The Investigation of Plasma Glucagon-like Peptide-1 Levels in Newly Diagnosed Type 1 Diabetic Children.

OBJECTIVE: To reveal the possible role of glucagon-like peptide-1 (GLP-1) in newly diagnosed Type 1 diabetic children. METHODS: Twenty-five newly diagnosed children and 22 healthy children were included in the study. RESULTS: In oral glucose tolerance tests, no correlation was observed between C-peptide and GLP-1 levels at 0 and 30 minutes, and plasma GLP-1 levels in both groups at 0 and 30 minutes were not statistically different. CONCLUSION: Consequently, fasting and postprandial GLP-1 levels in newly diagnosed Type 1 diabetic children are not different from healthy children. Glucagon-like peptide-1 levels in newly diagnosed Type 1 diabetic children suggest that plasma GLP-1 levels do not have any role in the pathogenesis of Type 1 diabetes mellitus.

Neurokinin B signalling in human puberty.

Recent identification of TAC3 or TACR3 (encoding neurokinin B and its receptor, NK3R, respectively) mutations as the causes of normosmic idiopathic hypogonadotrophic hypogonadism has provided compelling evidence for the involvement of neurokinin B (NKB) signalling in puberty. A surge of subsequent studies pointing towards an understanding of the exact mechanism through which NKB signalling exerts its effects in puberty led to a postulated sketch of the GnRH pulse generator, in which kisspeptin, NKB and dynorphin work in concert to elicit pulsatile gonadotrophin-releasing hormone release in the median eminence.

The effects of neurokinin B upon gonadotrophin release in male rodents.

Growing evidence suggests the tachykinin neurokinin B (NKB) may modulate gonadotrophin secretion and play a role in sex-steroid feedback within the reproductive axis. NKB signalling has recently been identified as being necessary for normal human reproductive function, although the precise mechanisms underpinning this role remain to be established. We have used rodents to explore further the role of NKB within the reproductive axis. In particular, we have studied its interactions with kisspeptin, a neuropeptide essential for reproductive function in rodent and human with close anatomical links to NKB within the hypothalamus. Intraperitoneal administration of NKB (50 nmol) to male mice had no effect on circulating luteinsing hormone (LH) levels and, although i.p. kisspeptin (15 nmol) increased LH five-fold, co-administration of NKB and kisspeptin was indistinguishable from kisspeptin alone. Intracerebroventricular administration of NKB (10 nmol) to male mice also had no effect on LH levels, with 1 nmol kisspeptin i.c.v. significantly increasing LH compared to control (0.37 +/- 0.18 versus 5.11 +/- 0.28 ng/ml, respectively). Interestingly, i.c.v. co-administration of NKB and kisspeptin caused a significant increase in LH concentrations compared to kisspeptin alone (8.96 +/- 1.82 versus 5.11 +/- 0.28 ng/ml respectively). We used hypothalamic explants from rats to assess the effect of NKB on gonadotrpohin-releasing hormone (GnRH) secretion ex vivo. Doses of NKB up to 1000 nm failed to stimulate GnRH secretion, whereas 100 nm kisspeptin robustly increased GnRH secretion. Of note, co-administration of NKB with kisspeptin abrogated the effect of kisspeptin, producing no GnRH release above basal state. Finally, we analysed the expression of Tac2/Tacr3 (genes encoding NKB and NK3R, respectively) within the arcuate nucleus in different nutritional states. After a 48-h fast, the expression of both Tac2 and Tacr3 showed a significant increase, in contrast to levels of Kiss1 and Kiss1r mRNA, which remained unchanged. In male rodent models, NKB and kisspeptin have different effects upon gonadotrophin release and appear to interact in a complex manner.

Growth hormone and insulin-like growth factor 1 levels and their relation to survival in children with bacterial sepsis and septic shock.

