Relation of health-related quality of life to near final height and body composition in adolescents with chronic endocrinopathies during transition period.

INTRODUCTION: We evaluated sequelae of disease and therapy in adolescents with chronic endocrinopathies using a medical and psychological workup to record health-related quality of life (HRQoL), near final height (NFH) and body compositions during the transition period from paediatric to adult care. METHODS: Near final height, weight, body mass index (BMI), grip strength (GS), hip and waist circumference (HC; WC), skin folds (SF) and HRQoL T-scores by KIDSCREEN and DISABKIDS were assessed in 134 patients (70 females and 64 males) from May 2010 to March 2016 diagnosed with congenital adrenal hyperplasia (CAH; n = 22), multiple pituitary hormone deficiency (MPHD; n = 17), growth hormone deficiency (GHD; n = 37), Turner syndrome (TS; n = 27), SGA-short stature (SGA; n = 20) and Klinefelter syndrome (KS; n = 11). RESULTS: Median HRQoL T-scores for KIDSCREEN (50.6-56.5) and DISABKIDS (52.7-58.9) ranged within references with considerable variations but without significant deficit in any diagnosis. Median-corrected height SDS (CoH-SDS: NFH-SDS-TH [target height]-SDS) was >-1, except in KS (SDS + 1.3) and in TS (SDS - 1.9; P < .0001) without correlations with HRQoL. Median BMI was below 25 kg/m2 in all patients except MPHD (26.5 kg/m2 ; SDS 1.5; P = .006). BMI correlated negatively in CAH females with self-perception (rs  = -.64, P = .0338), physical well-being (rs  = -.8; P = .0086), social exclusion rs  = -.65; P = .031) and emotions (rs  = -.7; P = .0169). CONCLUSION: Health-related quality of life and body compositions were similar to those of healthy adolescents. Lower scores in HRQoL dimensions as self-perception, physical well-being, social exclusion and emotions were detected and correlated negatively with BMI. Treatment strategies and psychological support should consider HRQoL and adapted in specific treatment guidelines.

Typical characteristics of children with congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency: a single-centre experience and review of the literature.

Background 11ß-hydroxylase deficiency (11ßOHD) is a rare disease representing the second most common cause of congenital adrenal hyperplasia (CAH) (5-8%) with an incidence of about 1:100,000. In contrast to 21-hydroxylase deficiency (21OHD), 11ßOHD is not included in neonatal screening programmes. The objective of this study was to demonstrate the typical features of male patients with 11ßOHD. Methods Clinical, biochemical and radiological data of patients with 11ßOHD were analysed in this retrospective single-centre analysis. Results Six male patients of four unrelated families with 11ßOHD were identified (0.1-13.5 years of chronological age [CA] at diagnosis). The predominant symptoms were arterial hypertension, tall stature and precocious pseudopuberty. Bone ages (BAs) were remarkably advanced at diagnosis in four index patients (median difference BA-CA: 5.5 years, range 1.5-9.2 years). Homozygous mutations were identified in exon 7 (c.1179_1180dupGA [p.Asn394Argfs*37]) and exon 8 (c.1398+2T>C) of the CYP11B1 gene leading both to a complete loss of function. The latter mutation has not yet been described in databases. 11ßOHD was identified by the measurement of 11-deoxycortisol in a newborn screening card of one patient retrospectively. Testicular adrenal rest tumours (TARTs) were detected in three patients at 3.7 years, 11 years and 14.4 years. Conclusion The diagnosis of CAH due to 11ßOHD is delayed and should be suspected in children with arterial hypertension, tall stature and precocious pseudopuberty. Patients may develop TARTs as early as infancy. 11ßOHD should be included in newborn screening programmes, at least in newborns of index families, to allow early diagnosis and the start of treatment to reduce morbidity.

Clinical Features and Response to Treatment of Prolactinomas in Children and Adolescents: A Retrospective Single-Centre Analysis and Review of the Literature.

