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1.  Effects of Growth Hormone (GH) Therapy Withdrawal on Glucose Metabolism in Not Confirmed GH Deficient Adolescents at Final Height 
PLoS ONE  2014;9(1):e87157.
Context, objective
Growth hormone deficiency (GHD) is associated with insulin resistance and diabetes, in particular after treatment in children and adults with pre-existing metabolic risk factors. Our aims were. i) to evaluate the effect on glucose metabolism of rhGH treatment and withdrawal in not confirmed GHD adolescents at the achievement of adult height; ii) to investigate the impact of GH receptor gene genomic deletion of exon 3 (d3GHR).
Design, setting
We performed a longitudinal study (1 year) in a tertiary care center.
23 GHD adolescent were followed in the last year of rhGH treatment (T0), 6 (T6) and 12 (T12) months after rhGH withdrawal with fasting and post-OGTT evaluations. 40 healthy adolescents were used as controls. HOMA-IR, HOMA%β, insulinogenic (INS) and disposition (DI) indexes were calculated. GHR genotypes were determined by multiplex PCR.
In the group as a whole, fasting insulin (p<0.05), HOMA-IR (p<0.05), insulin and glucose levels during OGTT (p<0.01) progressively decreased from T0 to T12 becoming similar to controls. During rhGH, a compensatory insulin secretion with a stable DI was recorded, and, then, HOMAβ and INS decreased at T6 and T12 (p<0.05). By evaluating the GHR genotype, nDel GHD showed a decrease from T0 to T12 in HOMA-IR, HOMAβ, INS (p<0.05) and DI. Del GHD showed a gradual increase in DI (p<0.05) and INS with a stable HOMA-IR and higher HDL-cholesterol (p<0.01).
In not confirmed GHD adolescents the fasting deterioration in glucose homeostasis during rhGH is efficaciously coupled with a compensatory insulin secretion and activity at OGTT. The presence of at least one d3GHR allele is associated with lower glucose levels and higher HOMA-β and DI after rhGH withdrawal. Screening for the d3GHR in the pediatric age may help physicians to follow and phenotype GHD patients also by a metabolic point of view.
PMCID: PMC3907518  PMID: 24498035
2.  Pediatric Obesity and Vitamin D Deficiency: A Proteomic Approach Identifies Multimeric Adiponectin as a Key Link between These Conditions 
PLoS ONE  2014;9(1):e83685.
Key circulating molecules that link vitamin D (VD) to pediatric obesity and its co-morbidities remain unclear. Using a proteomic approach, our objective was to identify key molecules in obese children dichotomized according to 25OH-vitamin D (25OHD) levels. A total of 42 obese children (M/F = 18/24) were divided according to their 25OHD3 levels into 25OHD3 deficient (VDD; n = 18; 25OHD<15 ng/ml) or normal subjects (NVD; n = 24; >30 ng/ml). Plasma proteomic analyses by two dimensional (2D)-electrophoresis were performed at baseline in all subjects. VDD subjects underwent a 12mo treatment with 3000 IU vitamin D3 once a week to confirm the proteomic analyses. The proteomic analyses identified 53 “spots” that differed between VDD and NVD (p<0.05), amongst which adiponectin was identified. Adiponectin was selected for confirmational studies due to its tight association with obesity and diabetes mellitus. Western Immunoblot (WIB) analyses of 2D-gels demonstrated a downregulation of adiponectin in VDD subjects, which was confirmed in the plasma from VDD with respect to NVD subjects (p<0.035) and increased following 12mo vitamin D3 supplementation in VDD subjects (p<0.02). High molecular weight (HMW) adiponectin, a surrogate indicator of insulin sensitivity, was significantly lower in VDD subjects (p<0.02) and improved with vitamin D3 supplementation (p<0.042). A direct effect in vitro of 1α,25-(OH)2D3 on adipocyte adiponectin synthesis was demonstrated, with adiponectin and its multimeric forms upregulated, even at low pharmacological doses (10−9 M) of 1α,25-(OH)2D3. This upregulation was paralleled by the adiponectin interactive protein, DsbA-L, suggesting that the VD regulation of adiponectin involves post-transciptional events. Using a proteomic approach, multimeric adiponectin has been identified as a key plasma protein that links VDD to pediatric obesity.
