Evaluation of growth hormone response to GHRH plus arginine test in children with idiopathic short stature: role of peak time.

PURPOSE: To describe the course of growth hormone response to growth hormone releasing hormone (GHRH) plus arginine provocative test in children with idiopathic short stature (ISS) and to evaluate the role of peak time. METHODS: A retrospective study was performed analyzing 344 GHRH plus arginine provocative tests performed in children and adolescents with short stature. Serum GH levels were measured at four-time points (T0', T30', T45' and T60') and GH peak was defined as the maximum value at any time point. Mean (T30'-T60') GH value and area under the curve (AUC) were calculated. RESULTS: When analyzing the time of peak at the provocative test, the most frequent peak time was T45' (53.8%) in the ISS group, with no differences in gender, age, and pubertal stage. Analyzing GHD subjects, the most frequent time of peak was T30 (50%). Analyzing the whole population, the GH T0' levels were significantly lower in subjects with the GH peak at T45' than those with the GH peak at T30' (1.7 ± 2.0 vs. 3.2 ± 4.0, p < 0.001). In subjects with GH peak at T45', the value of GH peak, AUC and mean GH were significantly higher than in those with GH peak at T30' and T60'. A direct correlation was found between the value of GH peak and growth velocity SDS (r = 0.127, p = 0.04) and a negative one between GH peak and GH level at T0' (r = - 0.111, p = 0.04), even when adjusted for gender, age, pubertal stage and BMI Z score. CONCLUSIONS: The time peak at 45 min seems to be associated with a better response to the test considering GH peak, mean and AUC. Patients with a GH peak at 30 min more probably could have a derangement in GH secretion showing worst growth pattern and/or a GH deficiency and should be carefully observed.

Vitamin D levels in a paediatric population of normal weight and obese subjects.

BACKGROUND: Vitamin D exerts pleiotropic effects and few studies are available in the Italian population. AIM: Aim of our study was to evaluate vitamin D status in children living in Northern Italy. METHODS: We studied vitamin D levels in a population of 113 normal weight (NW) and 444 obese (OB) children, prepubertal and pubertal. We considered vitamin D levels >20 ng/ml as normal, but also measured percentage of children with vitamin D levels higher than a cutoff of 30 ng/ml. RESULTS: 68.2 % of NW children showed normal levels of vitamin D, while 31.8 % showed a clear vitamin D deficiency. Only 28.3 % showed vitamin D levels higher than 30 ng/ml. Obese children showed 55.6 % of subjects with normal levels of vitamin D and 44.4 % of subjects a status of vitamin D deficiency. Only the 18.9 % showed vitamin D levels higher than 30 ng/ml. Mean vitamin D levels in NW children (27.3 ± 1.2 ng/ml) were higher than in OB children (21.8 ± 0.6 ng/ml). No differences have been found between prepubertal and pubertal children in terms of vitamin D levels. CONCLUSIONS: Our paediatric population demonstrates a low percentage of vitamin D sufficiency. In particular, obese children show only 19 % of subjects with normal levels while almost half of this population shows a clear deficiency. Further studies are needed to support these results and to evaluate the possible metabolic consequences.

Comparison of two classifications of metabolic syndrome in the pediatric population and the impact of cholesterol.

BACKGROUND: To establish the rate of agreement in predicting metabolic syndrome (MS) in different pediatric classifications using percentiles or fixed cut-offs, as well as exploring the influence of cholesterol. SUBJECTS AND METHODS: Cross-sectional study in a tertiary care center. Nine hundred and twenty-three obese children and adolescents were evaluated for metabolic characteristics, cholesterol levels, the agreement rate and prevalence of MS across age subgroups with pediatric National Cholesterol Education Program/ Adult Treatment Panel III (NCEP-ATP III) and International Diabetes Federation (IDF) classifications. RESULTS: The overall prevalence of MS was 36.2% and 56.7% with NCEPATP III and IDF. The overall concordance was fair (k: 0.269), with substantial values observed only in children older than 10 (k: 0.708) and 16 yr (0.694). Concordant subjects for both classifications, ≤6 yr, had higher triglycerides, blood pressure (p<0.05) and lower HDL-cholesterol (p<0.0001), with respect to those found to be discordant. Concordant subjects ranging 6-10 yr had all parameters higher than those discordant for IDF (p<0.01) and insulin resistance (p<0.05) than those discordant for NCEP-ATP III. Concordant subjects ≥10 yr presented more altered parameters than those included only in NCEP-ATP III (p<0.05). Overt glucose alterations were uncommon (7.4%; confidence interval 95% 0.1-14.9%), although glucose was modestly higher in MS subjects (p<0.01). Total and LDL-cholesterol was lower in subjects with MS than in those without (p<0.05), and in concordant rather than discordant subjects (p<0.05). CONCLUSIONS: Classifications of MS do not identify the same pediatric population. Subjects who satisfied any classification were the most compromised. Lipid alterations were precocious in the youngest. Obese youths with MS presented lower total and LDL-cholesterol.

