investigation.

Identification of Haptoglobin as a Readout of rhGH Therapy in GH Deficiency.

BACKGROUND: GH deficiency (GHD) is characterized by a cluster of cardiovascular risk factors and subtle inflammation. We aimed to demonstrate, through a proteomic approach, molecules directly modulated by GHD and involved in the inflammatory state. METHODS: Ten children with isolated GHD were studied before and after 1 year of treatment with rhGH and compared with 14 matched controls. A two-dimensional electrophoresis plasma proteomics analysis was performed at baseline and after GH treatment to identify the top molecules modulated by GH. In vitro studies on human hepatoma (HepG2) cells were performed to validate the data. RESULTS: Twelve of 20 proteomic spots were predicted to be isoforms α and ß of haptoglobin (Hp) and confirmed by liquid chromatography tandem mass spectrometry and Western immunoblot analyses. Hp levels were higher in patients with GHD than controls at baseline (P < 0.001) and were reduced following GH treatment (P < 0.01). In HepG2 cells, both GH and IGF-1 were able to downregulate IL-6-induced Hp secretion. Moreover, Hp secretion was restored in pegvisomant-treated HepG2 cells. CONCLUSIONS: Hp is a molecule acting in the inflammatory state of GHD and a possible biomarker for GH treatment. Nevertheless, the contribution of other factors and the molecular pathways involved in the GH downregulation of Hp remain to be clearly defined.

Genistein antagonizes gliadin-induced CFTR malfunction in models of celiac disease.

In celiac disease (CD), an intolerance to dietary gluten/gliadin, antigenic gliadin peptides trigger an HLA-DQ2/DQ8-restricted adaptive Th1 immune response. Epithelial stress, induced by other non-antigenic gliadin peptides, is required for gliadin to become fully immunogenic. We found that cystic-fibrosis-transmembrane-conductance-regulator (CFTR) acts as membrane receptor for gliadin-derived peptide P31-43, as it binds to CFTR and impairs its channel function. P31-43-induced CFTR malfunction generates epithelial stress and intestinal inflammation. Maintaining CFTR in an active open conformation by the CFTR potentiators VX-770 (Ivacaftor) or Vrx-532, prevents P31-43 binding to CFTR and controls gliadin-induced manifestations. Here, we evaluated the possibility that the over-the-counter nutraceutical genistein, known to potentiate CFTR function, would allow to control gliadin-induced alterations. We demonstrated that pre-treatment with genistein prevented P31-43-induced CFTR malfunction and an epithelial stress response in Caco-2 cells. These effects were abrogated when the CFTR gene was knocked out by CRISP/Cas9 technology, indicating that genistein protects intestinal epithelial cells by potentiating CFTR function. Notably, genistein protected gliadin-sensitive mice from intestinal CFTR malfunction and gliadin-induced inflammation as it prevented gliadin-induced IFN-γ production by celiac peripheral-blood-mononuclear-cells (PBMC) cultured ex-vivo in the presence of P31-43-challenged Caco-2 cells. Our results indicate that natural compounds capable to increase CFTR channel gating might be used for the treatment of CD.

Mutation-specific therapies and drug repositioning in cystic fibrosis.

Cystic fibrosis (CF) is an inherited, prematurely lethal rare disease affecting more than 85,000 people worldwide. CF is caused by more than 2000 loss-of-function mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). This review summarizes recent advances in the etiological therapies of CF that aim at repairing the functional defect of CFTR by means of CFTR modulators. We will discuss the state of art of the mutation-specific treatments that are designed to target different steps of the CFTR biogenesis perturbed by mutations in CFTR gene. Moreover, we will discuss how drug repositioning, namely the use of drugs already approved for the treatment of other human diseases, may be repurposed in CF patients to circumvent CFTR dysfunction. Finally, we highlight how the combined use of two or more compounds acting on different disease mechanisms is required to achieve clinical benefit in CF population.

Inhaled medications in cystic fibrosis beyond antibiotics.

Structural lung disease begins very early in children with cystic fibrosis (CF), often in the first three months of life. Inhaled medications represent an attractive therapeutic approach in CF that are routinely used as early intervention strategies. Two aerosolized solutions, hypertonic saline and dornase alfa, have significant potential benefits by improving mucociliary clearance, with minimal associated side-effects. In particular, they favor rehydration of airway surface liquid and cleavage of extracellular DNA in the airways, respectively, consequently reducing rate of pulmonary disease exacerbations. Indirect anti-inflammatory effects have been documented for both drugs, addressing each of the three interrelated elements in the vicious cycle of lung disease in CF: airway obstruction, inflammation and infection. This short review aimed to summarize the main papers that support potential clinical impact of inhaled solutions on pulmonary disease in CF.