Childrens Hospital Auf Der Bult

Hannover, Germany

Childrens Hospital Auf Der Bult

Hannover, Germany

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Hulur I.,University of Chicago | Hermanns P.,Johannes Gutenberg University Mainz | Nestoris C.,Endokrinologikum | Heger S.,Childrens Hospital Auf der Bult | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Dual oxidases (DUOX1 and DUOX2) play a crucial role in the generation of hydrogen peroxide required in the oxidation of iodide and the synthesis of thyroid hormone. Heterodimerization with specific maturation factors (DUOXA1 and DUOXA2) is essential for the maturation and function of the DUOX enzyme complexes. Biallelic loss-of-function mutations of DUOX2 result in congenital hypothyroidism (CH), whereas a single reported case of homozygous DUOXA2 mutation (Y246X) has been associated with mild CH. Objective: We now report an infant with transient CH due to a complex genetic alteration of the DUOX/DUOXA system. Results: Our patient was born to euthyroid nonconsanguineous parents and presented with an elevated TSH and enlarged thyroid gland at neonatal screening. Genetic analysis revealed a missense mutation (C189R) on the maternal DUOXA2 allele. The mutant DUOXA2 protein showed complete loss-of-function in reconstituting DUOX2 in vitro. The apparent C189R homozygosity of the proband in the absence of the same mutation in the father led to detailed gene mapping, revealing an approximately 43-kb pair deletion encompassing DUOX2, DUOXA1, and DUOXA2. Thus, in addition to being deficient in DUOXA2, the proband lacks one allele of DUOX2 and DUOXA1 but has two functioning DUOX1 alleles. Conclusion: The transient CH in the presence of only one functional maturation factor allele indicates a high level of functional redundancy in the DUOX/DUOXA system. Copyright © 2011 by The Endocrine Society.


Philotheou A.,University of Cape Town | Arslanian S.,University of Pittsburgh | Blatniczky L.,Buda Childrens Hospital | Peterkova V.,Russian Academy of Sciences | And 2 more authors.
Diabetes Technology and Therapeutics | Year: 2011

Background: We compared the efficacy and safety of insulin glulisine with insulin lispro as part of a basal-bolus regimen in children and adolescents with type 1 diabetes. Methods: Overall, 572 children and adolescents (4-17 years old) using insulin glargine or neutral protamine Hagedorn insulin as basal insulin were enrolled in a 26-week, multicenter, open, centrally randomized, parallel-group, noninferiority study. Subjects were randomized to receive glulisine (n=277) or lispro (n=295) 0-15min premeal. Results: Baseline-to-endpoint hemoglobin A1c changes were similar between the two insulins: adjusted mean change (glulisine vs. lispro), 0.10% versus 0.16%; between-treatment difference (glulisine-lispro), &minsu;0.06, 95% confidence interval (-0.24; 0.12); and prespecified noninferiority margin, 0.4%. Overall, for all age groups together, the percentage of patients achieving American Diabetes Association age-specific A1c targets at endpoint was significantly higher (P=0.039) with glulisine (38.4%) versus lispro (32.0%). From Month 4 to endpoint, both "all" and "severe" symptomatic hypoglycemia rates were similar (3.10 vs. 2.91 and 0.06 vs. 0.07 events/patient-month, respectively). Frequency and type of adverse events, serious adverse events, or hypoglycemia reported as serious adverse events were similar between both groups. Conclusions: Glulisine was as effective as lispro in baseline-to-endpoint A1c change, and both treatments were similarly well tolerated. © Copyright 2011, Mary Ann Liebert, Inc. 2011.


Hammes H.P.,University of Heidelberg | Kerner W.,Heart and Diabetes Center Mecklenburg Vorpommern | Hofer S.,Innsbruck Medical University | Kordonouri O.,Childrens Hospital Auf der Bult | And 2 more authors.
Diabetologia | Year: 2011