PMCID: PMC3880269  PMID: 24404137
3.  Vitamin D status in cord blood and newborns: ethnic differences 
A deficiency in vitamin D (25OHD) is common throughout the world in both adults and children, being related to skin pigmentation, sun exposure, dietary intake and obesity. Limited data are available for the neonatal age. The aim of the study is to understand the differences in 25OHD levels with respect to skin colour and ethnicity in newborns.
We randomly enrolled 62 neonates, born at term and appropriate for gestational age. Thirty two were born from Italian mothers with fair skin (FS) and 30 from non-Caucasian mothers (North African, African, Asian and Latin American): 10 with light olive/light brown (LOB) and 20 with medium brown/black skin (MBB). Vitamin D was measured in the cord blood at birth and in neonatal serum during metabolic screening.
25OHD levels were (mean ± SD) 21.4 ± 11 ng/ml in cord blood and 14.9 ± 7 ng/ml in serum after birth. 25OHD values were higher in cord blood (p < 0.01) and neonatal serum (p < 0.001) in subjects supplemented with Vitamin D. Newborn FS showed higher vitamin D levels in cord blood when compared to LOB and MBB (p < 0.01), and higher levels in neonatal serum when compared to LOB (p < 0.01). In cord blood, 25OHD levels were higher in Italian newborns than in North African (p < 0.004) and African (p < 0.01). In neonatal serum, 25OHD levels were higher in Italian infants only when compared with North African infants (p < 0.03).
The present study shows a high prevalence of vitamin D insufficiency and deficiency in newborns with significant differences observed to be due to ethnicity, skin colour and maternal supplementation during the pregnancy.
PMCID: PMC3685533  PMID: 23735116
Vitamin D; Newborn; Ethnicity; Skin colour
4.  Subclinical Hypothyroidism in Children: Natural History and When to Treat 
Subclinical hypothyroidism (SH) is a quite common disorder in the pediatric age group. The aim of this paper is to present a review of the studies investigating the natural course of SH and the effects of replacement therapy with levothyroxine in childhood. We systematically searched PubMed, Cochrane, and EMBASE (1990 to 2012) and identified 14 articles suitable to be included. SH is a benign process that does not influence anthropometric parameters or puberty onset, and in most cases, it is a remitting disease, with a low risk of development of overt hypothyroidism, more frequently evolving toward euthyroidism or steadily remaining in a condition of isolated hyperthyrotropinemia. Studies analyzing the effects of replacement therapy in SH have reported an increased growth velocity in children with short stature or chronic diseases, discordant effects on thyroid volume reduction, and no effects on neurocognitive function. SH in children and adolescent is often a self-remitting process and its treatment should be considered only when thyroid stimulating hormone values are higher than 10 mIU/L, when clinical signs or symptoms of impaired thyroid function or goiter are detected, or when SH is associated with other chronic diseases.
Conflict of interest:None declared.
PMCID: PMC3608012  PMID: 23154159
Subclinical hypothyroidism; children; natural history; treatment
5.  High-end normal adrenocorticotropic hormone and cortisol levels are associated with specific cardiovascular risk factors in pediatric obesity: a cross-sectional study 
BMC Medicine  2013;11:44.
The hypothalamic-pituitary-adrenal (HPA) axis, and in particular cortisol, has been reported to be involved in obesity-associated metabolic disturbances in adults and in selected populations of adolescents. The aim of this study was to investigate the association between morning adrenocorticotropic hormone (ACTH) and cortisol levels and cardiovascular risk factors in overweight or obese Caucasian children and adolescents.