Acylated/unacylated ghrelin ratio in cord blood: correlation with anthropometric and metabolic parameters and pediatric lifespan comparison.

CONTEXT: Ghrelin is a peptide with multiple functions that circulates in acylated (AG) and unacylated (UAG) forms. However, the role of ghrelin in neonates (NN) remains to be clarified. OBJECTIVE: The aim of this study was to determine ghrelin concentrations of the two forms in NN to clarify their biological roles. As such, ghrelin levels at birth were compared with those in later life. SETTING AND DESIGN: Tertiary Care Center. In this cross-sectional study, we evaluated AG, UAG, AG/UAG ratio, and insulin levels in venous cord blood from NN and in fasted normal weight (NW) and obese (OB) children, both prepubertal and pubertal. SUBJECTS: We studied 82 NN, 82 NW, and 58 OB children. RESULTS: AG levels were lower in NN than in NW and OB children (P<0.0001), more specifically the prepubertal NW and OB children (P<0.0001). UAG levels were higher in NN than in NW and OB children (P<0.0001). Therefore, the AG/UAG ratio was lower in NN than in NW and OB children (P<0.0001). NN showed insulin levels similar to NW and lower than OB children (P<0.0001). At birth UAG was positively correlated with AG (Pearson: 0.425; P<0.0001) and negatively with insulin (-0.253; P<0.02). In NW and OB, UAG and AG were positively correlated to each other and negatively correlated with insulin and body mass index (-0.566; P<0.0001). CONCLUSIONS: NN compared with children, showed higher UAG and lower AG levels. The AG/UAG ratio showed a very different profile in NN, being lower than in NW and OB children, thus suggesting a different metabolic function for the two forms in NN. Further studies are needed to clarify the exact role of the different ghrelin forms in NN.

[Growth hormone deficiency associated with 22q11.2 deletion: a case report]. / Deficit di ormone della crescita associato a delezione del cromosoma 22q11.2: descrizione di un caso.

The 22q11.2 microdeletion produces many syndromes, characterized by similar phenotypical features. The most known syndromes are: the DiGeorge syndrome, the velocardiofacial syndrome, the conotruncal anomaly face syndrome. The hallmark features are represented by cardiac anomalies, palate defects, immune and cognitive deficiencies, facial dysmorphisms. Less common disorders include: genito-urinary abnormalities, visual defects, autoimmune disorders and pituitary anomalies, being the last represented by growth hormone and/or insulin growth factor-I deficiency. We present the case of a 8 years old male admitted to our Division for failure to thrive. We found growth hormone deficiency and pituitary hypoplasia associated with some of the anomalies shown above, thus we suspected and confirmed the 22q11.2 deletion syndrome. In literature few cases of associated 22q11.2 deletion syndrome with growth hormone deficiency are described, while short stature between children with and children without cleft palate is reported to be more frequent in the first ones, suggesting that the 22q11.2 deletion syndrome remains undetected in many affected children and that the growth hormone deficiency prevalence in affected children has to be investigated. The wide phenotypical presentation of 22q11.2 deletion syndrome requires a multidisciplinary approach to the affected subject and, from the auxologic point of view, is good to monitoring the growing trend and, if short stature is present, check for the growth hormone deficiency.

[Early diagnosis of Fabry disease in children]. / Diagnosi precoce di malattia di Fabry in età pediatrica.

