Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs.

Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)1, which influences offspring development and adult phenotypes1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood8. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.

Health related quality of life associated with extreme obesity in adolescents - results from the baseline evaluation of the YES-study.

BACKGROUND: Obesity can significantly reduce health-related quality of life (HRQoL) and may lead to numerous health problems even in youths. This study aimed to investigate whether HRQoL varies among youths with obesity depending on grade of obesity and other factors. METHODS: For the Youths with Extreme obesity Study (YES) (2012-2014), a prospective multicenter cohort study, a baseline sample of 431 obese and extremely obese adolescents and young adults (age 14 to 24 years, BMI ≥30 kg/m2) was recruited at four German university medical centers and one job center. Obesity grade groups (OGG) were defined according to BMI (OGG I: 30-34.9 kg/m2, OGG II: 35-39.9 kg/m2, OGG III (extreme obesity): ≥40 kg/m2). HRQoL was measured with the Euroqol-5D-3 L (EQ-5D-3 L), DISABKIDS chronic generic (DCGM-31) and the KINDLR obesity module. Differences between OGGs were assessed with logistic and linear regression models, adjusting for age, sex, and study center in the base model. In a second regression analysis, we included other characteristics to identify possible determinants of HRQoL. RESULTS: Three hundred fifty-two adolescents (mean age: 16.6 (±2.4), mean BMI: 39.1 (±7.5) kg/ m2) with available HRQoL data were analysed. HRQoL of youths in all OGGs was markedly lower than reference values of non-obese adolescents. Adjusting for age and sex, HRQoL of youths in OGG III significantly impaired compared to OGG I. Youths in OGG III were 2.15 times more likely to report problems with mobility in the EQ-5D-3 L than youths in OGG I. A mean difference of 9.7 and 6.6 points between OGG III and I were found for DCGM-31 and KINDL respectively and 5.1 points between OGG II and I for DCGM-31. Including further variables into the regression models, showed that HRQoL measured by DCGM-31 was significantly different between OGGs. Otherwise, female sex and having more than 4 h of daily screen time were also associated with lower HRQoL measured by DCGM-31 and KINDL. CONCLUSION: HRQoL of adolescents with obesity is reduced, but HRQoL of adolescents with extreme obesity is particularly affected. Larger and longitudinal studies are necessary to understand the relation of extreme obesity and HRQoL, and the impact of other lifestyle or socioeconomic factors. TRIAL REGISTRATION: Clinicaltrials.gov NCT01625325; German Clinical Trials Register (DRKS) DRKS00004172.

Factors associated with the emotional health of children: high family income as a protective factor.

Anxiety and depressive symptoms have adverse effects on children's development. The present study investigates the associations of socioeconomic factors as well as maternal emotional health with children's emotional health status. The data were collected between 2011 and 2015 in the LIFE Child study, a population-based cohort study in Leipzig, Germany. The emotional health status of 1093 children (2.5-11.9 years old) was investigated using the subscale 'emotional problems' of the Strengths and Difficulties Questionnaire. Associations of maternal emotional health, family status, and socioeconomic status (SES) with the emotional health status of children were estimated via regression analyses. 21.13% of the participating children were assigned to the 'risk' group for emotional problems. The results furthermore revealed that children of mothers reporting more depressive symptoms, children living in single-parent families, and children of families with lower SES scored higher in the emotional problems scale. When considering the different indicators of SES (parental education, occupational status, and monthly net income) separately, only income showed significant associations with children's emotional health status. The prevalence of emotional problems in children in Leipzig, a city in East Germany, appears to be higher than the previously reported German average. Maternal depressive symptoms, single-parent families, lower SES, and especially lower income can be seen as risk factors for children's emotional health.