OBJECTIVES: Despite improved supportive care, the mortality of sepsis and septic shock is still high. Multiple changes in the neuroendocrine systems, at least in part, are responsible for the high morbidity and mortality. A reduced circulating level of insulin-like growth factor and an elevated level of growth hormone are the reported characteristic findings early in the course of sepsis and septic shock in adults. The aim of this study was to evaluate the changes of growth hormone/insulin-like growth factor 1 axis in sepsis and septic shock and investigate the relationship between these hormones and survival. METHODS: Fifty-one children with sepsis (S), 21 children with septic shock (SS) and 30 healthy, age- and sex-matched children (C) were enrolled in this study. Growth hormone, insulin-like growth factor 1 and cortisol levels of the sepsis and septic shock groups were obtained before administration of any inotropic agent. RESULTS: Growth hormone levels were 32.3 +/- 1.5 microIU/mL (range 4-56), 15.9 +/- 0.6 microIU/mL (range 11-28) and 55.7 +/- 2.7 microIU/mL (range 20-70) in S, C and SS groups, respectively. The difference between the growth hormone levels of the S and C groups, S and SS groups, and C and SS groups were significant (P < 0.001). Non-survivors (54.7 +/- 1.6 microIU/mL) had significantly higher growth hormone levels than survivors (29.4 +/- 1.5 microIU/mL) (P < 0.001). Insulin-like growth factor 1 levels were 38.1 +/- 2.1 ng/mL (range 19-100), 122.9 +/- 9.6 ng/mL (range 48-250) and 22.2 +/- 1.9 ng/mL (range 10-46) in the S, C and SS groups, respectively, and the difference between the insulin-like growth factor 1 levels of the S and C, S and SS, and C and SS groups were significant (P < 0.001). Non-survivors (8.8 +/- 1.1 micro g/dL) had significantly lower cortisol levels than survivors (40.9 +/- 2.1 microg/dL) (P < 0.001). We detected a significant difference between the levels of cortisol in non-survivors (19.7 +/- 1.8 microg/dL) and survivors (33.9 +/- 0.9 microg/dL) (P < 0.01). CONCLUSIONS: There were elevated levels of growth hormone with decreased levels of insulin-like growth factor 1 in children during sepsis and septic shock compared to healthy subjects. In addition, there were even higher levels of growth hormone and lower levels of insulin-like growth factor 1 in non-survivors than in survivors. We think that both growth hormone and insulin-like growth factor 1 may have potential prognostic value to serve as a marker in bacterial sepsis and septic shock in children. As there is insufficient data in the paediatric age group, more studies including large numbers of patients and additionally evaluating cytokines and insulin-like growth factor binding proteins are needed.

Urinary N-acetyl-beta-D-glucosaminidase activity in type I diabetes mellitus.

We measured urinary albumin excretion rate (AER) and N-acetyl-beta-D-glucosaminidase (NAG) activity in relation to disease duration, acetylated hemoglobin (HbA1c), hypertension and puberty in 44 children and adolescents with type 1 diabetes mellitus. AER and Urinary NAG activity were significantly higher in the patients compared to controls (AER 19.4 +/-; 35.8 vs 4.7 +/- 4.4, NAG activity 5.6 +/- 0.6U vs. 1.6 +/- 0.2U). Microalbuminuria was present in seven patients (15.9%), all of whom were pubertal. There was no correlation between AER and urinary NAG activity. There was a significant direct correlation between AER and disease duration (P <0.05), HbA1c (P < 0.05), diastolic blood pressure (P <0.05) and puberty (P <0.05). None of the microalbuminuria related variables was significantly correlated with urinary NAG activity. Puberty was an independent factor for elevated urinary NAG activity. This study shows that urinary NAG is elevated in children and adolescents with type 1 diabetes mellitus, but is not associated with AER related factors except for puberty. Urinary NAG activity does not appear to be a useful marker for early detection of diabetic nephropathy in children and adolescents with type 1 diabetes mellitus.

Evaluation of cerebral maturation by visual and quantitative analysis of resting electroencephalography in children with primary nocturnal enuresis.

This study was undertaken to evaluate resting electroencephalographic (EEG) changes and their relations to cerebral maturation in children with primary nocturnal enuresis. Cerebral maturation is known to be important in the pathogenesis of this disorder. Twenty-five right-handed patients with primary nocturnal enuresis, aged 6 to 14 years, and 23 age- and sex-matched healthy children were included in this cross-sectional case-control study. The abnormalities detected using such techniques as hemispheral asymmetry, regional differences, and hyperventilation response in addition to visual and quantitative EEG analysis were examined statistically by multivariate analysis. A decrease in alpha activity in the left (dominant hemisphere) temporal lobe and in the frontal lobes bilaterally and an increase in delta activity in the right temporal region were observed. We concluded that insufficient cerebral maturation is an important factor in the pathogenesis of primary nocturnal enuresis, and EEG, as a noninvasive and inexpensive method, could be used in evaluating cerebral maturation.

Primary hyperparathyroidism in an infant with three parathyroid glands and pulmonary calcinosis.

A 2 month-old male infant presented with severe hypercalcemia due to parathyroid hyperplasia. A total parathyroidectomy and partial heterotopic autotransplantation were carried out. Hypercalcemia recurred two months later. Normocalcemia was re-established after removing one half of the implanted tissue. Despite two separate surgical explorations and several imaging studies, including 99mTc-sestamibi scintigraphy, ultrasonography, and MRI, only three parathyroid glands were found. Severe pulmonary calcinosis has not previously been reported in children with PHPT. In conclusion, developmental variations of the parathyroid glands may be difficult to identify with present imaging techniques. This may pose difficulties in management of PHPT. The present report describes pulmonary calcinosis as a sequela which can cause additional morbidity in these infants.