Aims/hypothesis: The aim of this study was to analyse the risk profile for diabetic retinopathy under real-life conditions in a large cohort of patients with type 1 diabetes. Methods: Patients (n=18,891) with childhood, adolescent or adult onset of type 1 diabetes from the prospective German Diabetes Documentation System survey were analysed. A total of 8,784 patients fulfilled the inclusion criterion, which was availability of retinopathy status. Retinopathy grading (any retinopathy, advanced retinopathy), treatment regimens and risk factors were prospectively recorded and tested as covariates by Kaplan-Meier analysis and logistic regression. Results: Any retinopathy was present in 27.4% and advanced retinopathy (severe non-proliferative or proliferative diabetic retinopathy) in 8.0% of the cohort. After 40 years of diabetes, the cumulative proportion of patients with any retinopathy and advanced retinopathy was 84.1% and 50.2%, respectively. In multiple regression analysis, risk factors for any retinopathy were diabetes duration (OR 1.167 per year), HbA1c >7.0% (53 mmol/mol) (OR 2.225), smoking (OR 1.295) and male sex (OR 1.187) (p<0.0001 for all). Young age at onset (5 vs 15 years at disease onset) was protective (0.410, p<0.0001). No glycaemic threshold was detected for retinopathy protection. Risk factors for advanced retinopathy were duration (1.124 per year, p<0.0001), male sex (1.323, p=0.0020), HbA1c >7.0% (53 mmol/mol) (1.499, p<0.0001), triacylglycerol >1.7 mmol/l (1.398, p=0.0013) and blood pressure>140/90 mmHg (1.911, p<0.0001). Conclusions/interpretation: The prevalence of retinopathy remains significant in type 1 diabetes. Any improvement of metabolic control and non-smoking is protective, while hypertension affects progression to severe levels under real-life conditions. These data reinforce the validity of multifactorial concepts for morbidity protection in type 1 diabetes. © 2011 Springer-Verlag.


Mueller J.K.,Hannover Medical School | Dietzel A.,University of Leipzig | Lomniczi A.,Oregon Health And Science University | Loche A.,Oregon Health And Science University | And 6 more authors.
Molecular and Cellular Endocrinology | Year: 2011

Kisspeptin, the product of the KiSS1 gene, has emerged as a key component of the mechanism by which the hypothalamus controls puberty and reproductive development. It does so by stimulating the secretion of gonadotropin releasing hormone (GnRH). Little is known about the transcriptional control of the KiSS1 gene. Here we show that a set of proteins postulated to be upstream components of a hypothalamic network involved in controlling female puberty regulates KiSS1 transcriptional activity. Using RACE-PCR we determined that transcription of KiSS1 mRNA is initiated at a single transcription start site (TSS) located 153-156. bp upstream of the ATG translation initiation codon. Promoter assays performed using 293 MSR cells showed that the KiSS1 promoter is activated by TTF1 and CUX1-p200, and repressed by EAP1, YY1, and CUX1-p110. EAP1 and CUX-110 were also repressive in GT1-7 cells. All four TFs are recruited in vivo to the KiSS1 promoter and are expressed in kisspeptin neurons. These results suggest that expression of the KiSS1 gene is regulated by trans-activators and repressors involved in the system-wide control of mammalian puberty. © 2011 Elsevier Ireland Ltd.


Witt L.,Hannover Medical School | Dennhardt N.,Hannover Medical School | Eich C.,Childrens Hospital Auf der Bult | Mader T.,St. Elisabeth Krankenhaus | And 3 more authors.
Paediatric Anaesthesia | Year: 2013

Objectives Neonates and infants are at the highest risk of developing perioperative hypothermia. A number of methods to prevent hypothermia during pediatric anesthesia are in use, and despite the fact that conventional forced-air warmers are the most effective devices, they are not always sufficient enough to maintain body temperature. Therefore, recently a new forced-air warming system with an increased warm air flow was introduced to the market. Aim The aim of this study was to evaluate this new forced-air warming system in neonates and infants during pediatric anesthesia. We hypothesized that the new blanket alone is sufficient enough to prevent neonates and infants from intraoperative hypothermia. Methods Neonates and infants (body weight <10 kg) were enrolled in this prospective multicenter observational study. After admission to the operating room, the children were placed on the new forced-air warming blanket. Body temperature was measured continuously until admission to the recovery room or pediatric intensive care unit (PICU). Results Hundred and nineteen children with a median body weight of 4.1 kg (range: 0.7-9.8) were enrolled and received their intended treatment. Median body temperature at the induction of anesthesia was 36.5°C (range: 35.3-38.2°C) and increased with the length of the operation up to 37.8°C (37.1-38.2°C) after 180 min. Median body temperature after admission to the recovery room or PICU was 37.2°C (36.0-38.6°C) and remained significantly above baseline (P < 0.05). Conclusions The new forced-air warming system as a sole warming device is effective in preventing perioperative hypothermia during pediatric anesthesia in neonates and infants. © 2013 Blackwell Publishing Ltd.


