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It has been shown that changes in IGF-I and IGFBP levels in children with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) are correlated with different states of metabolic control. Our approach was to analyze the serum levels of IGF-I, IGFBP-3, their molar ratio IGF-I:IGFBP-3 (MR), and ALS in a cohort of CAH children and adolescents, and their associations with different clinical and biochemical parameters.56 patients, aged between 5.6 and 19.0 years were studied cross-sectionally. All patients had genetically proven CAH and received standard steroid substitution therapy. We measured serum levels of IGF-I, IGFBP-3, and ALS by commercial ELISA and calculated MR and assigned population-based SD scores (SDS).(median, quartiles) Overall IGF-I was not significantly altered (0.05 SDS, -1.21, 0.92), whereas IGFBP-3 was significantly elevated (1.50 SDS; 0.58, 1.95, p0.0001) compared to the reference population. Consecutively, MR was decreased (-0.64 SDS; -1.38, 0.32; p=0.0017). ALS was clearly decreased (-1.95 SDS; -3.075, -1.00; p0.0001). ALS, IGF-I, MR, and IGFBP-3 SDS were lower in pubertal than in prepubertal patients (p0.05). ALS SDS were lower in girls (p=0.0038). Correlation analyses (r(s), p) revealed correlations between MR/ALS and chronological age (-0.583,0.0001/-0.428, 0.0010), MR/ALS and Tanner stages (-0.500,0.0001/-0.334, 0.0118), MR/ALS and bone age (0.407, 0.0075/0.426, 0.0049), and between MR and ALS (0.405, 0.0020), respectively. For MR and ALS, we found no significant correlations for BMI, HOMA-IR, hydrocortisone and fludrocortisone dosage, or parameters of metabolic control.Our data provide evidence that the components of the trimeric IGF-I-IGFBP-3-ALS complex are altered in CAH children with possible implications on pubertal growth and final height.

This paper analyses potential future collaborative space exploration architectures in terms of 1) the technical capabilities of contributing partners; and 2) the constraints imposed by internal and international politics. We find that when international partners are considered endogenously, the argument for a “flexible path” approach is weakened substantially. This is because international contributions can make “Moon first” economically feasible; and characteristics of proposed “flexible path” approaches may preclude international involvement because of the disproportionate risk that those contributions inherently bear. This could have serious implications for future collaborations. We also note that while there are multiple feasible collaborative architectures, there is currently substantial overlap among the potential niche contributions identified by the international partners.

Inspiratory muscle training (IMT) has been shown to possibly improve exercise performance, but reports on IMT and running performance are rare. The objective of the present study was to examine the effect of target-flow IMT on running performance in recreational runners. Sixteen healthy recreational runners (five females) were recruited for the present study. They were randomly allocated into either an experimental or control group. Participants in the experimental group underwent a 6-week target-flow IMT programme, while those in the control group underwent a 6-week shoulder circumduction exercise programme. Running performance during a 1,500-m time trial run was assessed before and after the intervention period. After the intervention period, only the experimental group demonstrated an increase in inspiratory muscle strength (by 16.15 ± 7.44 cmH2O; p < 0.05) and reduced completion time in the 1,500-m time trial (by 9.63 ± 5.42 seconds; p < 0.05). Exertion sensation was reduced by 1.63 ± 0.74 points (p < 0.05). No changes were observed in maximal aerobic capacity and pulmonary function in either group after the intervention period. A 6-week target-flow IMT programme enhanced running performance in recreational runners.

Objective We analyzed postnatal growth in children with familial short stature (FSS) with regard to small (SGA) or appropriate (AGA) for gestational age status at birth. Study design We studied 96 otherwise healthy short-statured children (58 males; SGA: n = 41, AGA: n = 55). At least one of the parents was short-statured. Cross-sectional data for length/height and weight for the first 4 years of age were collected retrospectively. Results AGA children had a mean length of 0.09 ± 1.02 standard deviation score (SDS) at birth, −1.57 ± 1.16 SDS after 1 year of age, and −2.36 ± 0.72 SDS after 4 years. SGA children had a mean length of −2.04 ± 1.06 SDS at birth, −2.70 ± 1.12 SDS at 1 year of age, and −3.05±0.86 SDS at 4 years. The loss of length SDS within the first 2 years of life was greater in AGA than in SGA children. SGA children were significantly shorter than AGA children at all of the study points (p Conclusions Children with an FSS background born AGA show catch-down growth to their lower familial range during the first 2 years of life. SGA children did not catch up to their AGA peers at any time.