Fabry disease, a rare X-linked lysosomal storage disorder, is caused by deficiency of the enzyme α-galactosidase A. The incidence, ranging from one over 40 000 to one over 11 7000 worldwide is probably underestimated due to its unspecific pattern of presentation. The symptoms, including neurological, gastrointestinal, renal, ophthalmological and dermatologic manifestations, start in childhood and adolescence, cause a significant morbidity and are likely to affect the patient's quality of life. Furthermore, Anderson-Fabry disease always progress leading to a multiorgan dysfunction and life-threatening complications with end-stage renal disease, cardiomyopathy and high incidence of stroke. The estimated life in untreated patients is reduced by 15-20 years respectively in men and women. The enzyme replacement therapy, available in Europe from 2001, results in a reduction of major organs failure, morbidity and mortality. We present the case of an 8-year-old male admitted to our Division for overweight with a previous history of acroparesthesias, severe acute pain in hands and feet, abdominal pain, diarrhoea, constipation, bitemporal headache, dyshidrosis, recurrent fever, exercise intolerance and reduced quality of life. The physical examination was within normal limits. The α-galactosidase A activity was deficient in plasma and normal in peripheral leukocytes; the GLA gene showed a nucleotide substitution c.352C>T (p.Arg 118 Cys) in the eson 2 with a residual enzyme activity of the 29% suggesting the diagnosis of Fabry disease. Blood and urine chemistry, the slit-lamp examination and MRI of kidneys, heart and brain excluded any major organ involvement. The enzyme replacement therapy was then started almost three months ago using agasidase alfa at a dose of 0.2 mg/kg infused intravenously every two weeks but, unfortunately, no relief in the symptoms have been reported so far without any severe adverse reactions. This case report aims to point out the importance of an early diagnosis in order to prevent the progression of the disease, the multiorgan failure and to improve the long-term prognosis.

[Neurofibromatosis type 1 and hypertension in pediatrics: case report]. / neurofibromatosi 1 ed ipertensione arteriosa in eta pediatrica: caso clinico.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by cafe-au-lait spots, axillary and inguinal freckling, cutaneous neurofibromas with a variable clinical expression, iris Lisch nodules, and multiple tumors, in particular optic nerve and other central nervous system gliomas. About 6% of patients develop hypertension due to renovascular diseases, mid-aortic syndrome, or pheochromocytoma. We present a case of a 8 year old girl with primary diagnosis of NF1suffering of skin and encefalic neurofibromas, inguinal freckling, café-au-lait spots, optic nerve glioma, headache, facial flushing. The 24-h ambulatory blood pressure revealed hypertension without paroximal attacks. Urinary metanephrines, serum aldosteron, renin and kalemia were constantly normal. Magnetic resonance imaging (MRI) and angioMRI excluded stenoses of the renal arteries or adrenal masses. Standard 2D echocardiography was normal. The antihypertensive medication controlled pressure values. We concluded for hypertension due to a low-grade vasculopathy. The periodic monitoring of blood pressure in NF1 patients, accompanied by appropriate diagnostic modalities and physical examination, is essential to precociously diagnose hypertension and avoid life-threatening organ damages and increased mortality.

Etiopathogenetic advances and management of holoprosencephaly: from bench to bedside.

Holoprosencephaly (HPE) is a complex brain malformation caused by impaired or incomplete midline division of the prosencephalon. It's characterized by cerebral and facial anomalies of different levels of severity. Both genetic and environmental factors are known to cause HPE, but they cover only few cases. Genetic causes are responsible for about 20% of cases: they are chromosomal abnormalities and gene mutations: up to date, nine genes (SHH, ZIC2, SIX3, TGIF, PATCHED1, TDGF1/CRIPTO, FAST1, GLI2 and DHCR) are definitely associated with HPE, but many others candidate gene are under investigation. The diagnosis of HPE is usually prenatal and is based on systematic ultrasound scan (US) and magnetic resonance imaging (MRI). Children with HPE have many medical problems in agreement with the severity of the brain malformation: craniofacial abnormalities, neurological signs, endocrine disorders, oromotor and dysautonomic dysfunction, thus requiring a multidisciplinary team for symptomatic treatment of manifestations, prevention of complications and parental support. Genetic counselling is an important step, often made difficult by extreme phenotypic variability, genetic heterogeneity, and a high risk of recurrence in apparently sporadic cases. In conclusion it can be concluded that we are far from a complete explanation of the etiopathogenesis. Future researches on genomic rearrangements all over the genome with techniques like the CGH array should lead to the identification of other causal genes and could improve diagnosis and prognosis. A skill multidisciplinary approach is mandatory to offer the better clinical assistance to patients and their parents.

Complex dynamics of adaptation in a nonaxenic microcystis culture. 1. Effects of dinitrophenol on population growth.