Deichmueller C.M.C.,Childrens Hospital Auf der Bult | Welkoborsky H.-J.,Childrens Hospital Auf der Bult | Welkoborsky H.-J.,Academic Hospital
European Archives of Oto-Rhino-Laryngology | Year: 2010

The atlanto-axial subluxation (Grisel's syndrome) is a rare complication following operative procedures and/or infections in the upper aerodigestive tract. Pathogenetically the higher flexibility of the ligaments during the inflammation causes a subluxation between axis and atlas. When the inflammation heals, this can probably result in a fixation in the rotated position. The purpose of the present study was to describe the clinical and radiological characteristics of this rare disease in children. The clinical files of 12 patients with Grisel's syndrome were examined retrospectively. The clinical files of these patients were reviewed and analyzed along with the results of radiographic and laboratory examinations. The clinical parameters were compared with the patient's therapy and outcome. Of 12 children (6 males, 6 females, average age of 7.1 years), Grisel's syndrome developed following surgery in 8 patients, and in another 4 patients following a severe in infection of the upper aerodigestive tract. The duration of complaints differed from 2 days to 6 months. All patients had a torticollis as the first symptom of atlanto-axial dislocation and three children had accompanying cervical lymphadenopathy. All patients were given antiphlogistic therapy either with diclofenac or ibuprofen. Additionally, 11 patients were treated with intravenous antibiotics (amoxicillin, ampicillin, clindamycin or cephalosporins) and 1 child with oral antibiotics. In eight patients a remission during antibiotic therapy occurred. In four cases (2 with Grisel's syndrome following surgery, 2 following infection), however, the torticollis persisted despite adequate conservative treatment and required reposition of the atlanto-axial joint along with external fixation. In all of them, starting of therapy was delayed. An early diagnosis of Grisel's syndrome and immediate therapy is most important. Grisel's syndrome must be taken under consideration in children with acute torticollis following either an infection or operative procedure in the upper aerodigestive tract. Early adequate antibiotic and antiphlogistic therapy is mandatory and leads to a high remission rate. © 2010 Springer-Verlag.


Russo S.G.,University of Gottingen | Cremer S.,University of Gottingen | Eich C.,University of Gottingen | Eich C.,Childrens Hospital Auf der Bult | And 5 more authors.
British Journal of Anaesthesia | Year: 2012

BackgroundExact information on the anatomical in situ position of extraglottic airway (EGA) devices is lacking. We used magnetic resonance imaging (MRI) to visualize the positions of the i-gel™ and the LMA-Supreme™ (LMA-S) relative to skeletal and soft-tissue structures.MethodsTwelve volunteers participated in this randomized, prospective, cross-over study. Native MRI scans were performed before induction of anaesthesia. Anaesthesia was induced, and the two EGAs were inserted in a randomized sequence. Their positions were assessed functionally, optically by fibrescope, and with MRI scans of the head and neck.ResultsThe LMA-S protruded deeper into the upper oesophageal sphincter than the i-gel™ (P<0.001). Both devices reduced the area of the glottic aperture (P<0.001), and the LMA-S had the largest effect (P0.049). The i-gel™ significantly compressed the tongue (P<0.001). Both devices displaced the hyoid bone ventrally (P<0.001); the i-gel™ to a greater degree (P0.029). The fibreoptically determined position of the bowl of the devices was identical.ConclusionsThe LMA-S and i-gel™ differ significantly with regard to in situ position and spatial relationship with adjacent structures assessed by MRI, despite similar clinical and fibreoptical findings. This could be relevant with regard to risk of aspiration, glottic narrowing, and airway resistance and soft-tissue morbidity. © 2012 The Author [2012].