[Prevalence of Gastroschisis, Omphalocele, Spina Bifida and Orofacial Clefts of Neonates from January 2000 to December 2010 in Leipzig, Saxony, Saxony-Anhalt and Germany]. / Prävalenz von Gastroschisis, Omphalozele, Spina bifida und orofazialen Spaltbildungen bei Neugeborenen im Zeitraum Januar 2000­Dezember 2010 in Leipzig, Sachsen, Sachsen-Anhalt und Deutschland.

BACKGROUND: Malformations are the most common cause of death in infancy. Numerous studies indicate an increased prevalence of malformations in neonates in recent years in some countries around the world. This study analyzed local and national trends of the prevalences of gastroschisis, omphalocele, spina bifida and orofacial clefts during 2000 till 2010 in Leipzig, Saxony, Saxony-Anhalt and Germany. METHODS: The prevalence of neonatal malformations was studied retrospectively from January 2000 till December 2010 using 4 sources from Leipzig, Saxony, Saxony-Anhalt and Germany. RESULTS: Between 2000 and 2010, the prevalence in Germany and in Saxony, respectively was 1.97/2.12 (gastroschisis), 1.63/1.48 (omphalocele), 5.80/8.11 (orofacial clefts) and 2.92/2.50 (spina bifida) of 10 000 live births. In Saxony, a small increase in prevalence was detected (OR/year: 1.01-1.09). In Germany, the prevalence of malformations also increased significantly (OR/year: 1.01-1.04) with the exception of the prevalence of spina bifida which seemed to decline (OR/year 0.986 (0.97-1.0), p-adjust=0.04). CONCLUSION: Whether or not there has been an actual increase in the prevalence of neonatal malformations in Germany over the years or the apparent increase is just due to bias, coding errors, multiple reporting and/or false registration and codification remains unclear. Importantly, in Germany, since prevalence of malformations is monitored prospectively only in Saxony-Anhalt and Rhineland-Palatinate, only in these states is it possible to recognize recent changes. For early identification of changes in prevalence and timely implementation of preventive measures, a nationwide register or additional regional registers are deemed necessary.

Incompatibilities in paediatric intensive care - pitfalls in drug information.

Drug incompatibilities can lead to loss of effectiveness of drugs or to increased risk for undesirable effects that can even be life-threatening. Especially children are at high risk. Databases are an important source of information in routine care to avoid incompatibilities. However, they were supposedly developed considering drugs for use in adults. Thus, we analysed to what extent databases are appropriate for the identification of incompatibilities in intravenous (i.v.) drug therapy in paediatric intensive care. We analysed the information provided by two databases (Database A and B) on all pairs of two drugs prescribed to be administered via the same i.v. access line in a university paediatric intensive care unit during the study period of 50 days. A total of 50 different i.v. drugs was prescribed in 318 different combinations (drug pairs). We found information on (in)compatibilities in 23.0 % (73/318) in Database A and in 31.1 % (99/318) in Database B. Only in 11.0 % (35/318) of the drug pairs, both databases provided information. Considering those drug pairs, in 17.1 % (6/35) Database B indicated compatibility whereas Database A indicated incompatibility. Compatibility information delivered by databases on drugs used in paediatric intensive care is incomplete, heterogeneous, and partly contradictory. Thus, an increased awareness on the strengths and limitations of different databases is necessary to avoid patient harm.

METRNL decreases during adipogenesis and inhibits adipocyte differentiation leading to adipocyte hypertrophy in humans.

