Cytological, molecular, cytogenetic, and physiological characterization of a novel immortalized human enteric glial cell line.

Enteric glial cells (EGCs), the major components of the enteric nervous system (ENS), are implicated in the maintenance of gut homeostasis, thereby leading to severe pathological conditions when impaired. However, due to technical difficulties associated with EGCs isolation and cell culture maintenance that results in a lack of valuable in vitro models, their roles in physiological and pathological contexts have been poorly investigated so far. To this aim, we developed for the first time, a human immortalized EGC line (referred as ClK clone) through a validated lentiviral transgene protocol. As a result, ClK phenotypic glial features were confirmed by morphological and molecular evaluations, also providing the consensus karyotype and finely mapping the chromosomal rearrangements as well as HLA-related genotypes. Lastly, we investigated the ATP- and acetylcholine, serotonin and glutamate neurotransmitters mediated intracellular Ca2+ signaling activation and the response of EGCs markers (GFAP, SOX10, S100ß, PLP1, and CCL2) upon inflammatory stimuli, further confirming the glial nature of the analyzed cells. Overall, this contribution provided a novel potential in vitro tool to finely characterize the EGCs behavior under physiological and pathological conditions in humans.

Isolated childhood growth hormone deficiency: a 30-year experience on final height and a new prediction model.

PURPOSE: We aimed to evaluate the near-final height (nFHt) in a large cohort of pediatricpatients with growth hormone deficiency (GHD) and to elaborate a new predictive method of nFHt. METHODS: We recruited GHD patients diagnosed between 1987 and 2014 and followed-up until nFHt. To predict the values of nFHt, each predictor was run in a univariable spline. RESULTS: We enrolled 1051 patients. Pre-treatment height was -2.43 SDS, lower than parental height (THt) (-1.09 SDS, p < 0.001). The dose of recombinant human GH (rhGH) was 0.21mg/kg/week at start of treatment. nFHt was -1.08 SDS (height gain 1.27 SDS), higher than pre-treatment height (p < 0.001) and comparable to THt. 1.6% of the patients were shorter than -2 SDS from THt. The rhGH dose at nFHt was 0.19 mg/kg/week, lower than at the start (p < 0.001). The polynomial regression showed that nFHt was affected by gender, THt, age at puberty, height at puberty, age at the end of treatment (F = 325.37, p < 0.0001, R2 87.2%). CONCLUSION: This large national study shows that GHD children can reach their THt. The rhGH/kg/day dose significantly decreased from the start to the end of the treatment. Our model suggests the importance of a timely diagnosis, possibly before puberty, the beneficial effect of long-term treatment with rhGH, and the key-role of THt. Our prediction model has a very acceptable error compared to the majority of other published studies.

Incidental pineal gland cyst in girls with early onset of puberty.

BACKGROUND: The causes of an early onset of puberty are still not clearly defined and may vary from subject to subject. In girls, even if 90% of early puberty is idiopathic, magnetic resonance imaging (MRI) of the brain is performed to exclude secondary causes of precocious puberty, in particular pathological lesions as hypothalamic tumours (hamartoma). In some cases, other intracranial lesions are considered as incidental findings. Aim of the study is evaluating the prevalence of abnormal intracranial lesions detected by brain magnetic resonance imaging MRI with particular focus on the prevalence of pineal gland cysts in the diagnostic work-up of girls with central precocious puberty (CPP) as onset before 8 years and central early puberty (CEP) as onset before 10 years. MATERIAL AND METHODS: MRI data of girls referred from January 2010 to December 2015 to the Pediatric Endocrinology Unit of University of Pavia for early onset of breast development were collected. RESULTS: We collected 123 MRI data of girls referred to the Pediatric Endocrinology Unit of University of Pavia for early onset of breast development in the study period. Out of them, 25 (20.3%) had cerebral abnormalities and 15 (12.2%) had pineal gland cysts. No significant differences were noted in auxological, ultrasound and hormonal parameters at diagnosis among girls with or without pineal cysts. Patients have been observed for at least three years after the discontinuation of therapy. None of our patients had an unfavorable evolution. CONCLUSIONS: Although pineal cysts seem to be not involved in the onset of puberty, the relevance of the finding remains controversial. Our study wants to provide further insight into the incidence of pineal cysts in pubertal advances. Of note, pineal cysts are often asymptomatic and do not evolve over time.

Current clinical management of constitutional delay of growth and puberty.

