Synaptische und zelluläre Mechanismen der Gedächtnisbildung im Alter: Einfluss von D-Serin auf das räumliche Lernen und die Langzeitpotenzierung bei Ratten

Ziel der Arbeit war es (Tiermodell), den auch beim Menschen zu beobachtenden Verlust an Lernfähigkeit bei chronischer Temporallappenepilepsie zu quantifizieren. Die Untersuchungen ergaben, dass junge Ratten mit chronischer Temporallappenepilepsie eine geringere Fähigkeit haben, Langzeitpotenzierung auszubilden, als junge, gesunde Tiere. Außerdem weisen sie ein reduziertes räumliches Lernvermögen im Morris Water Maze auf. Alterung war bei den Lernexperimenten assoziiert mit einer verminderten Lernleistung gesunder Tiere. Entsprechend war auch die Langzeitpotenzierung der CA-1 Region vermindert

Functional Metaplasticity of Hippocampal Schaffer Collateral-CA1 Synapses Is Reversed in Chronically Epileptic Rats

Spatial learning and associating spatial information with individual experience are crucial for rodents and higher mammals. Hence, studying the cellular and molecular cascades involved in the key mechanism of information storage in the brain, synaptic plasticity, has led to enormous knowledge in this field. A major open question applies to the interdependence between synaptic plasticity and its behavioral correlates. In this context, it has become clear that behavioral aspects may impact subsequent synaptic plasticity, a phenomenon termed behavioral metaplasticity. Here, we trained control and pilocarpine-treated chronically epileptic rats of two different age groups (adolescent and adult) in a spatial memory task and subsequently tested long-term potentiation (LTP) in vitro at Schaffer collateral—CA1 synapses. As expected, memory acquisition in the behavioral task was significantly impaired both in pilocarpine-treated animals and in adult controls. Accordingly, these groups, without being tested in the behavioral training task, showed reduced CA1-LTP levels compared to untrained young controls. Spatial memory training significantly reduced subsequent CA1-LTP in vitro in the adolescent control group yet enhanced CA1-LTP in the adult pilocarpine-treated group. Such training in the adolescent pilocarpine-treated and adult control groups resulted in intermediate changes. Our study demonstrates age-dependent functional metaplasticity following a spatial memory training task and its reversal under pathological conditions

Cataract in children and adolescents with type 1 diabetes. Insights from the German/Austrian DPV registry

Objective To study diabetic cataract in type 1 diabetes in a large pediatric cohort. Methods The 92,633 patients aged 0.5-21 years from German/Austrian multicenter diabetes registry (DPV) were analyzed. The 235 patients (0.25%) with diabetic cataract were found, 200 could be categorized: 67 with early cataract (3 months before diabetes onset - 12 months afterwards), 133 with late cataract (>12 months after diabetes onset). Regression models adjusted for age and gender were used to compare clinical parameters at diabetes onset. Regression models for patients with late cataract were implemented for the total documentation period and additionally adjusted for diabetes duration. Results Rate of cataract development shows a peak at diabetes onset and declines with longer diabetes duration. Patients with cataract showed strong female preponderance. Patients developing early cataract were older at diabetes onset (12.8 years [11.8/13.9] vs. 8.9 [8.9/9.0]; p < 0.001) and showed higher HbA1c than patients without cataract (9.0% [8.55/9.38] vs. 7.6% [7.60/7.61]; p < 0.001). They had lower height-SDS, (-0.22 [-0.48/0.04] vs. 0.25 [0.24/0.26]; p < 0.001), lower weight-SDS (-0.31 [-0.55/-0.08] vs. 0.21 [0.20/0.21]; p < 0.001) and lower BMI-SDS (-0.25 [-0.49/-0.02] vs. 0.12 [0.12/0.13); p = 0.002). Patients with late cataract showed higher HbA1c at diabetes onset (8.35% [8.08/8.62] vs. 8.04% [8.03/8.05]; p = 0.023) and higher mean HbA1c during total documentation period (8.00% [7.62/8.34] vs. 7.62% [7.61/7.63]; p = 0.048). Conclusions Our data confirm known demographic and clinical characteristics of patients developing early cataract. Hyperglycemia-induced osmotic damage to lens fibers at diabetes onset might be the main pathomechanism. Long term glycemic control is associated with cataract development

Diagnostic performance of an artificial neural network to predict excess body fat in children

Background Waist circumference (WC) and z scores of body mass index (BMI) are commonly used to predict childhood obesity, although BMI and WC have a limited sensitivity. Objectives To generate an artificial neural network (ANN), using the input parameters age, height, weight, and WC, to predict excess body fat in children. Methods As part of the National Health and Nutrition Examination Survey (NHANES) study, in the years 1999 to 2004, the body fat percentage of randomly selected Americans from 8 to 19 years were measured using whole-body dual energy X-ray absorptiometry (DXA) scans. Excess body fat was defined as a body fat percentage >= 85th centile. Results The data of 1999 children (856 female) were eligible. In females, the sensitivity of the BMI, WC, and ANN approaches to predict excess body fat were 0.751 (95% CI, 0.730-0.771), 0.523 (0.487-0.559), and 0.782 (0.754-0.810), respectively. In males, the sensitivity of the BMI, WC, and ANN approaches to predict excess body fat were 0.721 (95% CI, 0.699-0.743), 0.572 (0.549-0.594), and 0.795 (0.768-0.821). Conclusions Only in boys, the diagnostic performance in identifying excess body fat was better by using an ANN than by applying BMI and WC z scores. In girls, the ANN and BMI z scores performed comparable and significantly better than WC z scores