BACKGROUND: Meteorin-like (METRNL) is a recently described circulating protein shown to be highly expressed in white adipose tissue and to beneficially affect energy metabolism in mice. OBJECTIVE: We systematically evaluated the role of METRNL for human adipogenesis and its association with obesity, browning and hyperinsulinemia in children. In addition, we assessed the functional relevance of METRNL for human adipogenesis. RESULTS: METRNL expression decreased during human adipocyte differentiation in vitro. Coherently, METRNL expression was lower in isolated adipocytes compared with stromal vascular fraction (SVF) cells in human samples. Withdrawal of the peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone from adipogenic media partially preserved the METRNL downregulation during adipogenesis. METRNL expression was higher in adipocytes of obese compared with lean children and correlated with adipocyte size, whereas in SVF METRNL expression correlated with proliferation capacity. Concordantly, overexpression of METRNL inhibited human adipocyte differentiation as shown by decreased lipogenesis and lower expression of PPARγ and markers of adipogenesis, whereas experimental downregulation promoted adipogenesis. Proliferation, in contrast, was advanced by METRNL overexpression. These interactions with adipose tissue dynamics may contribute to the clinically observed body mass index-independent association of METRNL expression with hyperinsulinemia and adipose tissue inflammation in human samples. METRNL was not associated with UCP1 expression or induction of browning in white adipocytes. CONCLUSIONS: Taken together, the downregulation of METRNL during adipogenesis and functional induction of increased proliferation in SVF cells with concomitant inhibition of adipocyte differentiation may result in hypertrophic AT accumulation. This may also explain our observations of increased METRNL expression in adipocytes but not SVF cells in obese children compared with lean children and the subsequent hyperinsulinemia.

Adipocyte C1QTNF5 expression is BMI-dependently related to early adipose tissue dysfunction and systemic CTRP5 serum levels in obese children.

BACKGROUND/OBJECTIVES: The recently identified adipocytokine C1QTNF5 (encodes for CTRP5) has been demonstrated to inhibit pro-metabolic insulin signaling in adipocytes. We hypothesized that adipocyte C1QTNF5 expression in subcutaneous (sc) adipose tissue (AT) would correlate with the degree of obesity, systemic CTRP5 serum levels, and early AT and metabolic dysfunction in children. SUBJECTS/METHODS: Sc AT samples were obtained from 33 healthy Caucasian lean children aged 10.06±4.84 years and 42 overweight and obese children aged 13.34±3.12 years. C1QTNF5 expression in sc AT as well as in investigated cell lines was assessed by quantitative real-time PCR. Systemic CTRP5 levels were assessed by ELISA. RESULTS: C1QTNF5 expression in sc adipocytes increased with body mass index (BMI) standard deviation score (SDS; R=0.48, P<0.001), body fat percentage (R=0.4, P=0.004), adipocyte number (R=0.69, P<0.001) and systemic CTRP5 serum levels (R=0.28, P=0.025) whereas expression in the stromal vascular fraction (SVF) was inversely correlated with BMI SDS (R=-0.24, P=0.04). Multiple regression analysis confirmed that BMI SDS was the strongest independent predictor for C1QTNF5 expression in sc adipocytes. SVF C1QTNF5 levels strongly correlated with SVF CD31 expression (R=0.54, P<0.001) indicating expression by endothelial cells. Primary human endothelial cells demonstrated stronger expression compared with human Simpson-Golahbi-Behmel syndrome pre-adipocytes and adipocytes. Adipocyte C1QTNF5 expression levels were BMI-dependently related to fasting insulin (R=0.3, P=0.03) and leptin serum levels (R=0.5, P<0.001). Sc AT samples containing crown-like structures (CLS) demonstrated increased adipocyte C1QTNF5 expression compared to CLS-negative samples (P=0.03). Functionally, tumor necrosis factor (TNF)α caused a fourfold induction of C1QTNF5 in human adipocytes (P<0.001) and a 50% reduction in primary human endothelial cells (P<0.001). CONCLUSIONS: In children adipocyte C1QTNF5 expression is already strongly related to the degree of obesity and is associated with obesity-related AT alterations, systemic CTRP5 serum levels as well as circulating markers of metabolic disease and is positively regulated by TNFα in vitro.

[Endocrine disruptors : Evidence from epidemiological studies necessitates a critical review of model systems]. / Endokrine Modulatoren : Hinweise aus epidemiologischen Studien bedürfen einer kritischen Überprüfung in Modellsystemen.