This cross-sectional study of 450 obese children and adolescents (aged 4 to 18 years) was performed in a tertiary referral center. ACTH, cortisol, cardiovascular risk factors (fasting and post-challenge glucose, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, and hypertension) and insulin resistance were evaluated. All analyses were corrected for confounding factors (sex, age, puberty, body mass index), and odds ratios were determined.
ACTH and cortisol levels were positively associated with systolic and diastolic blood pressure, triglycerides, fasting glucose and insulin resistance. Cortisol, but not ACTH, was also positively associated with LDL-cholesterol. When adjusted for confounding factors, an association between ACTH and 2 h post-oral glucose tolerance test glucose was revealed. After stratification according to cardiovascular risk factors and adjustment for possible confounding factors, ACTH levels were significantly higher in subjects with triglycerides ≥90th percentile (P <0.02) and impaired fasting glucose or glucose tolerance (P <0.001). Higher cortisol levels were found in subjects with blood pressure ≥95th percentile and LDL-cholesterol ≥90th percentile. Overall, the highest tertiles of ACTH (>5.92 pmol/l) and cortisol (>383.5 nmol/l) although within the normal range were associated with increases in cardiovascular risk factors in this population.
In obese children and adolescents, high morning ACTH and cortisol levels are associated with cardiovascular risk factors. High ACTH levels are associated with high triglyceride levels and hyperglycemia, while high cortisol is associated with hypertension and high LDL-cholesterol. These specific relationships suggest complex mechanisms through which the HPA axis may contribute to metabolic impairments in obesity, and merit further investigations.
PMCID: PMC3621818  PMID: 23425018
ACTH; cardiovascular risk; cortisol; glucose; hypertension; lipids; obesity; pediatric
6.  Menstrual pattern and menstrual disorders among adolescents: an update of the Italian data 
The most striking event in the whole process of female puberty is the onset of menstruation. To our knowledge, no large population-based studies have been performed on the topic of menstrual health among Italian adolescents in recent years.
The aims of this study were to produce up-to-date information on the menstrual pattern of Italian girls attending secondary school, and to estimate the prevalence of menstrual cycle abnormalities in this population.
This was a cross-sectional study on a population-based sample of Italian adolescents aged 13–21 years attending secondary school. Only girls who had already started menstruating were requested to participate. Information was collected by means of a questionnaire that included items on the girls’ demographic details, anthropometrics, smoking and drinking habits, use of contraceptive pills, and socioeconomic status. The questions on the girls’ menstrual pattern concerned their age at menarche, duration of the most recent menstruation intervals (<21, 21–35, >35 days, variable), average days of bleeding (<4, 4–6, >6 days), and any menstrual problems and their frequency.
A total of 6,924 questionnaires were administered and 4,992 (71%) were returned. One hundred girls failed to report their date of birth, so 4,892 subjects were analyzed. The girls’ mean age was 17.1 years (SD ±1.4); their mean age at menarche was 12.4 (±1.3) years, median 12.4 years (95%CI 12.3–12.5).
In our sample population, 3.0% (95%CI 2.5%-3.4%) of the girls had menstruation intervals of less than 21 days, while it was more than 35 days in 3.4% (95%CI 2.9%-3.9%). About 9% of the girls (95%CI 7.7%-9.4%) said the length of their menstruation interval was currently irregular. Short bleeding periods (<4 days) were reported in 3.2% of the sample population (95%CI 2.7%-3.7%), long periods (>6 days) in 19% (95%CI 17.9%-20.1%). Menstruation-related abdominal pain was reported by about 56% of our sample. About 6.2% of the girls (95%CI 5.4%-7.0%) were suffering from dysmenorrhea.
In conclusion, to the best of our knowledge, this is one of the largest studies on menstrual patterns and menstrual disorders among Italian adolescent girls. Adolescent girls referring persistent oligomenorrhoea, in first two years from menarche, had a higher risk for developing a persistent menstrual irregularity. They had longer bleeding periods (>6 days) and this has practical implications because it makes these adolescents potentially more susceptible to iron deficiency anemia. Clinicians need to identify menstrual abnormalities as early as possible in order to minimize their possible consequences and sequelae, and to promote proper health information.
