University Childrens Hospital Dusseldorf

Düsseldorf, Germany

University Childrens Hospital Dusseldorf

Düsseldorf, Germany
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Hadjipanayi E.,TU Munich | Hadjipanayi E.,Bogenhausen Hospital | Bauer A.T.,TU Munich | Moog P.,TU Munich | And 10 more authors.
Journal of Controlled Release | Year: 2013

Spatiotemporally-controlled delivery of hypoxia-induced angiogenic factor mixtures has been identified by this group as a promising strategy for overcoming the limited ability of chronically ischemic tissues to generate adaptive angiogenesis. We previously developed an implantable, as well as an injectable system for delivering fibroblast-produced factors in vivo. Here, we identify peripheral blood cells (PBCs) as the ideal factor-providing candidates, due to their autologous nature, ease of harvest and ample supply, and investigate wound-simulating biochemical and biophysical environmental parameters that can be controlled to optimize PBC angiogenic activity. It was found that hypoxia (3% O2) significantly affected the expression of a range of angiogenesis-related factors including VEGF, angiogenin and thrombospondin-1, relative to the normoxic baseline. While all three factors underwent down-regulation over time under hypoxia, there was significant variation in the temporal profile of their expression. VEGF expression was also found to be dependent on cell-scaffold material composition, with fibrin stimulating production the most, followed by collagen and polystyrene. Cell-scaffold matrix stiffness was an additional important factor, as shown by higher VEGF protein levels when PBCs were cultured on stiff vs. compliant collagen hydrogel scaffolds. Engineered PBC-derived factor mixtures could be harvested within cell-free gel and microsphere carriers. The angiogenic effectiveness of factor-loaded carriers could be demonstrated by the ability of their releasates to induce endothelial cell tubule formation and directional migration in in vitro Matrigel assays, and microvessel sprouting in the aortic ring assay. To aid the clinical translation of this approach, we propose a device design that integrates this system, and enables one-step harvesting and delivering of angiogenic factor protein mixtures from autologous peripheral blood. This will facilitate the controlled release of these factors both at the bed-side, as an angiogenic therapy in wounds and peripheral ischemic tissue, as well as pre-, intra- and post-operatively as angiogenic support for central ischemic tissue, grafts, flaps and tissue engineered implants. © 2013 Elsevier B.V.


Woopen C.,University of Cologne | Pauls K.A.M.,University of Cologne | Koy A.,University of Cologne | Koy A.,University Childrens Hospital Dusseldorf | And 2 more authors.
Progress in Neurobiology | Year: 2013

Deep brain stimulation (DBS) has proven to be a successful therapeutic approach in several patients with movement disorders such as Parkinson's disease and dystonia. Hitherto its application was mainly restricted to advanced disease patients resistant to medication or with severe treatment side effects. However, there is now growing interest in earlier application of DBS, aimed at improving clinical outcomes, quality of life, and avoiding psychosocial consequences of chronic disease-related impairments. We address the clinical and ethical aspects of two "early" uses of DBS, (1) DBS early in the course of the disease, and (2) DBS early in life (i.e. in children). Possible benefits, risks and burdens are discussed and thoroughly considered. Further research is needed to obtain a careful balance between exposing vulnerable patients to potential severe surgical risks and excluding them from a potentially good outcome. © 2013 Elsevier Ltd.


Salgin B.,University of Cambridge | Salgin B.,University Childrens Hospital Dusseldorf | Norris S.A.,University of Witwatersrand | Prentice P.,University of Cambridge | And 7 more authors.
International Journal of Obesity | Year: 2015