Endocrine disruptive chemicals (EDCs) cause adverse health effects through interaction with endocrine systems. They are classified by chemical structure, effects on specific endocrine systems, bioaccumulation, persistence in the environment, or clinically observable effects. For research of the complex mechanisms of action in the human body, only in vitro model systems have so far been available, that have insufficient high-throughput capacity, which makes risk evaluation more difficult. In addition, in industrial nations, living people are often exposed to mixtures of substances, with various effects. The clinical importance of epigenetic changes caused by the action of EDCs during vulnerable phases of development is currently unclear. Epidemiological studies are criticized because reproducibility is not always guaranteed. Nevertheless, they remain the method of choice for the development and analysis of suitable model systems. Positive associations, in spite of sometimes conflicting results, are key in the selection of factors that can then be analysed in model systems in an unbiased way. This article depicts the mainly positive epidemiological findings for EDC-caused effects in the fields of growth and metabolism, neurocognitive development and sexual development and reproduction. As a result, there is a need for closer linkage between epidemiological studies and mechanistic research into model systems, especially focusing on the interaction of different EDCs and the consequences of prenatal and early life exposure.

Insulin-Like Peptide 5 Interacts with Sex Hormones and Metabolic Parameters in a Gender and Adiposity Dependent Manner in Humans.

Insulin-like peptide 5 (INSL5) is a gut hormone produced by L-cells in the colorectal epithelium and may play a role in the regulation of metabolic processes. The biological role of INSL5 is poorly investigated and nothing is known about the role of this hormone in obese and lean humans. Two cohorts were analyzed in the study. In the first cohort (n=76) the relationship between serum levels of INSL5 and different metabolic and hormonal parameters in obese and lean men and women were investigated. In the second cohort 14 male subjects underwent bariatric surgery. Circulating levels of INSL5 were then measured before and after interventions.We report for the first time that circulating INSL5 interacts with multiple metabolic and hormonal variables in lean and obese men and women and is affected by bariatric surgery. Serum levels of INSL5 negatively correlated with testosterone and blood lipids but positively with cortisol in obese men. In contrast to males, obese women had a strong negative correlation of plasma levels of INSL5 with C-reactive protein (CRP). We observed that adipose tissue loss after bariatric surgery significantly reduced serum levels of INSL5 in obese men with and without Type 2 Diabetes Mellitus (T2DM) that was associated with the restoration of circulating levels of testosterone. All together, our data demonstrated that INSL5 may interact with some metabolic parameters in obese humans and this process is dependent of gender and obesity state.

[Evaluation and Utilization - Quality Management in a Paediatric University Outpatient Department]. / Evaluation und Inanspruchnahme - Qualitätssicherung in der pädiatrischen Ambulanz einer Universitätsklinik.

BACKGROUND: Based on an increasing number of outpatient treatments, an extensive demand planning is necessary to ensure the quality of medical care. University outpatient clinics are special parts of this sector and therefore it is necessary that a research demonstrates the nearly uninvestigated position of a paediatric outpatient clinic. PATIENTS: The research at the university hospital for children and adolescents in Leipzig started in 2009 to survey 2283 of in total 9391 patients and the physicians. METHODS: Sociodemographic data as well as economic and medical facts were determined by using questionnaires. In each case a questionnaire was answered by the children or their accompanying persons and a separate one was completed by the respective doctor. RESULTS: The results created a foundation, on the basis of patient volume per day and per daytime. Less than 20% of the children admitted to consult the clinic for their first time. The majority of patients visit them because of a letter of referral. Most of the patients (58%) were younger than 6 years old. Approximately 35% of patients did not come from the city region of Leipzig. CONCLUSION: The investigation evidenced the necessity of a day and night operating institution for children in the region of Leipzig as well as the high specialisation of the outpatient clinic. In need of further investigation is the cooperation between several physicians to find out if this lots of medical examination are necessary or if there took place overlapping.

Introducing excess body weight in childhood and adolescence and comparison with body mass index and waist-to-height ratio.