BACKGROUND: Constitutional delay of growth and puberty (CDGP) is classified as the most frequent cause of delayed puberty (DP). Finding out the etiology of DP during first evaluation may be a challenge. In details, pediatricians often cannot differentiate CDGP from permanent hypogonadotropic hypogonadism (PHH), with definitive diagnosis of PHH awaiting lack of puberty by age 18 yr. Neverthless, the ability in providing a precise and tempestive diagnosis has important clinical consequences. MAIN TEXT: A growth failure in adolescents with CDGP may occur until the onset of puberty; after that the growth rate increases with rapidity. Bone age is typically delayed. CDGP is generally a diagnosis of exclusion. Nevertheless, other causes of DP must be evaluated. A family history including timing of puberty in the mother and in the father as well as physical examination may givee information on the cause of DP. Patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions, such as celiac disease, inflammatory bowel diseases, kidney insufficiency and anorexia nervosa, may experience a functional hypogonadotropic hypogonadism. PHH revealing testosterone or estradiol low serum values and reduced FSH and LH levels may be connected to abnormalities in the central nervous system. So, magnetic resonance imaging is required in order to exclude either morphological alterations or neoplasia. If the adolescent with CDGP meets psychological difficulties, treatment is recommended. CONCLUSION: Even if CDGP is considered a variant of normal growth rather than a disease, short stature and retarded sexual development may led to psychological problems, sometimes associated to a poor academic performance. A prompt and precise diagnosis has an important clinical outcome. Aim of this mini-review is throwing light on management of patients with CDGP, emphasizing the adolescent diagnosis and trying to answer all questions from paediatricians.

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.

Effectiveness of basal LH in monitoring central precocious puberty treatment in girls.

OBJECTIVES: Treatment of central precocious puberty (CPP) is based on administration of GnRH agonists in order to suppress hypothalamic-pituitary-gonadal axis and thus induce the stabilization or regression of pubertal development. Our aim was to determine whether the single basal serum LH and/or FSH concentration could be an effective tool to assess the efficacy of treatment to suppress activation of hypothalamic-pituitary axis. PATIENTS AND METHODS: Serum LH and FSH were measured before and after the GnRH injection, as well as E2 basal levels in 60 girls with documented idiopathic CPP at diagnosis and 18 and 30 months after the beginning of therapy. RESULTS: At diagnosis, peaks of >5 IU/L of LH and of FSH were observed in 100 and 91.6% of girls, respectively, with basal LH values of <1 IU/L in 70% and basal FSH levels of <1 IU/L in 10%. E2 were <20 pg/mL in 36.6%. After 18 months, a suppressed peak (i.e. <3 IU/L) was recorded in 85% of girls (p<0.01) for LH and in 98.3% for FSH (p<0.01). Basal LH <1 IU/L was detected in 85% (p<0.01) and basal FSH ≤1 IU/L in 40% (p<0.01). Serum E2 ≤20 pg/mL was recorded in 61.6% (p<0.01). After 30 months, all patients showed LH suppressed peak (p<0.01) and 98.3% suppressed FSH peak (p<0.01). 100% showed basal LH concentrations <1 IU/L (p<0.01) and 38.3% FSH basal values <1 UI/mL (p<0.01). E2 ≤20 pg/mL was observed in 32.72% (p=NS). CONCLUSIONS: Basal LH values are a reliable indicator of the efficacy of GnRHa therapy after 30 months of GnRHa therapy.

Hospitalization for acute cerebellitis in children affected by varicella: how much does it cost?

BACKGROUND: Chickenpox is a highly contagious airborne disease caused by the varicella zoster virus. It is generally benign and self-limiting, but it may be responsible of life-threatening complications. Acute cerebellitis (AC) is the most common neurological complication and is associated with prolonged hospitalization in the acute phase (HAP). AIM OF THE STUDY: To estimate the costs of AC HAP in children affected by varicella. MATERIALS AND METHODS: We retrospectively reviewed the medical records of a pediatric cohort hospitalized for chickenpox AC over a period of 15 years (from October 2003 to October 2018) and we analyzed acute care costs. For any patient the HAP has been calculated. The final value includes cost of hospital accommodation and management at the Pediatric and Infectious Diseases Unit. To this cost, the price of procedures (imaging, laboratory exams, medical and paramedical evaluations) and medical treatments was added. RESULTS: In the study period, 856 children had been hospitalized for varicella. Out of them, 65 met a diagnosis of AC and were included in the study. The hospitalization length was of 10 days (range 3-20 days). The median cost of HAP for each patient was of 5366 euro, with an average annual cost of 23,252 €. The most significant part of HAP is due to the cost of hospital accommodation and management at the Pediatric Infectious Diseases Unit, which was about € 537.78 for a single day. DISCUSSION: Although AC post-varicella is rare, its HAP cost is not negligible resulting in substantial economic burden. Vaccination would have probably prevented varicella and AC complication, avoiding hospitalization. CONCLUSIONS: Financial studies are important for evaluate the cost saving in order to influence public funding decisions. Further studies are necessary to investigate the economic burden of the disease.