Background: Early postnatal rapid 'catch-up' weight gain has been consistently associated with subsequent higher obesity risk and earlier pubertal development. In many low- and middle-income countries, infancy catch-up weight gain is transient and often followed by growth faltering. We explored the hypothesis that even transient catch-up weight gain during infancy is associated with later obesity risk and earlier puberty. Methods: A total of 2352 (1151 male, 1201 female) black South African children in the birth to twenty prospective birth cohort study (Johannesburg-Soweto) underwent serial measurements of body size and composition from birth to 18 years of age. At the age of 18 years, whole-body fat mass and fat-free mass were determined using dual-energy X-ray absorptiometry. Pubertal development was assessed by the research team between ages 9 and 10 years, and it was recorded annually from the age of 11 years using a validated self-assessment protocol. Results: Catch-up weight gain from birth to the age of 1 year, despite being followed by growth faltering between ages 1 and 2 years, was associated with greater mid-upper arm circumference (P = 0.04) and skinfold thickness (P = 0.048) at 8 years of age, and with higher weight (P < 0.001) and body mass index (P = 0.001) at 18 years of age after adjustment for sex, age, smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status. Infancy catch-up weight gain was also associated with younger age at menarche in girls (P < 0.001). This association persisted after adjustment for smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status (P = 0.005). Conclusion: Transient catch-up weight gain from birth to the age of 1 year among children born in a low-income area of South Africa was associated with earlier menarche and greater adiposity in early adulthood. This observation suggests that modifiable determinants of rapid infancy weight gain may be targeted in order to prevent later obesity and consequences of earlier puberty in girls. © 2015 Macmillan Publishers Limited. All rights reserved.


Klingmann V.,University Childrens Hospital Dusseldorf | Spomer N.,University Childrens Hospital Dusseldorf | Lerch C.,Cochrane Metabolic and Endocrine Disorders Group | Stoltenberg I.,Heinrich Heine University Düsseldorf | And 4 more authors.
Journal of Pediatrics | Year: 2013

Objective To evaluate acceptability of 2 mm solid dosage forms (mini-tablets) as an alternative administration modality in young children in comparison with syrup. Study design Three hundred six pediatric in- and outpatients aged 6 months-5 years (51 in each of 6 age groups) were recruited. An open, randomized cross-over study was conducted to compare acceptability and capability to swallow 2 mm uncoated or coated mini-tablets vs 3 mL syrup. Results In the overall patient population of 306 children, the acceptability of uncoated mini-tablets was superior to syrup (difference in proportions 14.8%, 95% CI 10.2-19.4; P <.0001). In line with this finding, the level of capability to swallow was higher for uncoated mini-tablets compared with syrup as well (difference in proportions 12.3%, 95% CI 5.4-19.3; P =.0008). All 3 pharmaceutical formulations were well tolerated, and none of the 306 children inhaled or coughed because of the syrup or the uncoated mini-tablet; only 2 of the 306 children (both in age group 0.5-1 year) coughed because of the coated mini-tablet, in both cases without clinical relevance. Conclusions Mini-tablets are a valuable alternative to syrup for children 6 months-6 years of age and are more acceptable compared with liquid formulation. Regulatory bodies such as Food and Drug Administration and European Medicine Agency are encouraged to take our data into account for guideline updates and future drug approval processes. © 2013 Mosby Inc. All rights reserved.


Meissner T.,University Childrens Hospital Dusseldorf | Wolf J.,St Vincenz Children Hospital | Kersting M.,University of Bonn | Frohlich-Reiterer E.,Medical University of Graz | And 4 more authors.
Clinical Nutrition | Year: 2014

Background & aims: To compare reported and recommended carbohydrate intake in children and adolescents with type 1 diabetes (T1D) and to explore associations with BMI, HbA1c and lipid profile. Methods: A cross-sectional observational study of reported carbohydrate intake in 46,010 patients with T1D aged 1-18 years from 332 diabetes centres in Germany and Austria in comparison to age-matched healthy children and adolescents. Results: The median reported carbohydrate intake in T1D patients was markedly lower than in healthy children. It varied between 56% and 90% of recommended amounts across the paediatric age range with younger patients showing levels closer to recommend. Lower carbohydrate intake was associated with higher BMI-SDS (p<0.001), particularly during adolescence, higher total cholesterol (p<0.001), higher LDL-cholesterol (p=0.005) and lower HbA1c (p<0.001). Conclusions: The methodologically simple measure of reported carbohydrate intake may be a valuable addition to the information gathered on paediatric patients with T1D in an outpatient setting. Children and adolescents with T1D appear to restrict their consumption of carbohydrates, which may have adverse effects on BMI and the lipid profile, particularly if there is a compensatory increased fat intake. Health care providers should therefore advise patients and parents of the recommended age-dependent levels of carbohydrate intake. © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.