BACKGROUND: Weight status in children and adolescents is commonly defined using age- and gender-corrected standard deviation scores for body mass index (BMI-SDS, also called z-scores). Values are not reliable for the extremely obese however. Moreover, paediatricians and parents may have difficulties understanding z-scores, and while percentiles are easier to gauge, the very obese have values above the 99th percentile, making distinction difficult. The notion of excess body weight (EBW) is increasingly applied in adult patients, mainly in the context of bariatric surgery. However, a clear definition is not available to date for the paediatric population. METHODS: A simple definition of EBW for children and adolescents is introduced, with median weight as a function of height, age and gender (characterized by an asterisk): EBW (%) = 100x(weight-median weight*)/median weight*. EBW is compared with BMI-SDS and waist-to-height ratio (WHtR). Using two data sources (APV registry and German Health Interview and Examination Survey for Children and Adolescents (KiGGS)) including more than 14,000 children, the relationships between these anthropometric and various metabolic parameters are analysed for a group of overweight/obese children who have sought obesity therapy (APV), for the general paediatric population and for the subset of overweight/obese children from the general population (KiGGS). RESULTS: The three anthropometric parameters are strongly correlated, with the linear correlation coefficients exceeding 0.8 in the general population and 0.75 in those seeking obesity therapy. Moreover, their relationship to metabolic parameters is quite similar regarding correlations and area under the curve from receiver operating characteristic analyses. CONCLUSIONS: EBW has similar predictive value for metabolic or cardiovascular comorbidities compared with BMI and WHtR. As it is reliable at the extreme end of the obesity spectrum, easily communicable and simple to use in daily practice, it would make a very useful addition to existing tools for working with obese children and adolescents. Its usefulness in assessing weight change needs to be studied however.

Is there a predictive value of EEG and MRI after a first afebrile seizure in children?

BACKGROUND: After a first afebrile seizure, EEG in addition to cMRI is recommended for pediatric patients. Once indications requiring immediate treatment are excluded, it is of interest to determine if the results provide a prognostic tool for seizure relapses. METHODS: Patients aged between 1 month and 18 years who had a first afebrile seizure between 2006 and 2008 were retrospectively studied and monitored for another 48 months. RESULTS: Out of 248 patients, 62.5% had generalized and 36.3% focal seizures. 34.7% of the EEG results were pathological. 176 patients had a cMRI that showed in 23.3% probable epileptogenic lesions. 3 patients with benign cerebral tumours needed surgical therapy. In the following 48 months 29.4% of the children showed seizure relapses. There was a correlation between epileptic patterns in the EEG and further seizures (p=0.0001). However, the sensitivity of the EEG based diagnoses was 0.6, the specificity 0.78 and the positive predictive value 0.52. There was no correlation between epileptogenic lesions and the probability of seizure relapses. The sensitivity of the cMRI to this effect was 0.36, the specificity 0.74 and the positive predictive value 0.34. DISCUSSION: The EEG is superior to cMRI for predicting seizure relapses. The percentage of noticeable cMRI findings is high but this has low therapeutic relevance and is assumed to largely represent "incidental findings". It is important to question the value of MRI investigations for sedated small children except in the case of emergencies. The key question is whether the cMRI should be deployed to diagnose epilepsy, the probability of seizure recurrences or to classify the entity of a most likely epilepsy.

Bariatric surgery in adolescents and young adults--safety and effectiveness in a cohort of 345 patients.