Background: Females with Ullrich-Turner syndrome (UTS) have typical clinical features such as short stature, ovarian failure, visible dysmorphic stigmata, and abnormalities in different organs such as kidney or heart. Hypothesis: The aim of the present study was to analyze the distribution, prevalence, and relative risk of cardiovascular anomalies (CVA) in females with Ullrich-Turner syndrome (UTS) seen at one single center compared with that of the regional Bavarian population. Methods: The associations between CVA and karyotype were determined. In all, 117 girls and women with UTS, aged between 3 and 43 years (median 17.4 years) were studied retrospectively. The detailed cardiologic status including echo-cardiography was available in all patients. The prevalences of each cardiovascular anomaly were determined. On the basis of published epidemiologic data of CVA in Bavarian children, we assessed the relative risks of each CVA. Results: Thirty-five (29.9%) girls with UTS had at least one CVA. In all of these CVAs, coarctation of the aorta and bicuspid aortic valve occurred most often (18.5% each). The aortic malformations represented over two-thirds of all CVA (72.8%), whereas anomalies of the septum (8.6%), mitral valve (6.2%), pulmonary veins (4.9%), and other locations together accounted for the otherthird. Bicuspid aortic valve and partial anomalous pulmonary venous drainage were associated with the highest relative risk (RR) (3,603 and 1,293, respectively) compared with the Bavarian population. The overall RR of CVA was 48.7. Of the 117 girls and women examined, 64 (54.7%) had complete monosomy 45 X. Conclusions: Our data demonstrate that about every third female with UTS is affected with at least one CVA, mainly left sided and associated with aortic structures. Our results underline the necessity of thorough cardiologic evaluation.

We are pleased to present the chapter on Oncology and Chronic Disease. Most published papers with importance to pediatric endocrinology were about late effects of cancer. This is not surprising since significant improvements in diagnosis and intensive treatment modalities of childhood cancer during the last 20 years have led to increasing survival rates worldwide. In developed countries, 1/250 of the adult population is a long-term survivor of childhood cancer. However, children who survive childhood cancer are at risk of various late effects as young adults, such as second malignant neoplasms, cardiovascular disease, endocrine disorders, and effects on fertility and reproduction. The latter are of particular interest for the surviving patients. Regarding fertility, we selected three guidelines recommending long-term follow-up of survivors. Our impression is that the number of papers published on the topic ‘chronic disease’ in the year 2013 was less than in 2012. As before, we analyzed this topic from two sides: (1) from the perspective of affected patients, e.g. analyzing growth and pubertal development, and (2) from the perspective of side effects on the endocrine system in relation to the respective therapeutic regimens.

There have been only a few studies on adrenarche in girls with classic congenital adrenal hyperplasia (CAH) showing that dehydroepiandrosterone sulfate (DHEAS) levels did not rise at the physiological age of adrenarche. Objective: Longitudinal analysis of serum DHEAS levels and Tanner stages in CAH children. Design: We studied 98 CAH patients (52 females), aged between 1 month and 18.0 years. All patients had genetically proven classic CAH and received steroid substitution therapy. Results: Serum DHEAS levels did not differ between CAH children and healthy children from the age of 1 year until 5–6 years. Beginning at the age of 7–8 years, there was a continuous but blunted increase in DHEAS levels in CAH boys and girls compared to healthy children. There was no correlation of DHEAS levels with the genotype, glucocorticoid dosage, auxological data, or quality of metabolic control. Pubarche (PH2) as well as gonadarche (G2) and thelarche (B2) occurred significantly earlier in CAH boys and girls than in the reference group, but timing of menarche was normal. Conclusions: Pubarche and adrenarche are dissociated in classic CAH: earlier pubarche, gonadarche and thelarche, respectively, in both sexes contrast with the absence of typical adrenarche.