Klingmann V.,University Childrens Hospital Dusseldorf | Seitz A.,University Childrens Hospital Dusseldorf | Meissner T.,University Childrens Hospital Dusseldorf | Breitkreutz J.,Heinrich Heine University Düsseldorf | And 2 more authors.
Journal of Pediatrics | Year: 2015

Objective: To evaluate the suitability of drug-free solid dosage forms (2mm mini-tablets) as an alternative administration modality in neonates in comparison with syrup. Study design: A total of 151 neonates (inpatients; aged 2-28days; median 4days) were recruited. An open, randomized, prospective cross-over study was conducted to compare the acceptability and swallowability of 2mm uncoated mini-tablets compared with .5mL syrup. Results: All neonates (N=151) accepted the uncoated mini-tablet as well as the syrup (both formulations 100%; 95% CI 97.6%-100.0%; primary objective). The level of swallowability of uncoated mini-tablets was not inferior (P<.0001), in fact even higher (difference in proportions 10.0%; 95% CI 1.37%-19.34%; P=.0315) compared with syrup. Both pharmaceutical formulations were well tolerated, and in none of the 151 neonates, serious adverse events occurred; particularly none of the neonates inhaled or coughed in either of the formulations. Conclusions: The administration of uncoated mini-tablets proved to be a valuable alternative to syrup for term neonates. Our data on neonates close the age gap of prior findings in toddlers and infants: uncoated mini-tablets offer the potential of a single formulation for all age groups. These findings further shift the paradigm from liquid toward small-sized solid drug formulations for children of all age groups, as the World Health Organization proposes. Trial registration: German Clinical Trials Register (Deutsches Register Klinischer Studien [DRKS; germanctr.de]): DRKS00005609. © 2015 Elsevier Inc.


Klingmann V.,University Childrens Hospital Dusseldorf | Seitz A.,University Childrens Hospital Dusseldorf | Meissner T.,University Childrens Hospital Dusseldorf | Breitkreutz J.,Heinrich Heine University Düsseldorf | And 2 more authors.
The Journal of pediatrics | Year: 2015

OBJECTIVE: To evaluate the suitability of drug-free solid dosage forms (2 mm mini-tablets) as an alternative administration modality in neonates in comparison with syrup.STUDY DESIGN: A total of 151 neonates (inpatients; aged 2-28 days; median 4 days) were recruited. An open, randomized, prospective cross-over study was conducted to compare the acceptability and swallowability of 2 mm uncoated mini-tablets compared with .5 mL syrup.RESULTS: All neonates (N = 151) accepted the uncoated mini-tablet as well as the syrup (both formulations 100%; 95% CI 97.6%-100.0%; primary objective). The level of swallowability of uncoated mini-tablets was not inferior (P < .0001), in fact even higher (difference in proportions 10.0%; 95% CI 1.37%-19.34%; P = .0315) compared with syrup. Both pharmaceutical formulations were well tolerated, and in none of the 151 neonates, serious adverse events occurred; particularly none of the neonates inhaled or coughed in either of the formulations.CONCLUSIONS: The administration of uncoated mini-tablets proved to be a valuable alternative to syrup for term neonates. Our data on neonates close the age gap of prior findings in toddlers and infants: uncoated mini-tablets offer the potential of a single formulation for all age groups. These findings further shift the paradigm from liquid toward small-sized solid drug formulations for children of all age groups, as the World Health Organization proposes.TRIAL REGISTRATION: German Clinical Trials Register (Deutsches Register Klinischer Studien [DRKS; germanctr.de]): DRKS00005609. Copyright © 2015 Elsevier Inc. All rights reserved.


Marquard J.,University Childrens Hospital Dusseldorf | Palladino A.A.,Children's Hospital of Philadelphia | Stanley C.A.,Children's Hospital of Philadelphia | Mayatepek E.,University Childrens Hospital Dusseldorf | Meissner T.,University Childrens Hospital Dusseldorf
Seminars in Pediatric Surgery | Year: 2011

Rare forms of congenital hyperinsulinism (CHI) are caused by mutations in GLUD1 (encoding glutamate dehydrogenase), GCK (encoding glucokinase), HADH (encoding for L-3-hydroxyacyl-CoA dehydrogenase), SLC16A1 (encoding the monocarboxylat transporter 1), HNF4A (encoding hepatocyte nuclear factor 4α) or UCP2 (encoding mitochondrial uncoupling protein 2). The clinical presentation is very heterogeneous in regards to age of onset, severity, and manner of symptoms, as well as the response to medical treatment. Special individual characteristics have to be accounted in diagnosis and treatment. Diazoxide is the first-line drug for the rare forms of CHI for long-term treatment but is not entirely effective in some of these rarer defects (GCK, MCT1). The use of diazoxide is often limited by side effects and the use of octreotide as second-line drug has to be considered. A near-total pancreatectomy is only reserved for patients with diffuse disease and resistance to medical treatment as a last resort. Patients with CHI should be managed by centers with a highly experienced team in diagnostic work-up and treatment of this disease. © 2011 Elsevier Inc.