OBJECTIVE: To examine the safety and effectiveness of adolescent bariatric surgery and to improve treatment recommendations for this age group. DESIGN: Prospective longitudinal registry. Since January 2005, patients undergoing bariatric surgery in Germany are enlisted in an online registry called 'study for quality assurance in obesity surgeries'. SUBJECTS: Adolescents and young adults up to the age of 21 years, operated from January 2005 to December 2010. MEASUREMENTS: Weight, BMI, comorbidities, complication rates. RESULTS: N=345 primary procedures were recorded by 58 hospitals. N=51 patients were under the age of 18 years. Follow-up information was available for 48% (n=167) of patients, with an average observation period of 544±412 days (median: 388 days). The most common surgical techniques were gastric banding (n=118, 34.2%), gastric bypass (n=116, 33.6%) and sleeve gastrectomy (n=78, 22.6%). Short-term complications (intra-operative; general postoperative; specific postoperative) were slightly lower for gastric banding (0.8%; 2.5%; 0.8%) than for gastric bypass (2.6%; 5.2%; 1.7%) or sleeve gastrectomy (0%; 9.0%; 7.7%). In accordance with published findings, weight and BMI reduction were lower for gastric banding (-28 kg; -9.5 kg m(-2)) compared to gastric bypass (-50 kg; -16.4 kg m(-2)) P< 0.001 or sleeve gastrectomy (-46 kg; -15.4 kg m(-2)) P< 0.001. Outcomes did not differ between the <18 and ≥18-year-old patients. CONCLUSION: Like in adults, bariatric surgery has low short-term complication rates and results in sustained weight loss in adolescents. However, the missing long-term observations prohibit a final conclusion about lasting effectiveness and safety. Clinical trials with structured follow-up programs and mechanisms to ascertain patient adherences are needed.

[The impact of sleep endoscopy for obstructive sleep-disordered breathing in children and adolescents]. / Bedeutung der Schlafendoskopie bei obstruktiv-schlafbezogener Atmungsstörung im Kindes- und Jugendalter.

OBJECTIVE: Studies on the surgical treatment of OSAS in adults have shown an improved outcome after targeted therapy by drug-induced sleep endoscopy (DISE). So far, only a few studies have focused on this method in children. The aim of this study is to evaluate the impact of DISE for children with obstructive sleep-disordered breathing and to determine the influence of DISE on treatment recommendations. SUBJECTS AND METHODS: The medical records of children (n=25) who underwent polysomnography and DISE between 05/2012 and 12/2013 were retrospectively reviewed. The subjects were divided into an UARS (upper airway resistance syndrome)/mild OSAS group (AHI<5; n=10) and a moderate/severe OSAS group (AHI≥5; n=15). RESULTS: The oropharynx was the most common site of obstruction. Prevalence of complete obstruction at the oropharynx was significantly higher in moderate or severe OSAS (p=0.02). The obstruction pattern of the velopharynx was significantly associated with the size of the adenoids (p=0.02), but tonsil and adenoid size were not related to the severity of OSAS. 71% of children with grade IV tonsils showed complete obstruction of the oropharynx. After DISE, the initial management plan changed in 5 patients (20%). CONCLUSION: DISE is a promising technique to identify sites of obstruction in children with OSAS and to guide treatment decisions. Further studies are needed to predict persistent OSAS based on this tool.

Diurnal rythm of Nampt is gender and weight dependent.

RESEARCH AIM: Nicotinamide phosphoribosyltransferase (Nampt) is an adipocytokine that is elevated in obesity, type 2 diabetes and increased levels are associated with inflammatory processes. Nampt serum concentrations have been suggested to follow a diurnal rhythm peaking in the afternoon in lean males. However, no data exists regarding the effects of gender and body weight. MATERIAL AND METHODS: We measured Nampt serum levels over 24 h in a cohort of healthy individuals living with either normal weight or obesity. Furthermore, effects of meals, oral glucose tolerance test and physical exercise on Nampt concentrations were evaluated. Correlation analyses to other hormonal- and lab parameters and anthropometric measurements were performed. RESULTS: Nampt showed a diurnal rhythm with increased levels at daytime and a peak in the early afternoon. This diurnal rhythm was significant for all groups but obese males. The Nampt amplitude, measured both relatively and absolutely, was significantly higher in females than in males. Meals did not influence Nampt serum levels, whereas physical exercise and an OGTT did significantly influence Nampt serum levels. CONCLUSION: In conclusion, we found gender specific differences in Nampt amplitude and coefficient variation with both being higher in females. The circadian rhythm of Nampt was independent of gender in healthy lean individuals, whereas it was disturbed in men with obesity.

Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms associated with obesity, consequently implying a role in adipocyte biology for many closely residing genes. We investigated the functional relevance of such genes in human adipocytes. METHODS: We selected eight genes (BDNF, MAF, MTCH2, NEGR1, NPC1, PTER, SH2B1 and TMEM18) from obesity GWAS and analysed their effect in human adipogenesis using small interfering (si)RNA-mediated knockdown, their regulation by metabolic agents in adipocytes and pre-adipocytes, and gene expression in paired samples of human fat biopsies (68 non-obese, 165 obese) by quantitative real-time PCR. RESULTS: We show a two- to threefold upregulation of MAF, MTCH2 and NEGR1 and a two- to fourfold downregulation of BDNF and PTER during adipogenesis. Knockdown of BDNF (mean ± SEM; 83.8 ± 4.7% of control; p = 0.0002), MTCH2 (72.7 ± 9.5%; p = 0.0006), NEGR1 (70.2 ± 5.7%; p < 0.0001) and TMEM18 (70.8 ± 6.1%; p < 0.0001) significantly inhibited adipocyte maturation, while knockdown of the other proteins had no effect. Insulin slightly induced MAF (1.65-fold; p = 0.0009) and MTCH2 (1.72-fold; p < 0.0001), while it suppressed BDNF (59.6%; p = 0.0009), NEGR1 (58.0%; p = 0.0085) and TMEM18 (69.3%; p = 0.0377) in adipocytes. The synthetic glucocorticoid dexamethasone suppressed MAF (45.7%; p = 0.0022), BDNF (66.6%; p = 0.0012) and TMEM18 (63.5%; p = 0.0181), but induced NEGR1 (3.2-fold; p = 0.0117) expression. Furthermore, MTCH2, NEGR1 and TMEM18 were differentially expressed in subcutaneous and visceral adipose tissue. TMEM18 expression was decreased in the adipose tissue of obese patients, and negatively correlated with anthropometric variables and adipocyte size. CONCLUSIONS/INTERPRETATION: Our results imply a regulatory role for TMEM18, BDNF, MTCH2 and NEGR1 in adipocyte differentiation and biology. In addition, we show a variation of MAF expression during adipogenesis, while NPC1, PTER and SH2B1 were not regulated.

Longitudinal multicenter analysis on the course of glucose metabolism in obese children.

OBJECTIVE: Although there is evidence of increasing prevalence of impaired glucose metabolism in obese children from smaller single cohorts, data are lacking on the progression of glucose metabolism in this patient group.We aimed to assess the prevalence and the longitudinal course of impaired glucose metabolism assessed by oral glucose tolerance test (oGTT) in a large multi-center pediatric obesity registry. SUBJECTS: We performed an observational multicenter (n=84) cross-sectional (n=11 156) and longitudinal analysis (n=1008) on the course of glucose metabolism evaluated by oGTT in obese children documented in the Adiposity Patients Verlaufsbeobachtung (APV) registry. Patients were stratified with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and Type 2 diabetes (T2D), according to American Diabetes Association criteria. RESULTS: A total of 12.6% of the children presented with abnormal glucose metabolism (5.99% IFG, 5.51% IGT, 1.07% T2D). Body mass index (BMI) correlated modestly with 2-h blood glucose (r=0.04, P<0.001).In the 1008 patients with follow-up oGTT, metabolic parameters improved and the percentage of abnormal glucose metabolism decreased from 18.7 to 14.2%. Of the children with initial IGT, 70.6% converted to normal glucose tolerance. The improvement in oGTT results was associated with, but not dependent on, a reduction of BMI s.d. score. CONCLUSION: In summary, we provide evidence for significant improvement of oGTT parameters in obese children treated in specialized treatment centers, even though reduction in BMI was modest.