A practical GnRH analogue (triptorelin) stimulation test to distinguish constitutional delay of puberty from hypogonadotropic hypogonadism in prepubertal boys.

At present, no established practical and reliable endocrine test exists for differentiating between constitutional delay of puberty (CDP) and hypogonadotropic hypogonadism (HH). The most discriminating results have been reported by measuring LH and testosterone (T) responses to gonadotropin-releasing hormone (GnRH) analogues. In this study, 23 prepubertal boys aged 14 to 16.5 years underwent a modified triptorelin (a GnRH analogue) stimulation test, and they were followed clinically for up 24 to months. Sixteen subjects developed spontaneous puberty during the follow-up period and thus were diagnosed with CDP, and the remaining seven were diagnosed with HH. Retrospective evaluation of their LH, FSH and T responses revealed significant differences without any overlaps in serum LH levels at 4 h (CDP: 33.2 +/- 9.3 vs. HH: 3.3 +/- 2.6 mIU/ml, p < 0.0002) and in serum T levels at 24 h (CDP: 369.3 +/- 128.1 vs. HH: 61.4 +/- 22.6 ng/dl p < 0.0002). We conclude that CDP can be clearly differentiated from HH by the LH response at 4 h and/or T response at 24 h after a single-dose triptorelin administration.

Lack of association between plasma leptin levels and appetite in children with iron deficiency.

A negative correlation between leptin and appetite or food intake has been shown in healthy individuals. However, the role of leptin in clinical conditions characterized by anorexia has not been established. One of the well-known clinical features of iron-deficiency anemia is poor appetite. We examined the changes in plasma leptin levels in relation to expected improvement in appetite with iron treatment in children with iron deficiency. In 24 infants and small children (mean age +/- standard deviation = 19.6 +/- 7.7 months) with iron deficiency, we studied plasma leptin levels before and after iron therapy. After 15.0 +/- 2.4 wk of iron treatment, serum ferritin levels improved significantly, with accompanying increases in their subjective appetite scores and food intakes. However, as their mean age and plasma leptin levels adjusted their body mass indexes were unchanged. Serum ferritin correlated significantly with appetite score (r = 0.680, P < 0.001) and food intake (r = 0.480, P < 0.01). Leptin correlated only with body mass index (r = 0.405, P < 0.01). Lack of association between plasma leptin levels and degree of appetite in iron-deficient children treated with iron suggests a leptin-independent mechanism for the observed increase in appetite.

Denver developmental screening test II for early identification of the infants who will develop major neurological deficit as a sequalea of hypoxic-ischemic encephalopathy.

BACKGROUND: The primary aim of this study was to find widely available, inexpensive, and non-invasive parameters for early identification or prediction of the infants with hypoxic-ischemic encephalopathy (HIE) who will have a severe adverse outcome (classified as death or a major neurological deficit). METHODS: Fifty-seven full-term or near-term newborn infants with a diagnosis of HIE were consecutively admitted to the neonatal intensive care unit and studied. Occurrence of seizures during the first 24 h, cranial ultrasonography (US) findings within the first 5 days of life, and Denver developmental screening test II (DDST II) at 6 months of age, were analyzed in relation to mortality and neurological status at 2 years of age. RESULTS: Of the 57 infants, 10 were lost to follow-up. Twenty of the remaining 47 infants had a severe adverse outcome. Among the predictors of severe adverse outcome, occurrence of seizures was found to have a poor predictive accuracy. Cranial US had 100% sensitivity, however with a rather low specificity (55%). However, DDST II at 6 months of age, yielded a very high predictive accuracy (sensitivity=100%, specificity=95%). CONCLUSION: We conclude that DDST II at 6 months of age could be used in predicting severe neurological outcome in infants with HIE.

Influence of metabolic control on growth in homocystinuria due to cystathionine B-synthase deficiency.

The etiology of the tall stature almost invariably seen in homocystinuric patients is not known. The effect of metabolic control and the role of the GH-IGF system on growth were investigated in 10 patients with homocystinuria. There was a direct correlation between the plasma free homocyst(e)ine and growth velocity SD scores in 18 patient years (r, 0.46; p < 0.05). Plasma 2-y cumulative free homocyst(e)ine and height SD scores were directly correlated (r, 0.82; p < 0.01). Growth velocity SD scores were lower in patients with optimal metabolic control than in those with poorer control (-0.10 +/- 0.65 versus 0.95 +/- 0.68, p < 0.01). Height SD scores were also lower in the optimally controlled group (-0.01 +/- 0.81 versus 1.73 +/- 0.88, p < 0.05). GH and GH-related peptides did not deviate significantly from the reference ranges. These findings suggest that overgrowth is directly mediated by homocysteine, that the GH-IGF axis is not involved, and that it may be prevented by optimal metabolic control.