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.

Identification of novel genetic variants associated with short stature in a Baka Pygmies population.

Human growth is a complex trait determined by genetic factors in combination with external stimuli, including environment, nutrition and hormonal status. In the past, several genome-wide association studies (GWAS) have collectively identified hundreds of genetic variants having a putative effect on determining adult height in different worldwide populations. Theoretically, a valuable approach to better understand the mechanisms of complex traits as adult height is to study a population exhibiting extreme stature phenotypes, such as African Baka Pygmies. After phenotypic characterization, we sequenced the whole exomes of a cohort of Baka Pygmies and their non-Pygmies Bantu neighbors to highlight genetic variants associated with the reduced stature. Whole exome data analysis revealed 29 single nucleotide polymorphisms (SNPs) significantly associated with the reduced height in the Baka group. Among these variants, we focused on SNP rs7629425, located in the 5'-UTR of the Hyaluronidase-2 (HYAL2) gene. The frequency of the alternative allele was significantly increased compared to African and non-African populations. In vitro luciferase assay showed significant differences in transcription modulation by rs7629425 C/T alleles. In conclusion, our results suggested that the HYAL2 gene variants may play a role in the etiology of short stature in Baka Pygmies population.

MKRN3 and KISS1R mutations in precocious and early puberty.

BACKGROUND: Pubertal timing is known to be influenced by interactions among various genetic, nutritional, environmental and socio-economic factors, although the ultimate mechanisms underlying the increase in pulsatile GnRH secretion at puberty have yet to be fully elucidated. The aim of our research was to verify the role of KISSR1 (previously named GPR54) and MKRN3 genes on pubertal timing. METHODS: We analyzed the DNA sequence of these genes in 13 girls affected by central precocious puberty (CPP) who showed onset of puberty before 8 years of age, and in 6 girls affected by early puberty (EP) between 8 and 10 years of age. RESULTS: Direct sequencing of the KISS1R (GPR54) gene revealed two SNPs. One SNP is a missense variant (rs 350,132) that has been previously reported in connection to CPP in Korean girls. The other variant that we found in the GPR54 gene (rs764046557) was a missense SNP located in exon 5 at position 209 of the aminoacid. We identified this variant in only one CPP patient. Automatic sequencing of MKRN3 in all patients revealed three variants in eight subjects. In 6 out of 19 (31.5%) patients (3/13 CPP patients and 3/6 EP patients) we found the synonymous variant c.663C > T (rs2239669). Another synonymous variant (rs140467331) was found in one of our CPP patients, as well as one missense variant (rs760981395) in another CPP patient. CONCLUSION: In conclusion, we identified sequence variations of the KISS1R and MKRN3 genes, two of the most frequent genetic causes of ICPP. Our results suggest that these variants might be inducible factors in the pathogenesis of CPP.

Anxiety disorders in acute central nervous system infections.

BACKGROUND: Patients affected by acute central nervous system (ACNS) infectionsmay present different complications, including neuropsychological disorders. Nevertheless, psychopathological impairment has been rarely measured by appropriate and validated tests. MATERIAL AND METHODS: Survivors of childhood ACNS infections admitted to the Bambino Gesù Children's Hospital, Rome, Italy, from June 2013 to June 2015 were re-evaluated at follow-up from June 2016 to June 2017. Both patients and their parents underwent a psychological interview and neuropsychological tests (the Leiter International Performance Scale - revised (Leiter-R), the Child Behaviour Checklist (CBCL), the K-SADS-PL test). RESULTS: Thirty children were included in the study. The mean score of IQ and fluid reasoning was within the normal range. A percentage of 20% of the children enrolled showed criteria for generalized anxiety disorder. CONCLUSION: Our study revealed the importance of follow-up evaluations after ACNS infections, in order to prevent mayor psychological sequelae and to perform treatment or rehabilitation.