We recommend that adolescents should be encouraged to chart their menstrual frequency and regularity prospectively from the menarche onwards.
PMCID: PMC3462713  PMID: 22892329
Menstrual pattern; Menstrual disorders; Menstrual cycle length; Bleeding length; Polymenorrhea; Oligomenorrhea; Dysmenorrhea; Adolescents
7.  Booster vaccination of pre-school children with reduced-antigen-content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine co-administered with measles-mumps-rubella-varicella vaccine 
Background: Pertussis occurs in older children, adolescents and adults due to waning immunity after primary vaccination. Booster vaccination for pre-school children has been recommended in Italy since 1999. In this study (NCT00871000), the immunogenicity, safety and reactogenicity of a booster dose of reduced-antigen content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (dTpa-IPV; GSK Biologicals Boostrix™-Polio; 3-component pertussis) vs. full-strength DTPa-IPV vaccine (sanofi-pasteur—MSD Tetravac™; 2-component pertussis) was evaluated in pre-school Italian children.
Methods: Healthy children aged 5–6 y primed in a routine vaccination setting with three doses of DTPa-based vaccines were enrolled and randomized (1:1) in this phase IIIb, booster study to receive a single dose of dTpa-IPV or DTPa-IPV; the MMRV vaccine was co-administered. Antibody concentrations/titers against diphtheria, tetanus, pertussis and poliovirus 1–3 were measured before and one month post-booster. Reactogenicity and safety was assessed.
Results: 305 subjects were enrolled of whom 303 (dTpa-IPV = 151; DTPa-IPV = 152) received booster vaccination. One month post-booster, all subjects were seroprotected/seropositive for anti-diphtheria, anti-tetanus, anti-PT, anti-FHA and anti-poliovirus 1–3; 99.3% of dTpa-IPV and 60.4% of DTPa-IPV subjects were seropositive for anti-PRN; 98–100% of subjects were seropositive against MMRV antigens post-booster. Pain at the injection site (dTpa-IPV: 63.6%; DTPa-IPV: 63.2%) and fatigue (dTpa-IPV: 26.5%; DTPa-IPV: 23.7%) were the most commonly reported solicited local and general symptoms, during the 4-d follow-up period. No SAEs or fatalities were reported.
Conclusions: The reduced-antigen-content dTpa-IPV vaccine was non-inferior to full-strength DTPa-IPV vaccine with respect to immunogenicity. The vaccine was well-tolerated and can be confidently used as a booster dose in pre-school children.
PMCID: PMC3426082  PMID: 22327497
pre-school; MMRV; diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine; Italy; 2 + 1 schedule
8.  Effect of Arginine Infusion on Ghrelin Secretion in Growth Hormone Sufficient and GH Deficient Children 
The physiological link between ghrelin and growth hormone (GH) has not yet been fully clarified. Furthermore, the existence of a negative feedback mechanism between growth hormone–insulin-like growth factor (GH–IGF)-I axis and ghrelin and the influence of amino acids on ghrelin secretion in children remain matters of debate.
To understand the regulation of ghrelin secretion and clarify the relationship between ghrelin and GH secretion in GH-deficient (GHD) and GH-sufficient (GHS) children.
Patients and Methods
Ten GHD (male/female [M/F], 6/4; age [mean ± SEM], 10.7 ± 0.9 years) and 10 GHS prepubertal children (M/F, 6/4; age [mean ± SEM], 10.3 ± 0.6 years), underwent an arginine (ARG) test (infusion, 0.5 g/kg, iv). Levels of GH, total ghrelin, and acylated ghrelin (AG) were assayed every 30 min from 0 to +120 min.
Peak GH values were lower in GHD subjects than in GHS subjects (P < 0.0001). The baseline levels, peak levels, or area under the curves (AUC) for total ghrelin and AG were similar between GHD and GHS children. ARG infusion was followed by a slight to significant decrease in total ghrelin levels, but not AG levels, both in GHD and GHS subjects with a nadir at +30 min. No correlation was seen between GH, total ghrelin, or AG response and ARG infusion.