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Objective: It has been shown that adiponectin serves as an insulin-sensitizing adipokine. Serum concentrations of adiponectin are low in children with obesity, and increase with fat mass loss, indicating that adiponectin can serve as a biomarker. Since the prevalence of overweight and obesity is increased in children with congenital adrenal hyperplasia (CAH), our study aimed to evaluate serum levels of adiponectin in a cohort of CAH children and adolescents, and their associations with clinical parameters such as chronological age (CA), body mass index (BMI), Tanner stage (TS), medication and metabolic control. Patients and methods: We studied 51 patients, aged between 5.6 and 19.6 years (median 11.8; 30 females, 21 males), cross-sectionally. All patients had genetically confirmed CAH and received standard steroid substitution therapy. Adiponectin was measured by an enzyme linked immunoassay. Since BMI SDS of the CAH cohort were significantly higher compared to the reference population, we built matched pairs with healthy Caucasian subjects from a normal representative cohort for sex, Tanner stage, chronologic age and BMI. Results: Adiponectin concentrations were significantly higher in CAH patients (median 11 μg/L) compared to the matched controls (6.7 μg/L, p < 0.0001). Correlation analyses in CAH patients revealed a significant inverse relationship between adiponectin and CA, TS, BMI, serum DHEAS and serum testosterone, but no correlation with hydrocortisone and fludrocortisone dosage. Conclusion: Currently, the importance of the elevated adiponectin concentrations in CAH children for risk assessment is not clear. However, our data imply that besides adequate metabolic control of glucocorticoid substitution, a long-term follow-up of other metabolic markers of insulin resistance should be conducted in CAH patients.

ObjectiveCongenital adrenal hyperplasia (CAH) patients are at a higher risk to develop obesity. The role of leptin in CAH is still controversial. Our study aimed to evaluate serum levels of leptin, the soluble leptin receptor (sOB-R), and the sOB-R: leptin molar ratios in a cohort of CAH children and adolescents, and their associations with clinical and metabolic parameters.MethodsWe studied 51 CAH patients, aged 5.6–19.6 years (median 11.8, n=30 females) cross-sectionally. All patients had genetically proven CAH and received standard steroid substitution therapy. Blood specimens were taken after overnight fasting between 0800 and 1000 h. For the analyses of leptin and sOB-R, matched pairs were built with healthy Caucasian patients for sex, Tanner stage (TS), chronologic age (CA), and body mass index (BMI).ResultsBMI and SDS were significantly elevated compared with the reference population. Leptin levels were not different between matched pairs, whereas sOB-R levels were significantly lower in CAH. Consequently, the sOB-R: leptin molar ratios were significantly decreased in CAH. Correlation analyses in CAH patients revealed significant relationship between leptin and CA, TS, BMI, and homeostasis model assessment of insulin resistance. Similar results were obtained for the matched control group. For sOB-R, we found no significant correlation for CA, TS, or BMI in CAH, but we did in the controls. There were significant correlations for androgens within the CAH group. Additional analyses revealed no correlation with steroid medication or metabolic control.ConclusionsOur data show that an altered leptin axis with normal serum leptin concentrations but decreased sOB-R serum levels may contribute to the increased risk of overweight and obesity in CAH.

Objective: Extracellular ATP has been reported as an important signaling molecule mediating quite divergent specific biological effects. Recent clinical trials suggest a potential role of ATP in cancer treatment. The aim of our study was to analyze the mechanisms of UTP in comparison to ATP-mediated cell death in an established cell line model (A-431). Methods: Cell culture and proliferation assays, separation of nucleotides by thin-layer technique, measurement of cytosolic free Ca2+, flow cytometry analysis (annexin V), ultra structure, semi-quantitative RT-PCR, standard statistics. Results: ATP, when added as a single dose between 100 and 500 μM to A-431 cell cultures, showed increasing cytotoxicity, mainly as apoptosis, with a paradoxically decreasing effect at higher concentrations up to 1500 μM. Doses exceeding 1500 μM again led to increasing cytotoxicity. UTP at doses between 500 and 3000 μM resulted in increasing cell death following a normal sigmoid dose-response model. ATP and UTP were degraded by membrane-bound ectoenzymes. ATP degradation products, e.g. adenosine, also induced cell death. Dipyridamole, an adenosine uptake inhibitor, was able to abolish ATP toxicity, which was also counteracted by the addition of uridine. In addition, we found functional and transcriptional evidence for P2 receptors on A-431 cells. Conclusion: Extracellular ATP seems to act via degradation to adenosine and consecutive induction of apoptosis. In contrast, we were not able to demonstrate analogous mechanisms for cell death mediated by extracellular UTP, but were able to provide some evidence of classical ligand-receptor action of uncleaved UTP on A-431 cells.