Chronic exposure to toxicants is a selective pressure affecting populations and also the interactions between populations. Nonaxenic cultures of the blue-green alga Microcystis aeruginosa were used to investigate the ecological dynamics and the effect of preexposure to 2,4-dinitrophenol (DNP) on the tolerance toward subsequent DNP inputs. It was predicted that preexposure would induce an increased tolerance to further inputs. This should cause a higher population growth rate under a given DNP exposure, a broader tolerance range (the range of concentrations over which population growth can be sustained), a higher EC(50), and a lesser variability in growth rates, over the range of experimental exposure concentrations. DNP reduced Microcystis growth proportionally to exposure concentration. Light, inorganic carbon, and DNP were likely limiting factors for algal growth. Heterotrophic bacteria presumably used the dead cells and the exudate of living algae as substrates. Some unexpected effects occurred, such as an apparent increase in dissolved DNP in the medium following its initial decline and fluctuations of the bacterial population. The hypotheses were verified as concerns the effect of preexposure on tolerance. Changes were apparent in the EC(50) and in the breadth of the tolerance range. Moreover, the variability of preexposed populations, in terms of algal growth rate, over the range of exposure concentrations, was smaller than that of non-preexposed populations. Such a decrease in variability may reduce the potential of a population to resist further stresses.

Complex dynamics of adaptation in a nonaxenic microcystis culture. 2. Computer simulation of dinotrophenol effects.

A hypothesis was modeled to account for complex 20-day dynamics in a culture of blue-green algae Microcystis and heterotrophic bacteria exposed to 2,4-dinitrophenol (DNP). In trials with little or no added DNP, a limiting factor (light or CO(2)) may cause algal density to fluctuate after 14 days of increase. Such factors may be unimportant at levels of DNP that restrict photosynthesis. Bacterial growth may be limited by organic substrate, and bacteria may be more resistant to DNP than blue-green algae. Hence, at intermediate levels of DNP, substrate provided by increased algal death stimulates bacterial growth more than DNP retards it, causing a bacterial peak. Sorption of DNP to cells may cause the DNP decline. Greater growth and slower DNP decline in experiments with preexposed organisms indicate lower DNP sorption affinity in preexposed cells. Bacterial assimilation of DNP-containing substrate may cause the reappearance of DNP. The model reproduced the fluctuation in algal density after growth was limited and better growth and lower DNP decline with preexposed organisms. Reappearance of DNP occurred, but was not obvious. Bacterial dynamics were least well reproduced. Changes in bacterial constants most affected output. Despite model inadequacies, probable aspects of toxicant action in nature have been revealed. Ecological relationships among populations of different species and genetic differences among individuals may have led to lower than expected toxicity, adaptation, and even growth stimulation. Responses of single species tested in isolation may be inadequate to predict toxicant impact.

Influence of the energy relationships of organic compounds on their specificity toward aquatic organisms.

Unifying concepts are needed in ecotoxicology to deal with the various aspects of the behavior of substances, such as their mobility in the physical environment, bioaccumulation, toxicity, and specificity. The concept of transformity (the relative amount of energy required to generate a component or a flow in a transformation process) may provide a synthetic approach. Transformity correlates positively with the bioaccumulation tendency and toxicity. Since increasing amounts of energy are required in biological or industrial processes that generate increasingly unusual, complex, and specific substances, transformity and specificity may correlate positively as well. This latter hypothesis was tested for a set of 45 compounds, including simple and chlorinated alkanes, alkenes, alcohols, benzenes, and phenols. Published data on their Gibbs energy of formation (an estimate of transformity) and their acute toxicity to 21 species of aquatic organisms (measured as the EC50 or LC50, the duration of the test depending on the life span of the species) were used. To quantify specificity, the coefficient of variation of the toxicity data for the various species, which expresses the relative variability of the data around the mean, was calculated. There was a significant positive correlation between these two quantities. Thus, transformity may provide a conceptual framework for predicting the specificity of substances. The functional relationship between transformity and specificity could not, however, be established with certainty.

Influence of the energy relationships of organic compounds on toxicity to the cladoceran Daphnia magna and the fish Pimephales promelas.