Total ghrelin and AG levels seemed unaffected by GH status in prepubertal children. ARG infusion was unable to blunt ghrelin secretion irrespective of GH status in childhood. Moreover, since ARG influences GH secretion via modulation of somatostatin release, ghrelin secretion seems to be partially refractory to somatostatin action.
PMCID: PMC3693617  PMID: 23843806
Acylated Ghrelin; Growth Hormone; Growth Hormone Deficiency
9.  Randomized Trial on the Safety, Tolerability, and Immunogenicity of MenACWY-CRM, an Investigational Quadrivalent Meningococcal Glycoconjugate Vaccine, Administered Concomitantly with a Combined Tetanus, Reduced Diphtheria, and Acellular Pertussis Vaccine in Adolescents and Young Adults▿ †  
This study evaluated the safety, tolerability, and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, when administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis (Tdap) vaccine, in subjects aged 11 to 25 years. Subjects received either MenACWY-CRM and Tdap, MenACWY-CRM and saline placebo, or Tdap and saline placebo. No significant increase in reactogenicity and no clinically significant vaccine-related adverse events (AEs) occurred when MenACWY-CRM and Tdap were administered concomitantly. Similar immunogenic responses to diphtheria, tetanus, and meningococcal (serogroups A, C, W-135, and Y) antigens were observed, regardless of concomitant vaccine administration. Antipertussis antibody responses were comparable between vaccine groups for filamentous hemagglutinin and were slightly lower, although not clinically significantly, for pertussis toxoid and pertactin when the two vaccines were administered concomitantly. These results indicate that the investigational MenACWY-CRM vaccine is well tolerated and immunogenic and that it can be coadministered with Tdap to adolescents and young adults.
PMCID: PMC2849330  PMID: 20164251
10.  Safety and Immunogenicity of a 13-Valent Pneumococcal Conjugate Vaccine Compared to Those of a 7-Valent Pneumococcal Conjugate Vaccine Given as a Three-Dose Series with Routine Vaccines in Healthy Infants and Toddlers ▿ †  
A 13-valent pneumococcal conjugate vaccine (PCV13) has been developed to improve protection against pneumococcal disease beyond that possible with the licensed 7-valent vaccine (PCV7). This study compared the safety and immunogenicity of PCV13 with those of PCV7 when given as part of the pediatric vaccination schedule recommended in Italy. A total of 606 subjects were randomly assigned to receive either PCV13 or PCV7 at 3, 5, and 11 months of age; all subjects concomitantly received diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type B (DTaP-HBV-IPV/Hib) vaccine. Vaccine reactions were monitored. Antibody responses to DTaP-HBV-IPV/Hib antigens, serotype-specific anticapsular polysaccharide IgG responses, and antipneumococcal opsonophagocytic assay (OPA) activity were measured 1 month after the two-dose primary series and 1 month after the toddler dose. Overall, the safety profile of PCV13 was similar to that of PCV7. The response to DTaP-HBV-IPV/Hib antigens was substantially the same with both PCV13 and PCV7. PCV13 elicited antipneumococcal capsular IgG antibodies to all 13 vaccine serotypes, with notable increases in concentrations seen after the toddler dose. Despite a lower immunogenicity for serotypes 6B and 23F after the primary series of PCV13, responses to the seven common serotypes were comparable between the PCV13 and PCV7 groups when measured after the toddler dose. PCV13 also elicited substantial levels of OPA activity against all 13 serotypes following both the infant series and the toddler dose. In conclusion, PCV13 appeared comparable to PCV7 in safety profile and immunogenicity for common serotypes, demonstrated functional OPA responses for all 13 serotypes, and did not interfere with immune responses to concomitantly administered DTaP-HBV-IPV/Hib vaccine.