BACKGROUND: Paediatric prolactinomas are rare. The aim of this study was to investigate the clinical features and outcome of paediatric patients with prolactinomas. METHODS: In this single-centre retrospective analysis, clinical, biochemical, and radiological features of all paediatric patients with pituitary adenomas diagnosed between 2000 and 2016 were evaluated. RESULTS: Among 21 patients with pituitary adenomas, 12 patients with prolactinomas (median age 14.2 years, range 11-16.6 years, 8 females, 4 males) were identified (7 macro- and 5 microprolactinomas). The most common clinical symptoms were headaches (67%) and pubertal delay (67%). All patients with macroprolactinomas with prolactin concentrations >10,000 mU/L had at least 1 pituitary hormone deficiency. Cabergoline as first-line treatment (n = 11, median follow-up of 37 months, range 12-89 months) induced normoprolactinemia (n = 8), reduced the mean tumour volume by 80%, and ameliorated headaches (p = 0.016) and pubertal delay (p = 0.031), whereas intermittent moderate side effects occurred in 55%. CONCLUSION: Adolescents with headaches and pubertal delay should be investigated for prolactinomas. Treatment with cabergoline is well tolerated and effective in reducing clinical symptoms and prolactin concentrations was well as inducing tumour shrinkage. Further clinical prospective studies are needed to standardize paediatric treatment modalities.

Puberty marks major changes in the hippocampal and cortical c-Fos activation pattern induced by NMDA receptor antagonists.

Non-selective and subunit (GluN2B)-specific N-methyl-d-aspartate receptor (NMDAR) antagonists represent promising alternative antidepressant drugs with fast onset of the therapeutic action. The neuronal activation pattern induced by NMDAR antagonists is well characterized by c-Fos expression analysis only in the adult rodent brain. In contrast, there is little information available regarding their effects during postnatal development. Here we performed a systematic c-Fos brain mapping of the non-selective NMDAR antagonist MK-801 and the GluN2B-specific antagonist Ro 25-6981 from postnatal day 16 (P16) to P40. We found significant regional differences with gender-specificity in the activation pattern compared to the adult. Surprisingly, in the hippocampus, MK-801 triggered at pre-pubertal stages (especially at P24) very strong c-Fos expression, followed by low levels after P30, the approximate time point of puberty onset in mice. The cortical distribution of MK-801-triggered c-Fos expression before puberty differed also substantially from the adult brain, showing high levels only in deep cortical layers at pre-pubertal stages. In comparison, the cortical activation induced by Ro 25-6981 diminished from high pre-pubertal levels and was in comparison with that triggered by MK-801 low in the hippocampus. These results reveal highly dynamic changes in the c-Fos activation pattern induced by NMDAR antagonists during puberty. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain.

NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.

Guanine nucleotide-binding protein α subunit hypofunction in children with short stature and disproportionate shortening of the 4th and 5th metacarpals.

BACKGROUND: GNAS encodes the α subunit of the stimulatory G protein (Gsα). Maternal inherited Gsα mutations cause pseudohypoparathyroidism type Ia (PHP-Ia), associated with shortening of the 4th and 5th metacarpals. AIMS: Here we investigated the Gsα pathway in short patients with distinct shortening of the 4th and 5th metacarpals. METHODS: In 571 children with short stature and 4 patients with PHP-Ia metacarpal bone lengths were measured. In identified patients we analysed the Gsα protein function in platelets, performed GNAS sequencing, and epigenetic analysis of four significant differentially methylated regions. RESULTS: In 51 patients (8.9%) shortening of the 4th and 5th metacarpals was more pronounced than their height deficit. No GNAS coding mutations were identified in 20 analysed patients, except in 2 PHP-Ia patients. Gsα activity was reduced in all PHP-Ia patients and in 25% of the analysed patients. No significant methylation changes were identified. CONCLUSIONS: Our findings suggest that patients with short stature and distinct metacarpal bone shortening could be part of the wide variety of PHP/PPHP, therefore it was worthwhile analysing the Gsα protein function and GNAS gene in these patients in order to further elucidate the phenotype and genotype of Gsα dysfunction.

Height gain in Ullrich-Turner syndrome after early and late growth hormone treatment start: results from a large retrospective German study and potential basis for an individualized treatment approach.