Anthropometric measurements to identify undernutrition in children with cerebral palsy

Aim To evaluate the diagnostic performance of anthropometric indicators to identify undernutrition in children with cerebral palsy (CP). Method The present study was a monocentric retrospective analysis of prospectively collected data among children and adolescents with CP participating in a rehabilitation program. Undernutrition was defined as a z-score for dual-energy X-ray absorptiometry (DXA) determined body fat percentage less or equal to -2.0. The cut-off values for body mass index (BMI) of the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), and the cut-off values for BMI and height for age of the Robert Koch Institut (RKI) were evaluated. Results In total, 329 children with CP (181 males, 148 females, Gross Motor Function Classification System levels I-V) were eligible for analysis. The mean age was 12 years 4 months (SD 2y 9mo). The BMI cut-off values showed the following sensitivities and specificities: WHO, sensitivity of 0.474 (95% confidence interval [CI] 0.244-0.711), specificity of 0.897 (95% CI: 0.857-0.928); CDC, sensitivity of 0.632 (95% CI: 0.384-0.837), specificity of 0.819 (95% CI: 0.772-0.861); RKI, sensitivity of 0.789 (95% CI: 0.544-0.939), specificity of 0.732 (95% CI: 0.679-0.781); and for height for age, sensitivity of 0.263 (95% CI: 0.091-0.512), specificity of 0.668 (95% CI: 0.612-0.720). Interpretation BMI had a high specificity but very low sensitivity in identifying undernutrition in children with CP. Z-scores for height for age had even lower specificity and sensitivity and seemed not to be appropriate for predicting undernutrition in children with CP. What this paper adds Body mass index (BMI) z-scores had a high specificity but very low sensitivity in identifying undernutrition in children with cerebral palsy (CP). Height z-scores were not appropriate for predicting undernutrition in children with CP. Undernutrition assessed by BMI was overestimated in children with CP versus when assessed by dual-energy X-ray absorptiometry (DXA)

Current and Emerging Therapeutic Options for the Management of Rare Skeletal Diseases

Increasing knowledge in the field of rare diseases has led to new therapeutic approaches in the last decade. Treatment strategies have been developed after elucidation of the underlying genetic alterations and pathophysiology of certain diseases (e.g., in osteogenesis imperfecta, achondroplasia, hypophosphatemic rickets, hypophosphatasia and fibrodysplasia ossificans progressiva). Most of the drugs developed are specifically designed agents interacting with the disease-specific cascade of enzymes and proteins involved. While some are approved (asfotase alfa, burosumab), others are currently being investigated in phase III trials (denosumab, vosoritide, palovarotene). To offer a multi-disciplinary therapeutic approach, it is recommended that patients with rare skeletal disorders are treated and monitored in highly specialized centers. This guarantees the greatest safety for the individual patient and offers the possibility of collecting data to further improve treatment strategies for these rare conditions. Additionally, new therapeutic options could be achieved through increased awareness, not only in the field of pediatrics but also in prenatal and obstetric specialties. Presenting new therapeutic options might influence families in their decision of whether or not to terminate a pregnancy with a child with a skeletal disease

Individualized treatment with denosumab in children with osteogenesis imperfecta - follow up of a trial cohort

Background Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1 year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually. Methods Ten patients (age range: 6.16-12.13 years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1 mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12 month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting. Results During follow-up mean relative change of lumbar aBMD was - 6.4%. Lumbar spine aBMD z-Scores decreased from - 1.01 +/- 2.61 (mean +/- SD) to - 1.91 +/- 2.12 (p = 0.015). Mobility changed not significantly (GMFM-88 -6.49 +/- 8.85% (p = 0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12 weeks previously to 20.3 weeks. Conclusions On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1 year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children

Inverse Association of High-Density Lipoprotein Cholesterol Concentration with Muscle Mass in Children

Background: Obesity was often associated with low high-density lipoprotein (HDL) cholesterol concentration, which is an established cardiovascular risk factor. Objectives: To evaluate the association of HDL-cholesterol concentration with fat and muscle mass in children and adolescents. Methods: Data of the National Health and Nutrition Examination Survey (1999-2004) were used to estimate fat and muscle mass by dual-energy X-ray absorptiometry (DXA) of the participants who had also an examination of their lipid profiles. Fat mass was assessed by DXA-determined fat mass index (FMI). Muscle mass was operationalized by appendicular lean mass index (LMI). Low HDL-cholesterol concentration was defined as Results: For the evaluation of the association of HDL-cholesterol concentration with FMI and LMI Z-scores, the data of 6288 children and adolescents (age 8-19 years) (2535 females) were eligible. In the study population, the prevalence of low HDL-cholesterol concentration increased with rising FMI and appendicular LMI Z-scores. Conclusions: The study results suggested that there is a counterintuitive, inverse association of muscle mass and HDL-cholesterol concentration