Acute two-compartment low pressure hydrocephalus--a case report.

A case of an 8-year-old-boy with shunt-dependent occlusive hydrocephalus after resection of a cerebellar medulloblastoma is presented, who experienced repeated episodes of severe neurologic deterioration with signs and symptoms of raised intracranial pressure after spinal tapping. However, intracranial pressure was recorded within low ranges, only up to the opening pressure of the implanted adjustable shunt valve. Multiple shunt revisions were performed, until the condition was recognized as acute normal pressure hydrocephalus. Either enforced recumbency and downadjustment of the valve system to 0 cm H(2)O alone or external ventricular drainage seems to be successful to resolve the critical condition, depending on severity of the symptoms. The case illustrates that acute pathologic enlargement of the ventricular system is not always associated with increased intracranial pressure, even when typical signs and symptoms are present. The very rare entity of acute normal pressure hydrocephalus by two separated compartments is postulated based on the pulsatile vector force theory of brain water circulation.

The use of 5-aminolevulinic acid fluorescence guidance in resection of pediatric brain tumors.

INTRODUCTION: Whereas in the adult population 5-Aminolevulinic acid (5-ALA) fluorescence guidance has been widely accepted for improving the extent of tumor resection, the application in children remains an off-label use. Even though most pediatric study protocols require a complete resection for improving outcome parameters, only few pediatric patients have been operated with fluorescence guidance, and it remains questionable, whether and which pediatric tumors show useful fluorescence. We present casuistic reports of application of 5-ALA in children collected from three different neurosurgical departments. PATIENTS AND METHODS: In children with suspected malignant intracerebral tumor or recurrence, individual informed consent was obtained in each case from the parents. 5-ALA was administered according to the adult protocol, with 20 mg/kg, 2 h before induction of anesthesia. We retrospectively analyzed 18 patients (13 male, 5 female; age 3-18 years), using the intraoperative neurosurgical protocol, the postoperative MRI results, and the follow-up clinical examinations. RESULTS: The use of 5-ALA fluorescence guidance proved to be safe in our group of pediatric patients. Fluorescence guidance was most useful for recurrent glioblastoma resection. Medulloblastoma tissue displayed fluorescence only inconsistently, and most pilocytic astrocytoma remained without staining. Ganglioglioma showed partial staining in the central tumor areas, without allowing the use for circumferent resection. CONCLUSION: The off-label use of 5-ALA fluorescence guidance in pediatric patients appears to be most useful in recurrent high-grade gliomas. Fluorescence accumulation in other pediatric brain tumor entities is not predictable and should be evaluated in future clinical studies before being integrated into the current treatment protocols.

Ambulatory care of children treated with anticonvulsants - pitfalls after discharge from hospital.

BACKGROUND: Anticonvulsants require special consideration particularly at the interface from hospital to ambulatory care. PATIENTS AND METHOD: Observational study for 6 months with prospectively enrolled consecutive patients in a neuropediatric ward of a university hospital (age 0-<18 years) with long-term therapy of at least one anticonvulsant. Assessment of outpatient prescriptions after discharge. Parent interviews for emergency treatment for acute seizures and safety precautions. RESULTS: We identified changes of the brand in 19/82 (23%) patients caused by hospital's discharge letters (4/82; 5%) or in ambulatory care (15/82; 18%). In 37/76 (49%) of patients who were deemed to require rescue medication, no recommendation for such a medication was included in the discharge letters. 17/76 (22%) of the respective parents stated that they had no immediate access to rescue medication. Safety precautions were applicable in 44 epilepsy patients. We identified knowledge deficits in 27/44 (61%) of parents. CONCLUSION: Switching of brands after discharge was frequent. In the discharge letters, rescue medications were insufficiently recommended. Additionally, parents frequently displayed knowledge deficits in risk management.