BACKGROUND: Ullrich-Turner syndrome (UTS) girls often present with short stature in adolescence to the endocrinologist when the efficacy of growth hormone (GH) to improve growth remains unknown and parameters to estimate individual GH responsiveness have yet to be determined. OBJECTIVE: Retrospective evaluation of adult height (AH) and predicted adult height at GH start (descriptive model of Ranke, Model PredAH) in early and late GH-treated German UTS patients. SUBJECTS/METHODS: 313 patients treated with GH, early [chronological age (CA) at GH start <12 years, n = 259] or late (CA at GH start ≥12 years, n = 54) who reached AH were selected from KIGS (Pfizer International Growth Database). RESULTS: AH (152.5 ± 5.9 vs. 151.1 ± 5.4 cm, p = n.s.) after GH treatment for 7.5 ± 2.12 years (GH start early) and for 5.2 ± 1.2 years (GH start late) were similar (p = n.s.) as Model PredAH (155.7 ± 4.8 vs. 154.7 ± 4.8 cm; p = n.s.) but higher (p < 0.001) than projected adult height (Ranke, ProjAH; 148.2 ± 5.5 vs. 145.2 ± 6.7 cm; p = 0.001). Total height gain over ProjAH was 4.3 ± 4.6 cm (GH start early) and 5.8 ± 4.7 cm (GH start late, p = 0.021), respectively. CONCLUSIONS: GH may improve AH in UTS patients even when started late. The individual growth response could be estimated by the descriptive Model PredAH independent of age at treatment start.

Correlation of soluble gp130 serum concentrations with arterial blood pressure.

OBJECTIVES: An increased blood pressure can elicit remodeling of the cardiovascular system. Experimental data have implicated gp130, a subunit of the receptor for interleukin-6 (IL-6)-related cytokines, in the regulation of proliferation and apoptosis of cardiomyocytes and vascular smooth muscle cells (VSMC). Here, we investigate whether serum soluble gp130 concentrations correlate with blood pressure in humans, whether gp130 expression in the aorta differs between hypertensive and control rats, and whether angiotensin II or endothelin regulate gp130 expression in human VSMC. METHODS: We measured serum concentrations of soluble gp130, IL-6, the soluble IL-6 receptor, and the intima-media thickness of the common carotid artery in stroke patients (n = 48) and in elderly controls (n = 48). Furthermore, soluble gp130 levels were measured in young controls (n = 200). Expression of gp130 in Wistar-Kyoto (n = 12), spontaneously hypertensive rats (n = 12), and human VSMC was detected by real-time reverse transcription-PCR and immunohistochemistry. RESULTS: Soluble gp130 serum concentrations correlated with blood pressure in stroke patients and in elderly and young controls and with the intima-media thickness of the common carotid artery in stroke patients. The hypothesis that elevated soluble gp130 derives from the vascular system was supported by the enhanced expression of gp130 in the aortic wall of spontaneously hypertensive rats. Furthermore, treatment of human VSMC with angiotensin II stimulated gp130 expression. CONCLUSION: Our data suggest that soluble gp130 serum concentrations are correlated with blood pressure and may reflect vascular remodeling in response to arterial hypertension.

NF-kappaB p50/RelA and c-Rel-containing dimers: opposite regulators of neuron vulnerability to ischaemia.

Diverse nuclear factor-kappaB subunits mediate opposite effects of extracellular signals on neuron survival. While RelA is activated by neurotoxic agents, c-Rel drives neuroprotective effects. In brain ischaemia RelA and p50 factors rapidly activate, but how they associate with c-Rel to form active dimers and contribute to the changes in diverse dimer activation for neuron susceptibility is unknown. We show that in both cortical neurons exposed to oxygen glucose deprivation (OGD) and mice subjected to brain ischaemia, activation of p50/RelA was associated with inhibition of c-Rel/RelA dimer and no change p50/c-Rel. Targeting c-Rel and RelA expression revealed that c-Rel dimers reduced while p50/RelA enhanced neuronal susceptibility to anoxia. Activation of p50/RelA complex is known to induce the pro-apoptotic Bim and Noxa genes. We now show that c-Rel-containing dimers, p50/c-Rel and RelA/c-Rel, but not p50/RelA, promoted Bcl-xL transcription. Accordingly, the OGD exposure induced Bim, but reduced Bcl-xL promoter activity and decreased the content of endogenous Bcl-xL protein. These findings demonstrate that within the same neuronal cell, the balance between activation of p50/RelA and c-Rel-containing complexes fine tunes the threshold of neuron vulnerability to the ischaemic insult. Selective targeting of different dimers will unravel new approaches to limit ischaemia-associated apoptosis.