A concern of ecotoxicology is to predict the toxicity of substances to living systems. Existing models of structure-activity relationships (SARs) are statistical and applicable within classes of substances only. Predictive models derived from first principles are wanting. Transformity, a measure of the relative amount of energy required to generate a component or a flow in a transformation process, may help predict toxicity. This notion derives from two concepts. First, common substances are more likely to be processed by the biosphere than are rare substances. Second, transformity expresses energy relationships between parts of a system. Substances that require more energy to form are also the more unusual and the more difficult to process. A correlation was hypothesized to occur between the rarity and complexity of a substance, and thus its transformity, and its toxicity. To search for general patterns that transcend individual studies, this hypothesis was tested by using data available for 79 compounds, including simple and chlorinated alkanes, alkenes, alcohols, benzenes, phenols, biphenyls, organic acids, and acetaldehyde. Published data on their Gibbs energy of formation were used as an estimate of transformity. These were compared to published data on their acute toxicity to the cladoceran Daphnia magna and the fish Pimephales promelas (measured as the 48- and 96-hr LC50 values, respectively). For both species there were significant positive correlations across compound classes between transformity and toxicity. In contrast, some correlations within classes were negative, with chemical reactivity and physicochemical properties presumably exerting the prevailing influences within these classes. This suggests that the general (across-classes) and smaller-scale (within-class) patterns are complementary perspectives. The functional relationship across classes was a monotonous increase in toxicity followed by a plateau, though the exact form could not be established with certainty. Gibbs energy of formation has limitations as an estimate of transformity and therefore these observations await confirmation. The correlation between transformity and toxicity may be an important generalization in ecotoxicology, because it may contribute a conceptual framework for making a cross-class comparisons of toxicity. Moreover, transformity may provide a unifying approach to the study of bioaccumulation, toxicity, and specificity.

Influence of the energy relationships of trophic levels and of elements on bioaccumulation.

A concern of ecotoxicology is to predict to which trophic levels in biocenoses bioaccumulation of compounds or of elements occurs. Transformity, a measure of the energy required to produce and maintain a component or a flow resulting from an energy transformation process, may help predict bioaccumulation potential. This notion derives from two concepts. First, common substances are more likely to be processed by the biosphere. Moreover, the uptake of rare ones from the physical environment by organisms of low trophic levels makes them less unusual to organisms of high trophic levels, which may evolve a capability of processing them. Second, transformity expresses energy relationships between parts of a system. Substances that require more energy to form or concentrate are also the more unusual. The hypothesis was formulated that there is a correlation between the rarity, complexity, and energy required for concentrating a substance, and thus its transformity, and the transformity of the trophic level to which it bioaccumulates. This hypothesis was tested for a set of elements with published data on their biogeochemistry and bioaccumulation and on energy transfers between trophic levels in ecosystems. The transformities of the elements were calculated from the energy required by the biosphere for maintaining a difference in concentration compared to its physical environment. Transformities of corresponding trophic levels were calculated from the energy driving the energy flows. There was a significant rank correlation between the transformity of elements and that of trophic levels. This may be an important generalization in ecotoxicology because it may lead to the possibility of predicting bioaccumulation tendency.

Short-term effect of a toxicant on scope for change in ascendency in a microcosm community.

A need in the field of toxicity testing is the development of parallel tests applicable to all levels of biological organization: single-species tests alone cannot predict effects at ecosystem levels. Scope for change in ascendency (SfCA) is a comparative index applicable to the short-term assessment of stress effects on any biological system. The SfCA of a community, defined by analogy to scope for growth of an organism, is the balance of ascendency (network size and organization) of population inputs and outputs. It takes into account the interrelated processes of growth and development, both of which can be affected by stress factors. To illustrate this approach, the effect of atrazine on SfCA of a simple epilimnetic microcosm community was investigated. Simultaneous, short-term measurements of all carbon flows between populations were made and SfCA was calculated. Compounded effects of stress on populations, measured as a relative drop in community SfCA in the presence of atrazine, were observed within 2-3 weeks. This indicates that SfCA may be useful as a comparative index for the short-term assessment of perturbation effects. A refinement of the methodology for measuring resource flows at levels other than the organism would allow full advantage of this assessment tool to be taken.

Sensory discrimination and the incipient advantage of mutations.

Perception follows logarithmic or power functions, rather than linear functions, of stimulus intensity. A small increment in stimulus strength can be sufficient to elicit discrimination between individuals of different phenotypes when the initial stimulus magnitude is near zero. This may confer an incipient advantage to the mutation that caused it. The psychophysics of signal receivers may be a good predictor of the extent of phenotypic changes. For example, slight similarities in color of Batesian mimics to their distasteful model can be sufficient to cause predators to reject the mimics. Color changes produced by single mutations in incipient Batesian mimics should be more extensive in mimicry complexes where the predators are less sensitive to color differences.