UNLABELLED Precocious puberty is not a typical manifestation of patients with Klinefelter syndrome (KS). However, there is an increased incidence of mediastinal germ cell tumors (M-GCT) in KS, whereas the discussion of a generally higher tumor risk in this condition is still controversial. A rare subgroup of KS patients consists of prepubertal children with precocious puberty due to human chorionic gonadotropin (hCG)-producing M-GCTs. We present clinical data on a boy with KS and sexual precocity, and summarize the published data on 12 boys with KS out of 54 cases of KS and M-GCT. CLINICAL REPORT an 8.5-year-old boy presented with signs of precocious puberty. Laboratory analyses (suppressed gonadotropins, elevated testosterone) and thoracic CT demonstrated a beta-human chorionic gonadotropin (beta-hCG) and alpha(1)-feto protein (alpha-FP) secreting mediastinal tumor. Histological analysis showed a mixed germ cell tumor comprising choriocarcinoma (CH), embryonal carcinoma (EC), mature teratoma (MT), and yolk sac tumor (YS). He was successfully treated by surgery and adjuvant chemotherapy. Epianalysis of published cases: all KS patients (n = 12), age 4-9 years, presented with precocious sexual development (PP), whereas the older ones showed thorax-associated symptoms, mainly chest pain, dyspnea, and cough. The histological distribution was also age-dependent with mixed germ cell tumors predominantly in younger patients. Thus, M-GCTs are strongly associated with precocious puberty in young boys with KS. Therefore, a karyotype analysis should be included in the clinical work-up of boys with precocious puberty and M-GCT. There is still no convincing explanation for the association of M-GCTs and KS.

OBJECTIVES. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common inherited disorder of adrenal steroid biosynthesis. Patients with the classic form of CAH show androgen excess, with or without salt wasting. There are few studies reporting on higher rates of overweight and obesity among children with CAH. In addition to its role in the regulation of energy balance, leptin is involved in various endocrine and metabolic pathways. In this context, elevated serum leptin levels were reported recently for patients with CAH and were thought to be involved in the development of obesity among these patients. Therefore, the aim of this study was to analyze BMI values, compared with population-based references, for children and adolescents with CAH. Possible contributing factors, such as glucocorticoid therapy, skeletal maturation, birth weight and length, and parental BMI, were correlated with current BMI SD scores (SDS). In addition, the implications of serum leptin levels, corrected for BMI, gender, and Tanner stage, were investigated.METHODS. We performed a cross-sectional retrospective study of 89 children and adolescents with cah (48 female and 41 male subjects; age: 0.2-17.9 years) who presented in our outpatient department during 1 year. All individuals had classic cah, confirmed with molecular genetic analyses, and received substitution therapy (glucocorticoids and mineralocorticoids, if necessary). The quality of therapy was monitored in follow-up visits every 3 to 6 months, on the basis of clinical presentation and laboratory measurement findings according to current guidelines. We grouped the patients into salt wasting and simple virilizing groups, as well as according to current metabolic control. Leptin levels were measured with a commercial radioimmunoassay and calculated as sds. For statistical analyses, standard parametric and nonparametric methods were used.RESULTS. The chronologic ages of the children with CAH were between 0.20 and 17.9 years (mean ± SD: 8.9 ± 4.6 years). The BMI SDS of the whole group ranged from −2.7 to 4.3 (mean ± SD: 0.88 ± 1.3) and was significantly elevated above 0. Fifteen subjects (16.8%) had BMI SDS of >2.0, which indicated a significantly greater frequency of obesity among patients with CAH than expected for the normal population (expected: 2.27%). There was no significant difference in age and BMI between genders and clinical forms (salt wasting versus simple virilizing). BMI SDS was correlated positively with chronologic age. The BMI SDS did not differ significantly between children receiving hydrocortisone, prednisone, or dexamethasone. Hydrocortisone dosages (including equivalent dosages of prednisone and dexamethasone) ranged from 6.2 to 30.1 mg/m2 body surface area (mean ± SD: 14.7 ± 4.8 mg/m2 body surface area). Hydrocortisone dosages were correlated positively with BMI SDS. The relative risk of having a BMI SDS of >2.0 was not significantly elevated among children with prednisone/dexamethasone medication, compared with those with hydrocortisone treatment. In contrast to this, fludrocortisone dosage was not correlated with BMI SDS. Bone age delay, as calculated from the difference of bone age and chronologic age, ranged from −2.9 years to 5.6 years (mean ± SD: 1.11 ± 1.8 years) and was significantly elevated; it was correlated positively with BMI SDS. The BMI of parents ranged from 17.8 to 39.0 kg/m2 (median: 24.2 kg/m2). Median BMI values did not differ significantly between fathers and mothers. The relative risk for obesity among our children (BMI SDS of >2.0) was significantly elevated for children with obese parents, compared with those with nonobese parents (relative risk: 4.86). There was no significant correlation of birth length, birth weight, or gestational age with BMI SDS. Serum leptin values ranged from 0.10 to 32 μg/L (median: 4.4 μg/L); they were correlated positively with BMI SDS, chronologic age, and Tanner stage. After transformation into leptin concentration SDS values, the median SDS of 0.42 (range: −5.4 to 3.1) did not differ significantly from 0.CONCLUSIONS. Children and adolescents with CAH have a higher risk of obesity. Glucocorticoid dosage, chronologic age, advanced bone age maturation, and parental obesity contributed to elevated BMI SDS, whereas birth weight and length, serum leptin levels, used glucocorticoid, and fludrocortisone dosage were not associated with obesity. Therefore, children with CAH who become obese should be tightly monitored and should participate concurrently in weight management programs that include obese family members.