Induction of the cytokine TWEAK and its receptor Fn14 in ischemic stroke.

Stroke outcome is determined by delayed neuronal cell death and edema formation. TWEAK, a cytokine of the TNF superfamily, and its membrane receptor Fn14 promote ischemia-induced neuronal apoptosis and leakage of the blood-brain barrier. Both TWEAK and Fn14 are upregulated in experimental stroke models. In this study, we investigated whether TWEAK and Fn14 are upregulated in stroke patients. We measured serum concentrations of TWEAK in stroke patients and matched control subjects by ELISA. Expression of Fn14 in the brain was evaluated by real-time RT-PCR and immunohistochemistry. TWEAK serum concentrations were elevated in stroke patients. In autopsy samples, we found elevated mRNA levels of the receptor Fn14 and a trend towards higher TWEAK mRNA levels. In the infarcted and peri-infarct tissue immunostaining for Fn14 was enhanced. These data show that the cytokine TWEAK and its membrane receptor Fn14 are upregulated in stroke and suggest that they contribute to stroke outcome.

Neuronal NF-kappaB influences thermoregulation and survival in a sepsis model.

Gene regulation in sepsis is known to be controlled by the transcription factor NF-kappaB. However, the function of neuronal NF-kappaB in sepsis is not well defined. In a mouse model of sepsis induced by i.p. injection of lipopolysaccharides (LPS), we found an activation of NF-kappaB in the brain as shown by the induction of a transgenic NF-kappaB reporter. Inhibition of neuronal NF-kappaB by cell-specific expression of the NF-kappaB super-repressor IkappaBalpha-SR improved LPS-induced hypothermia and survival but had no effect on body weight or on the humoral response to LPS. In contrast, glial inhibition of NF-kappaB did not influence body temperature and survival. By immunohistochemistry, we detected the active NF-kappaB subunit RelA in neuronal nuclei of the organum vasculosum of the lamina terminalis. Our data reveal an important role of neuronal NF-kappaB in thermoregulation and survival. The upcoming group of NF-kappaB inhibitors may have a place in the treatment of the acute-phase response.

Bim and Noxa are candidates to mediate the deleterious effect of the NF-kappa B subunit RelA in cerebral ischemia.

The transcription factor nuclear factor kappaB (NF-kappaB) is well known for its antiapoptotic action. However, in some disorders, such as cerebral ischemia, a proapoptotic function of NF-kappaB has been demonstrated. To analyze which subunit of NF-kappaB is functional in cerebral ischemia, we induced focal cerebral ischemia in mice with a germline deletion of the p52 or c-Rel gene or with a conditional deletion of RelA in the brain. Only RelA deficiency reduced infarct size. Interestingly, expression of the proapoptotic BH3 (Bcl-2 homology domain 3)-only genes Bim and Noxa in cerebral ischemia depended on RelA and the upstream kinase IKK (IkappaB kinase). RelA stimulated Bim and Noxa gene transcription in primary cortical neurons and bound to the promoter of both genes. Thus, the deleterious function in cerebral ischemia is specific for the NF-kappaB subunit RelA and may be mediated through Bim and Noxa.

IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors.

Cytokine-dependent mechanisms in the CNS have been implicated in the pathogenesis of depression. Interleukin-6 is upregulated in depressed patients and dowregulated by antidepressants. It is, however, unknown whether IL-6 is involved in the pathogenesis of depression. We subjected IL-6-deficient mice (IL-6(-/-)) to depression-related tests (learned helplessness, forced swimming, tail suspension, sucrose preference). We also investigated IL-6 in the hippocampus of stressed wild-type mice. IL-6(-/-) mice showed reduced despair in the forced swim, and tail suspension test, and enhanced hedonic behavior. Moreover, IL-6(-/-) mice exhibited resistance to helplessness. This resistance may be caused by the lack of IL-6, because stress increased IL-6 expression in wild-type hippocampi. This suggests that IL-6 is a component in molecular mechanisms in the pathogenesis of depression. IL-6(-/-) mice represent tools to study IL-6-dependent signaling pathways in the pathophysiology of depression in vivo. Moreover, these mice may support the screening of compounds for depression by altering cytokine-mediated signaling.