Wolfgang Rascher

The Virtual Family—development of surface-based anatomical models of two adults and two children for dosimetric simulations

The objective of this study was to develop anatomically correct whole body human models of an adult male (34 years old), an adult female (26 years old) and two children (an 11-year-old girl and a six-year-old boy) for the optimized evaluation of electromagnetic exposure. These four models are referred to as the Virtual Family. They are based on high resolution magnetic resonance (MR) images of healthy volunteers. More than 80 different tissue types were distinguished during the segmentation. To improve the accuracy and the effectiveness of the segmentation, a novel semi-automated tool was used to analyze and segment the data. All tissues and organs were reconstructed as three-dimensional (3D) unstructured triangulated surface objects, yielding high precision images of individual features of the body. This greatly enhances the meshing flexibility and the accuracy with respect to thin tissue layers and small organs in comparison with the traditional voxel-based representation of anatomical models. Conformal computational techniques were also applied. The techniques and tools developed in this study can be used to more effectively develop future models and further improve the accuracy of the models for various applications. For research purposes, the four models are provided for free to the scientific community.

Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension

Hypertension in children and adolescents has gained ground in cardiovascular medicine, thanks to the progress made in several areas of pathophysiological and clinical research. These guidelines represent a consensus among specialists involved in the detection and control of high blood pressure in children and adolescents. The guidelines synthesize a considerable amount of scientific data and clinical experience and represent best clinical wisdom upon which physicians, nurses and families should base their decisions. They call attention to the burden of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers, to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents.

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Women encounter ADRs more often than do men

BackgroundSeveral publications indicate that the female gender experiences a higher incidence of adverse drug reactions (ADRs) than does the male gender. The reasons, however, remain unclear. Gender-specific differences in the pharmacokinetic and pharmacodynamic behaviour of drugs could not be identified as an explanation. The aim of this study was to analyse ADR risk with respect to gender, age and number of prescribed drugs.MethodsA prospective multicenter study based on intensive pharmacovigilance was conducted. Information on patient characteristics and evaluated ADRs was stored in a pharmacovigilance database—KLASSE.ResultsIn 2,371 patients (1,012 female subjects), 25,532 drugs were prescribed. In 782 patients, at least one ADR was found. A multivariate regression analysis adjusting for age, body mass index (BMI) and number of prescribed drugs showed a significant influence of female gender on the risk of encountering ADRs [odds ratio (OR) 1.596, confidence interval (CI) 1.31–1.94; p < 0.0001). Dose-related ADRs (51.8%) were the dominant type in female subjects. Comparing system organ classes of the World Health Organisation (SOC-WHO), cardiovascular (CV) ADRs were particularly frequent in female subjects (OR 1.92, CI 1.15–3.19; p = 0.012).ConclusionOur data confirm the higher risk of ADRs among female subjects compared with a male cohort. Several explanations were investigated. No single risk factor could be identified.

Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions

Glial cells missing a (GCMa) belongs to a new transcription factor family. Syncytin was shown to be a target gene of GCMa. Here, we demonstrate that the protein kinase A (PKA) pathway acts upstream of GCMa. After transient transfection of BeWo cells with PKA, GCMa transcriptional activity and both GCMa and syncytin transcripts were upregulated. This increase was accompanied by further cellular differentiation. Using normoxic or hypoxic conditions to mimic pathophysiological settings known to diminish trophoblast differentiation, we found that gene repressive effects of oxygen deficiency were compensated by the induction of the PKA pathway. We propose that GCMa‐driven syncytin expression is the key mechanism for syncytiotrophoblast formation.

Sustained delivery of therapeutic concentrations of human clotting factor IX--a comparison of adenoviral and AAV vectors administered in utero.

Prenatal somatic gene therapy has been considered for genetic disorders presenting with morbidity at birth. Haemophilia is associated with an increased risk of catastrophic perinatal bleeding complications such as intracranial haemorrhage, which could be prevented by gene transfer in utero. Prenatal gene therapy may be more promising than postnatal treatment, as the fetus may be more amenable to uptake and integration of therapeutic DNA and the immaturity of its immune system may permit life‐long immune tolerance of the transgenic protein, thus avoiding the dominant problem in haemophilia treatment, the formation of inhibitory antibodies.