Coexistence of common variable immunodeficiency and autoimmune polyglandular syndrome type 2.

A six year-old boy with common variable immunodeficiency developed insulin dependent diabetes mellitus, autoimmune thyroiditis, and total alopecia leading to the diagnosis of autoimmune polyglandular syndrome type 2. Previously unreported co-occurence of these two entities may be explained by strong autoimmunity and HLA association of both conditions.

Effect of gestational age on plasma fibronectin concentrations in the neonate.

BACKGROUND: Fibronectin (FN) is known to have important roles in host defense against infection. The risk for neonatal sepsis increases with the degree of immaturity of the host. Conflicting results have been reported on the relationship between plasma FN levels and gestational age (GA) in the preterm neonate. METHODS: In the present study, we determined plasma FN concentrations with an immunodiffusion method in 40 newborns of various gestational ages, ranging from 30 to 42 weeks. RESULTS: We found a strong direct correlation between plasma FN levels and GA (r = 0.86; P < 0.001). CONCLUSIONS: We speculate that the increased risk for neonatal sepsis with degree of prematurity may, in part, be explained by impaired defense with decreasing plasma FN levels seen with lessening GA.

Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.

BACKGROUND: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A). The nature of the molecular lesions in the alpha-Gal A gene in 30 unrelated families was determined to provide precise heterozygote detection, prenatal diagnosis, and define genotype-phenotype correlations. MATERIALS AND METHODS: Genomic DNA was isolated from affected males and/or carrier females from 30 unrelated families with Fabry disease. The entire alpha-Gal A coding region and flanking intronic sequences were analyzed by PCR amplification and automated sequencing. RESULTS: Twenty new mutations were identified, each in a single family: C142R, G183D, S235C, W236L, D244H, P259L, M267I, I289F, Q321E, C378Y, C52X, W277X, IVS4(+4), IVS6(+2), IVS6(-1), 35del13, 256del1, 892ins1, 1176del4, and 1188del1. In the remaining 10 unrelated Fabry families, 9 previously reported mutations were detected: M42V, R112C, S148R, D165V, N215S (in 2 families), Q99X, C142X, R227X, and 1072del3. Haplotype analysis using markers closely flanking the alpha-Gal A gene indicated that the two patients with the N215S lesion were unrelated. The IVS4(+4) mutation was a rare intronic splice site mutation that causes Fabry disease. CONCLUSIONS: These studies further define the heterogeneity of mutations in the alpha-Gal A gene causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis, and help delineate phenotype-genotype correlations in this disease.

Effects of hydrazine sulfate on galactosamine-sensitized endotoxic shock in ten-day-old rats.

Patients who have liver diseases are susceptible to septic shock. Galactosamine induces liver damage and increases endotoxin-sensitivity. Hydrazine stimulates pituitary-adrenal axis and decreases mortality in galactosamine-sensitized endotoxic shock in the adult. However, as pituitary-adrenal function in the newborn is immature, the effects of hydrazine on galactosamine-sensitized endotoxic shock in the newborn remained unclear. In the present study, galactosamine-sensitized endotoxic shock was induced and treated with hydrazine in ten-day-old rats. Galactosamine (600 mg/kg) plus Salmonella enteritidis lipopolysaccharide (LPS; 0.01 mg/kg) induced hypoglycemia, lactacidemia and resulted in high mortality. Hydrazine at the dose of 20, 50 or 80 mg/kg did not alter the hypoglycemia, lactacidemia or morality. Dexamethasone ameliorated the hypoglycemia and lactacidemia (p < 0.05) and decreased the morality (p < 0.05). The lack of beneficial effects of hydrazine in galactosamine-sensitized endotoxic shock in ten-day-old rats may be related to immature pituitary-adrenal function and suppression of gluconeogenesis by hydrazine.

Galactosamine alters glucose regulation in ten-day-old rats treated with a low dose of endotoxin.

Hypoglycemia develops rapidly during septic shock and is a common and life-threatening problem in the human newborn. In adult animals, galactosamine alter glucose metabolism and increases mortality of endotoxic shock. Galactosamine may alter tissue glucose uptake and induce hypoglycemia in ten-day-old rats. The present study showed that galactosamine induced hypoglycemia and a high mortality without an increase in plasma insulin concentration in ten-day-old rats treated with a low dose of endotoxin. Galactosamine decreased tissue glucose uptake in endotoxin-treated animals. Hypoglycemia induced by galactosamine could be due to decreased gluconeogenesis.