Neubauer A.-P.,Childrens Hospital Auf der Bult | Voss W.,Sozialpadiatrisches Zentrum | Wachtendorf M.,Sozialpadiatrisches Zentrum | Jungmann T.,Leibniz University of Hanover
Annals of Neurology | Year: 2010

Objective: Erythropoietin has been reported to possess neuroprotective properties in animal studies. No previous studies have investigated the neurodevelopmental outcome of extremely low birth weight (ELBW) infants treated with recombinant human erythropoietin (rEpo) and evaluated it at school age. Methods: Of 200 ELBW infants treated from 1993 to 1998, 171 (86%) survived, and 148 (87%) were followed up to the age of 10 to 13 years. The neurodevelopmental and school outcome of the ELBW infants receiving rEpo treatment for stimulation of erythropoiesis in the first weeks of life (n = 89) was compared to that of untreated children (n = 57). To test for a neuroprotective effect of erythropoietin therapy, analyses of variance (ANOVAs) were conducted with erythropoietin treatment and intraventricular hemorrhage (IVH) as independent variables and Hamburg-Wechsler Intelligence Test for Children-III (HAWIK-III) intelligence quotient (IQ) scores as dependent variables. Results: The rEpo group scored significantly better than untreated children in the overall developmental assessment (55% vs 39% normally developed, p < 0.05) as well as in the psychological examination (mean composite HAWIK-III IQ score, 90.8 vs 81.3, p < 0.005). The results of ANOVAs show that these differences were ascribable to children with IVH. Whereas those children with IVH treated with rEpo scored significantly better than untreated children (52% vs 6% normally developed, composite HAWIK-III IQ score, 90.3 vs 67.0), treated and untreated children without IVH did not differ in their outcome. The treatment and control groups were comparable in perinatal parameters relevant to prognosis. Interpretation: The results of our observational study confirm the hypothesis of a neuroprotective effect of rEpo in ELBW infants with IVH. This offers a promising preventative therapeutic option for the treatment of these high-risk infants. © 2010 American Neurological Association.


Mueller J.K.,Hannover Medical School | Heger S.,Hannover Medical School | Heger S.,Childrens Hospital Auf der Bult
Reproductive Toxicology | Year: 2014

Endocrine disrupting chemicals have been shown to alter the pubertal process. The controlling levels of the Gonadotropin releasing hormone (GnRH) network involve GnRH itself, KiSS1, and the transcriptional regulators enhanced at puberty 1 (EAP1), Thyroid Transcription Factor 1 (TTF1), and Yin Yang 1 (YY1). While Genistein and Bisphenol A (BPA) have been shown to advance the advent of puberty, exposure to Dioxin delayed pubertal onset.Utilizing in vitro approaches, we observed that Genistein and BPA suppress inhibitory and activate stimulatory components of the GnRH network, while Dioxin exhibit an inhibitory effect at all regulatory hierarchical levels of the GnRH network. It repressed KiSS1, Gnrh, Ttf1 and Yy1 transcription via the xenobiotic response element (XRE), while EAP1 was not affected.Therefore, EDCs alter the neuroendocrine GnRH regulatory network at all hierarchical levels. © 2013 Elsevier Inc.


Dissen G.A.,Oregon Health And Science University | Lomniczi A.,Oregon Health And Science University | Heger S.,Oregon Health And Science University | Heger S.,Childrens Hospital Auf der Bult | And 2 more authors.
Endocrinology | Year: 2012

Mammalian reproductive cyclicity requires the periodic discharge of GnRH from hypothalamic neurons into the portal vessels connecting the neuroendocrine brain to the pituitary gland. GnRH secretion is, in turn, controlled by changes in neuronalandglial inputs to GnRH-producing neurons. The transcriptional control of this process is not well understood, but it appears to involve several genes. One of them, termed enhanced at puberty 1 (EAP1), has been postulated to function in the female hypothalamus as an upstream regulator of neuroendocrine reproductive function. RNA interference-mediated inhibition of EAP1 expression, targeted to the preoptic region, delays puberty and disrupts estrous cyclicity in rodents, suggesting that EAP1 is required for the normalcy of these events. Here, we show that knocking down EAP1 expression in a region of the medial basal hypothalamus that includes the arcuate nucleus, via lentiviral-mediated delivery of RNA interference, results in cessation of menstrual cyclicity in female rhesus monkeys undergoing regular menstrual cycles. Neither lentiviruses encoding an unrelated small interfering RNA nor the placement of viral particles carrying EAP1 small interfering RNA outside the medial basal hypothalamus-arcuate nucleus region affected menstrual cycles, indicating that region-specific expression of EAP1 in the hypothalamus is required for menstrual cyclicity in higher primates. The cellular mechanism by which EAP1 exerts this function is unknown, but the recent finding that EAP1 is an integral component of a powerful transcriptional-repressive complex suggests that EAP1 may control reproductive cyclicity by inhibiting downstream repressor genes involved in the neuroendocrine control of reproductive function. Copyright © 2012 by The Endocrine Society.

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