The classical triad of McCune-Albright syndrome (MAS) consists of polyostotic fibrous dysplasia (FD), skin hyperpigmentation (café-au-lait spots), and endocrine dysfunction, frequently seen in females as precocious puberty. Patients with MAS display mosaicism of activating somatic mutations of the alpha-subunit of Gs. Thus, the clinical presentation of each individual is dependent on the particular distribution of affected cells, causing a broad spectrum of endocrine and non-endocrine manifestations. Typical endocrinopathies are precocious puberty, hyperthyroidism, growth hormone excess, hyperprolactemia, and hypercortisolism. The onset of these manifestations is usually during infancy and childhood. Since specific treatment is required, the prognosis depends on the severity of each individual endocrine manifestation. Additionally, there are non-endocrine manifestations, such as fibrous dysplasia of bone (FD), renal phosphate wasting, and skin hyperpigmentation, i.e. café-au-lait spots. FD, mostly polyostotic, causes fractures needing surgical and orthopedic treatment. Since previous studies have suggested the overall prognosis of patients with McCune-Albright syndrome to be non-fatal, recent data have drawn our attention to non-endocrine affections, including hepatobiliary dysfunction and cardiac disease, which are probably an important risk factor for early death. In summary, the clinical picture in MAS is related to its mosaic nature, i.e. any cell, tissue and organ in any site of the body could be affected to varying degrees, ranging from one or two mild clinical signs with excellent long-term prognosis to a severe life-threatening multiorgan disease.

Objective: To analyze spontaneous nocturnal GH profiles, IGF1 and IGFBP3 serum levels, as well as IGF1:IGFBP3 molar ratios in SGA children without postnatal catch-up growth. Methods: Short statured prepubertal SGA children (n=24) were matched retrospectively for sex, age and BMI to short statured children born appropriate for gestational age (AGA), who underwent the same diagnostic program. GH deficiency was excluded in all children by a normal increase of GH in two stimulation tests (>8µg/L). For assessment of spontaneous nocturnal GH secretion, GH serum levels were measured every 20min for 10 hours. Pulsatility was analyzed with Pulsar. Results: None of the Pulsar derived descriptive parameters showed a significant difference between SGA and AGA children. Overall, median IGF1 levels were approximately 1 SDS below zero SDS (p