Spontaneous Nocturnal Leptin Secretion in Children with Myelomeningocele and Growth Hormone Deficiency

Objective: To examine the spontaneous leptin secretion in patients with myelomeningocele (MMC) and growth hormone deficiency (GHD). Methods: Serum leptin levels were studied in 10 prepubertal MMC patients with GHD (CA 6.2 ± 0.5 years), 10 patients with idiopathic GHD (IGHD; CA 7.6 ± 0.7 years) and 12 children with normal variant short stature (NVSS; CA 7.6 ± 0.5 years). Mean BMI (kg/m2) values of the groups did not differ significantly. Nocturnal leptin levels were analyzed over 10 h (blood samples every 20 min) and measured by specific radioimmunoassay. Results: Mean leptin concentrations did not correlate with BMI in MMC patients. Nocturnal leptin secretion of MMC patients was significantly different to those of children with IGHD and NVSS. Morning leptin levels did not decline as observed in both other groups. Conclusion: Since all groups were matched for BMI values, we suggest a hypothalamic dysregulation of leptin secretion in MMC patients.

Increase of endothelial nitric oxide synthase and endothelin-1 mRNA expression in human placenta during gestation

OBJECTIVE To investigate the maturation of the paracrine systems endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), endothelin-1 (ET-1) and adrenomedullin (AM) in human placenta during the 2nd and 3rd trimester of pregnancy. STUDY DESIGN Placental tissue from 14 healthy women with normal pregnancy and from 13 patients giving birth to premature infants following premature labor was obtained. Messenger RNA expression was determined using quantitative TaqMan real-time PCR. RESULTS Placental eNOS/GAPDH and ET-1/GAPDH mRNA expression significantly increased as a function of gestational age (r=0.63, P<0.001 and r=0.53, P=0.007, respectively). There was no change in gene expression of neither iNOS nor AM mRNA/GAPDH during gestation (r=0.02, P=0.75 and r=0.001, P=0.99, respectively). CONCLUSION There is a maturation of eNOS and ET-1 in human placenta with gestation reflecting developmental changes of important paracrine endothelial and trophoblastic regulators. AM and iNOS show no maturation during pregnancy.

Endocrine Effects of Food Intake: Insulin, Ghrelin, and Leptin Responses to a Single Bolus of Essential Amino Acids in Humans

Background: This study deals with the physiological effects of an oral bolus of essential amino acids (AA) on the secretion of insulin, ghrelin and leptin in fasting humans. Methods: 12 healthy adults (age 18–40 years, 10 males, 2 females, body mass index 18.0–23.5 kg/m2) were included in our study. Seven fasted volunteers consumed an AA mixture (0.35 g/kg BW), 5 served as controls. Serum AA, glucose, albumin, urea and hormones were measured at 0, 15, 30 min and thereafter at 30-min intervals up to 5 h. Results: Glucose, albumin and urea remained constant, peak AA concentrations were achieved at 30 min for methionine (Met), at 60 min for all other AA. The insulin peak (533% compared to basal level, p < 0.01) at 30 min was earlier than the peaks of all AA except for Met. Ghrelin showed a continuous rise towards the end of the experiment leading to a 3-fold increase in initial concentrations in the study group (p < 0.001), significantly higher than in the control group (p < 0.05). In contrast, both groups exhibited almost constant leptin concentrations. Conclusion: Our data indicate that an oral low-dose AA bolus not only causes considerable hyperaminoacidemia and hyperinsulinemia but is also accompanied by an increased ghrelin secretion in fasted humans. This may be a specific effect or may be due to the fact that a single bolus of AA is not a sufficient stimulus to induce satiety. Leptin, however, is not a key mediator in this setting.

Hyponatraemia as a complication of colonoscopy

A case of colonoscopy-induced hyponatraemic encephalopathy led us to study the risk of hyponatraemia after gastrointestinal endoscopy. We assessed 40 patients before and after colonoscopy. 20 gastroscopy patients served as controls. Our findings show a high incidence (7.5%) of hyponatraemia after colonoscopy, in association with raised serum concentrations of arginine vasopressin. Physicians should be aware of this complication, since it may contribute to psychological and neurological symptoms after colonoscopy.