Salgin B.,University of Cambridge | Salgin B.,University Childrens Hospital Dusseldorf | Ong K.K.,University of Cambridge | Ong K.K.,Institute of Metabolic Science | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: There are limited data in humans on the association between fasting free fatty acid (FFA) levels and pancreatic β-cell function. Objective: Our objective was to examine this association in children and adults with normal glucose tolerance and to explore fasting FFA levels in relation to subsequent risk of impaired glucose tolerance (IGT) and type 2 diabetes (T2D). Design: We measured FFA, glucose, and insulin levels after an overnight fast and 30 min after an oral glucose load in 797 children aged 8 yr in the Avon Longitudinal Study of Parents and Children and 770 adults aged 44-71 yr in the Medical Research Council Ely Study. We calculated the homeostasis model assessment to estimate fasting insulin sensitivity, the insulinogenic index to estimate insulin secretion, and the disposition index to assess insulin secretion corrected for insulin sensitivity. Results: Higher fasting FFA levels were associated with lower insulin secretion in children (boys, P = 0.03; girls, P = 0.001) and adults (men, P = 0.03, women, P = 0.04). Associations with insulin sensitivity were more variable, but after adjustment for insulin sensitivity, higher fasting FFA levels remained associated with lower insulin secretion (disposition index). Compared with adults in the lowest tertile of fasting FFA levels, those in the middle and highest tertiles had a 3-fold higher incidence of IGT or T2D over the following 5-8 yr. Conclusions: Higher fasting FFA levels were consistently associated with lower insulin secretion in children and adults with normal glucose tolerance. Furthermore, higher fasting FFA levels were prospectively associated with a greater risk of subsequent IGT and T2D. Copyright © 2012 by The Endocrine Society.


Koy A.,University of Cologne | Koy A.,University Childrens Hospital Dusseldorf | Hellmich M.,University of Cologne | Pauls K.A.M.,University of Cologne | And 4 more authors.
Movement Disorders | Year: 2013

Secondary dystonia encompasses a heterogeneous group with different etiologies. Cerebral palsy is the most common cause. Pharmacological treatment is often unsatisfactory. There are only limited data on the therapeutic outcomes of deep brain stimulation in dyskinetic cerebral palsy. The published literature regarding deep brain stimulation and secondary dystonia was reviewed in a meta-analysis to reevaluate the effect on cerebral palsy. The Burke-Fahn-Marsden Dystonia Rating Scale movement score was chosen as the primary outcome measure. Outcome over time was evaluated and summarized by mixed-model repeated-measures analysis, paired Student t test, and Pearson's correlation coefficient. Twenty articles comprising 68 patients with cerebral palsy undergoing deep brain stimulation assessed by the Burke-Fahn-Marsden Dystonia Rating Scale were identified. Most articles were case reports reflecting great variability in the score and duration of follow-up. The mean Burke-Fahn-Marsden Dystonia Rating Scale movement score was 64.94 ± 25.40 preoperatively and dropped to 50.5 ± 26.77 postoperatively, with a mean improvement of 23.6% (P < .001) at a median follow-up of 12 months. The mean Burke-Fahn-Marsden Dystonia Rating Scale disability score was 18.54 ± 6.15 preoperatively and 16.83 ± 6.42 postoperatively, with a mean improvement of 9.2% (P < .001). There was a significant negative correlation between severity of dystonia and clinical outcome (P < .05). Deep brain stimulation can be an effective treatment option for dyskinetic cerebral palsy. In view of the heterogeneous data, a prospective study with a large cohort of patients in a standardized setting with a multidisciplinary approach would be helpful in further evaluating the role of deep brain stimulation in cerebral palsy. © 2013 Movement Disorder Society.

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