Media use during adolescence: the recommendations of the Italian Pediatric Society.

BACKGROUND: The use of media device, such as smartphone and tablet, is currently increasing, especially among the youngest. Adolescents spend more and more time with their smartphones consulting social media, mainly Facebook, Instagram and Twitter because. Adolescents often feel the necessity to use a media device as a means to construct a social identity and express themselves. For some children, smartphone ownership starts even sooner as young as 7 yrs, according to internet safety experts. MATERIAL AND METHODS: We analyzed the evidence on media use and its consequences in adolescence. RESULTS: In literature, smartphones and tablets use may negatively influences the psychophysical development of the adolescent, such as learning, sleep and sigh. Moreover, obesity, distraction, addiction, cyberbullism and Hikikomori phenomena are described in adolescents who use media device too frequently. The Italian Pediatric Society provide action-oriented recommendations for families and clinicians to avoid negative outcomes. CONCLUSIONS: Both parents and clinicians should be aware of the widespread phenomenon of media device use among adolescents and try to avoid psychophysical consequences on the youngest.

GH-IGF-1 Axis in Children with Cystic Fibrosis.

OBJECTIVE: To verify whether growth hormone receptor (GHR) gene expression plays a role in growth of children with cystic fibrosis (CF), as a consequence of the chronic inflammatory condition and malnutrition. DESIGN: We enrolled 49 prepubertal patients (24 males and 25 females) affected by CF in a stable clinical condition, 19 of whom had been diagnosed through newborn screening and 30 following presentation of symptoms. Patients had no significant comorbidity affecting growth or cystic fibrosis transmembrane conductance regulator (CFTR)-related diabetes requiring insulin therapy. Blood was collected during two follow-up visits to measure insulin-like growth factor (IGF-I), growth hormone-binding protein (GHBP), and GHR gene expression. Recruited as a control group were 52 healthy children, sex- and age-matched, were recruited as a control group. METHODS: We compared body mass index (BMI), height, weight, IGF-I, GHBP, and GHR gene expression values (evaluated by Chemiluminescent Immunometric assay; ELISA and real-time PCR, respectively) in CF patients diagnosed through newborn screening (NBS) or by symptoms (late diagnosis [LD]) and in healthy controls. RESULTS: BMI increased significantly in patients between the time of diagnosis and check-up (P<0.001), particularly in the LD group; median value was lower at diagnosis and significantly higher (P<0.001) at follow-up visits compared to controls. At initial evaluation, higher levels of IGF-I (not statistically significant) were found in both the NBS group and the LD group compared to the control group. At the second evaluation, significantly higher levels of IGF-I (P=0.003) were found in both the NBS and LD groups compared to controls; GHR mRNA expression had significantly increased (P=0.013) in LD patients compared with the first evaluation and was significantly higher in the NBS and LD groups than in controls. GHBP values had significantly increased (P=0.047) in the NBS group after one year of therapy compared to first visit levels and were significantly higher (P<0,0001) in the NBS and LD groups compared to controls. CONCLUSION: In our LD patients during childhood, we observed good auxological values and a GH/IGF-I axis function within normal range for the factor evaluated. However, earlier diagnosis through NBS might further minimize and prevent growth retardation, by reducing the duration of symptoms before treatment.

Trehalose Modulates Autophagy Process to Counteract Gliadin Cytotoxicity in an In Vitro Celiac Disease Model.

Celiac disease (CD) is a chronic systemic autoimmune disorder that is triggered by the ingestion of gliadin peptides, the alcohol-soluble fraction of wheat gluten. These peptides, which play a key role in the immune response that underlies CD, spontaneously form aggregates and exert a direct toxic action on cells due to the increase in the reactive oxygen species (ROS) levels. Furthermore, peptic-tryptic digested gliadin peptides (PT-gliadin) lead to an impairment in the autophagy pathway in an in vitro model based on Caco-2 cells. Considering these premises, in this study we have analyzed different mTOR-independent inducers, reporting that the disaccharide trehalose, a mTOR-independent autophagy activator, rescued the autophagy flux in Caco-2 cells treated with digested gliadin, as well as improved cell viability. Moreover, trehalose administration to Caco-2 cells in presence of digested gliadin reduced the intracellular levels of these toxic peptides. Altogether, these results showed the beneficial effects of trehalose in a CD in vitro model as well as underlining autophagy as a molecular pathway whose modulation might be promising in counteracting PT-gliadin cytotoxicity.