PMCID: PMC2884425  PMID: 20427630
11.  Access to paediatric emergency departments in Italy: a comparison between immigrant and Italian patients 
The aim of the study was to investigate whether access to paediatric emergency departments differed between foreign and Italian patients.
We performed a cross-sectional study between January-December 2007 to analyse attendance's characteristics in the paediatric emergency departments of ten Italian public hospitals. The study population included each foreign patient and the following Italian patient admitted to the same emergency department. All causes of admission of these subjects were evaluated, together with the child's age, gender, country of birth, parents' nationality, time of admission, severity code and discharge-related circumstances.
We enrolled 4874 patients, 2437 foreign (M:F = 1409:1028) and 2437 Italian ones (M:F = 1368:1069). Most of foreign and Italian patients' admissions were sorted as green (72.5% and 87.8%, respectively) or white codes (25.2% and 9.8%, respectively). The most frequent causes for attendance concerned respiratory tract diseases, followed by gastroenteric ones and injuries in both groups.
In our survey immigrants didn't access to emergency departments more than Italian children. Both of them referred to emergency departments mainly for semi-urgent or non-urgent problems. Foreign and Italian patients suffered from the same pathologies. Infectious diseases traditionally thought to be a potential problem in immigrant populations actually seem to be quite infrequent.
PMCID: PMC2687543  PMID: 19490660
12.  The impact of national and international guidelines on newborn care in the nurseries of Piedmont and Aosta Valley, Italy 
BMC Pediatrics  2005;5:45.
Care procedures for preventing neonatal diseases are carried out according to nurseries' traditions and may be not consistent with the evidence based medicine issues.
A multi-centric survey was conducted in 2 Regions located in NW Italy (Piedmont and Aosta Valley) in order to collect information on some healthy newborn care procedures. During 2001, a questionnaire was sent to the chief pediatrician in charge to the all 33 nurseries of the region asking the methods used during 2000 as prevention of ophthalmia neonatorum, early and late hemorrhagic disease of newborn, umbilical cord care and recommendations of vitamin D administration. Thereafter, during 2004 the same questionnaire was sent to the 34 chief pediatrician of nurseries to evaluate if the procedures were changed during 2003 according to guidelines. The nurseries care for 32,516 newborns in 2000 and 37,414 in 2003.
Aminoglycoside eyes drops as prevention of ophthalmia neonatorum were the first choice in both periods (23 out 33 nurseries in 2000 and 24 out 34 in 2003 p > 0.05; the corresponding figures for newborns were18,984 out 32,516 newborns vs. 28,180 out of 37,414 p < 0.05). The umbilical cord care was carried out with alcohol in 12/33 centers (13,248 newborns) and dry gauze in 3/33 centers (2,130 newborns) in 2000, the corresponding figures in 2003 were 6/34 centers (p > 0.05), (6,380 newborns, p < 0.05) and 12/34 centers (p < 0.05), (18,123 newborns, p < 0.05). The percentage of newborns receiving of i.m. vitamin K. at birth increased during the study period (15,923/32,104 in 2000 vs. 19,684/37,414 in 2003, p < 0.01), but not the number of nurseries (16 in 2000 and 17 in 2003 p > 0.05). The numbers of parents of newborns who receive the recommendations of oral vitamin K during the first months life decreased from 2000 (25,516/30,606) to 2003 (29,808/37,414, p < 0.01) as well as for Vitamin D recommendation (14,582/30,616 in 2000 vs. 11,051/37,414 in 2003, p < 0.01). Oral vitamin K during the first months of life was recommended by 25 nurseries in 2000 and 27 in 2003 (p > 0.05), the corresponding figures for Vitamin D were 15 and 14 (p > 0.05).
In the present study a large variability of procedures among the nurseries was observed. During the study periods, guidelines and evidence based medicine issues have only partially modified the neonatal care procedures In Piedmont and Aosta Valley nurseries. These observations suggest to implement local forum/consensus conference to standardized procedures as much as possible.
PMCID: PMC1315318  PMID: 16329760

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