Normal Growth despite Combined Pituitary Hormone Deficiency.

BACKGROUND: The paradox of normal growth despite a lack of growth hormone (GH) is an unexplained phenomenon described in some pathological (sellar, suprasellar, and hypothalamic disorders) and overgrowth syndromes. It has been suggested that the paradoxical growth is due to other GH variants, GH-like moieties, prolactin, insulin, insulin-like growth factors (IGFs), and unidentified serum factors or growth mechanisms. The objective of this study was to determine the mechanism underlying this normal growth without GH. CASE DESCRIPTION: We describe here growth, hormonal, and genetic analyses for an adolescent boy with panhypopituitarism who achieved an adult height above his genetic potential. RESULTS: Normal growth was observed despite low serum GH, IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) concentrations, but the IGF-II/IGFBP-3 molar ratio was slightly high. Panhypopituitarism was associated with a heterozygous missense mutation of HESX1, with variable penetrance in heterozygous relatives. Exome analysis detected heterozygous missense mutations of various genes involved in intracellular signaling pathways. The growth-promoting activity of the patient's serum was unable to induce AKT phosphorylation in the MCF-7 cell line. CONCLUSION: The high IGF-II/IGFBP-3 molar ratio was not the cause of the sustained high growth velocity, due to the low affinity of IGF-II for IGF type 1 receptor. The key finding was the HESX1 mutation, as similar cases have been described before, suggesting a common mechanism for growth without GH. However, the variable penetrance of this variant in heterozygous relatives suggests that modifier genes or mechanisms involving combinations with mutations of other genes involved in intracellular signaling pathways might be responsible.

Pediatric meningococcocal meningitis in the acute phase: how much does it cost?

BACKGROUND: Meningococcal meningitis (MM) is known to be responsible of high cost for the Public Health Administration. Aim of the work is to calculate the costs for the hospitalization of pediatric patients affected by MM. METHODS: We calculate the costs for the hospitalization of pediatric patients affected by MM in the acute phase (HAP) over a nine year period. We performed a MEDLINE search to verify the cost of MM HAP reported in other studies. RESULTS: At Bambino Gesù Children Hospital, the median cost of HAP was of 12,604 euro (range from 9203 to 35,050 euro). Comparing our data with the previous studies, we find out similar results of approximately 16,750 euro (range 12,000-20,000 euro). DISCUSSION: Despite the relative rarety of the disease, MM is associated to direct high cost of HAP. CONCLUSIONS: Hospital costs are an important end-point in health economic evaluation of the disease and may be useful to policy makers and health economists to understand the potential benefit of improving meningococcal vaccination programmes.

Menstrual Cycle and Headache in Teenagers.

OBJECTIVE: This population-based study on school-aged girls aimed to estimate the rate of peri-menstrual headache, evaluate headache pain pattern during the menstrual cycle, and verify its relationships with physical, psychosocial and life-style factors. METHODS: The students (n = 4973) fulfilled a self-administered questionnaire on demographic and behavioral characteristics, menarche, menstrual pattern and features including headache and dysmenorrhea. The prevalence of headache and the mean pain intensity score at the three menstrual cycle phases (premenstrual, menstrual, in-between period) were estimated, both overall and by gynecological year. Furthermore, the prevalence of three different patterns of headache (peri menstrual/mid-cycle/acyclic) was evaluated, together with the mean pain intensity score. RESULTS: The overall prevalence of headache at least once at any time during the menstrual cycle was 64.4%. At multivariable logistic analysis, gynecological age (OR 1.07; 95%CI 1.03-1.12), middle social level (1.24; 1.01-1.55, compared to high social level), physical activity (0.67; 0.51-0.89), oral contraceptive use (1.34; 1.04-1.73) and dysmenorrhea (2.30; 1.54-3.42) were significantly associated with headache. Among girls with headache, 83.4% had peri-menstrual headache (44.6% premenstrual, 38.8% menstrual), 3.5% mid-cycle headache and 13.2% acyclic headache. The gynaecological age and dysmenorrhea were significantly associated with the headache pattern (p = 0.03 and p < 0.0001, respectively). CONCLUSIONS: This study suggests that peri-menstrual headache is highly prevalent among adolescents. In girls, the headache rate linearly raises with higher gynecological age; menses-related painful syndromes, such as headache and dysmenorrhea, are strongly interrelated. The anamnesis and monitoring of menstrual health should be mandatory when taking care of girls with headache.

Age at Menarche and Menstrual Abnormalities in Adolescence: Does it Matter? The Evidence from a Large Survey among Italian Secondary Schoolgirls.

OBJECTIVE: To explore the independent role of age at menarche on menstrual abnormalities among adolescents. METHODS: The present study was a multicenter cross-sectional study on a large sample (n = 3782) of Italian girls aged 13-21 y attending secondary school who already had menarche. Girls were asked to fill in a questionnaire on menarcheal age and menstrual features during the latest three menses. The gynecological age was computed as the difference between age at the survey and the age at menarche. Main outcome measures were: prevalence of oligomenorrhea, polymenorrhea, menstrual cycle irregularity, abnormal bleeding length and dysmenorrhea. Irregularity in the recent past and since menarche was also studied. Multiple logistic models were used to identify any independent association between each abnormal feature and age at menarche or gynecological age. Adjusted ORs and 95%CI were performed. RESULTS: After adjusting for covariates, menarcheal age was not independently associated with polymenorrhea (OR = 0.81; 95%CI 0.63-1.04), oligomenorrhea (OR = 1.16; 95%CI 0.94-1.43), menstrual cycle irregularity (OR = 0.99; 95%CI 0.86-1.14), abnormal bleeding length (OR = 0.96; 95%CI 0.87-1.06) and dysmenorrhea (OR = 1.03; 95%CI 0.85-1.24). The multivariate analysis suggests that the higher prevalence of oligomenorrhea and menstrual cycle irregularity among the girls who were older at menarche might be purely explained by their younger gynecological age. CONCLUSIONS: No evidence of any independent influence of age at menarche on menstrual abnormalities among young girls was shown by the investigation. The findings suggest that, after menarche, adolescent girls' menstrual health should be checked to monitor the endocrine system maturation and to early intercept latent disorders becoming symptomatic.

Tall Stature: A Challenge for Clinicians.

Clinicians generally use the term "tall stature" to define a height more than two standard deviations above the mean for age and sex. In most cases, these subjects present with familial tall stature or a constitutional advance of growth which is diagnosed by excluding the other conditions associated with overgrowth. Nevertheless, it is necessary to be able to identify situations in which tall stature or an accelerated growth rate indicate an underlying disorder. A careful physical evaluation allows the classification of tall patients into two groups: those with a normal appearance and those with an abnormal appearance including disproportion or dysmorphism. In the first case, the growth rate has to be evaluated and, if it is normal for age and sex, the subjects may be considered as having familial tall stature or constitutional advance of growth or they may be obese, while if the growth rate is increased, pubertal status and thyroid function should be evaluated. In turn, tall subjects having an abnormal appearance can be divided into proportionate and disproportionate syndromic patients. Before initiating further investigations, the clinician needs to perform both a careful physical examination and growth evaluation. To exclude pathological conditions, the cause of tall stature needs to be considered, although most children are healthy and generally do not require treatment to inhibit growth progression. In particular cases, familial tall stature subject can be treated by inducing puberty early and leading to a complete fusion of the epiphyses, so final height is reached. This review aims to provide proposals about the management of tall children.

Growth Hormone Receptor Gene Expression Increase Reflects Nutritional Status Improvement in Patients Affected by Crohn's Disease.

Background: We proposed to verify the role of growth hormone receptor gene expression in growth failure of children with Crohn's disease (CD). Methods: We measured serum levels of growth hormone binding protein (GHBP) and insulin-like growth factor-I (IGF-I), and growth hormone receptor (GHR) gene expression in peripheral blood mononuclear cells of 21 patients with CD (before and after therapy) and in 27 age-sex-matched controls. Results: At diagnosis, significantly lower insulin-like growth factor-I and growth hormone binding protein levels were found in the CD group compared to the controls. Growth hormone receptor mRNA expression was lower in patients at diagnosis compared to the controls, even though the difference did not reach statistical significance, and significantly increased in patients in the following year. Insulin-like growth factor-I levels showed significant improvements 1 year after diagnosis compared to basal levels. On the contrary, growth hormone binding protein values had not significantly changed after 1 year of therapy. Conclusion: Our study raises the hypothesis of another mechanism through which cytokines interact with the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis.