Toxicity of β-blockers in a rat whole embryo culture: concentration-response relationships and tissue concentrations

Beta-adrenoceptor blockers are widely used drugs for the treatment of cardiovascular diseases. Since β-blockers cross the placenta, it is essential to consider possible adverse effects on the embryo. Six β-adrenoceptor blockers were tested at various concentrations (10 – 5000 μM) in a rat whole embryo culture. Although inducing a very similar pattern of dysmorphogenetic effects (incomplete flexure, disturbed development of the neural tube, the head, the heart and the tail bud), the compounds exhibited a wide range of embryotoxic potency. Estimation of the EC₅₀ (median-concentration producing dysmorphogenesis in 50% of the embryos) for the six compounds revealed differences of more than two orders of magnitude: propranolol 25 μM, alprenolol 30 μM, metoprolol 100 μM, pindolol 150 μM, acebutolol 500 μM, atenolol 4000 μM. Measurements of the concentrations of the various drugs in the cultured embryos at corresponding EC₅₀ levels showed differing values: metoprolol 4.5 μM, propranolol 5.2 μM, alprenolol 8.4 μM, pindolol 9.0 μM, acebutolol 12.5 μM and atenolol 77.0 μM. With regard to the EC₅₀ and the degree of substance transfer to the embryo it can be stated that propranolol and metoprolol show a much higher intrinsic potency to interfere with normal in vitro embryonic development than, e.g. atenolol. Received: 1 September 1993 / Accepted: 16 February 1994     

Fabry disease: clinical, biochemical and electron microscopical studies (author's transl)]

Biochemical investigations on blood-plasma and serum as well as well as electron microscopic investigations on skin lesions biopsy specimens were carried out in one case of morbus Fabry 35 years of age distinctly showing cardio-renal symptoms. The diagnosis of Fabry disease was made when the patient was hospitalized for treatment of a chronic glomerulonephritis. The patients' serum alpha-galactosidase activity was reported to be 10 to 13% of normal controls, whereas the values of trihexosyl-ceramids for blood-plasma and serum were increased. Electron microscopic studies revealed that the endothelial cells and pericytes of the cutaneous vessels as well as the fibroblasts contain numerous liposome-like cytoplasmic inclusions of different size showing an internal lamellar structure with exact periodizity of 65 A. These inclusion are not surrounded by a membrane structure, however, it is possible that the arise from defect lysosomes which accumulate trihexosyl-ceramids owing to insufficient of alpha-galactosidase activity.     

Flow dynamics of human sickle erythrocytes in the mesenteric microcirculation of the exchange-transfused rat

To analyze the microvascular rheology of sickle cells in an intact animal model, rats were isovolemically exchange transfused with human normal (hemoglobin AA) or sickle (hemoglobin SS) erythrocytes (blood group O) or autologous red cells under ambient conditions, and the effects of the heterologous or autologous cells on (a) hemodynamics and respiration, (b) blood gases, and (c) acid-base status of the recipients were determined. Exchange transfusion of rats with autologous red cells or hemoglobin AA or hemoglobin SS erythrocytes was associated with stable mean arterial blood pressure, central venous pressure, respiration rate, blood pH, pCO2, and pO2 during the experimental period, except for tachycardia among the group of rats that received HbSS cells. Arteriovenous oxygen content varied among the three groups of animals, but, nonetheless, suggested adequate tissue oxygen supply under the conditions of the study. Acid-base status also was similar in the three groups of rats. The exchange-transfused rats were utilized to investigate the flow dynamics of red cells in the mesenteric microcirculation by applying intravital microscopy. Time-averaged velocities of the autologous red cells in 16- to 30-microns (id) vessels ranged from 1.07 to 1.25 mm/sec in single unbranched arterioles with varying flux and wall shear rates. Time-averaged velocities of the HbAA cells in single 15- to 35-microns arterioles ranged from 1.16 to 1.24 mm/sec with wall shear rates similar to the estimates for the autologous cells. For both rat and human HbAA RBCs, the flow dynamics were indicative of normal shear-dependent and deformability characteristics of the cells under the flow conditions. Sickle cells exhibited time-averaged velocities of 0.384 to 0.452 mm/sec, lower wall shear rates in 10- to 35-microns single unbranched arterioles, and three times less volumetric flux. In some arterioles, sickle cells with high axial ratio and low deformability showed definite adhesion to the endothelial surface, residing at such sites for several seconds until dislodged by the force of flow. Within single unbranched vessels or at microvascular bifurcations, sickle elliptocytes and sickle echinocytes with low deformability and high axial ratio obstructed flow and exhibited residence times of 2 to 88 sec, thereby causing stasis. These data illustrate the microvascular flow behavior of sickle cells and demonstrate the rheological disequilibrium state that can result as sickle cells course through successive segments of the microcirculation.     

Medulloblastoma: Survey of factors possibly influencing the prognosis

Summary In a series of 310 cases the role of the factors age, sex, location of the tumour (midline or lateral), and medulloblastoma type (classic or desmoplastic) were analysed with regard to the prognosis. The influence of therapy is not considered because of the inhomogeneity of the material and the view nowadays that treatment is insufficient. The occurrence of lateral (or hemispheric) medulloblastomas increases in the group of the 11–15 years old patients. The proportion of the desmoplastic type is greater in adults than in children, but they are distributed almost equally medially and laterally. There seems to be no definite correlation between sex and the survival time. The mean survival time increases with age. With regard to the histological subclassification into children and adults, the mean survival times are nearly identical. The only obvious factor with a decisive influence on the prognosis seems to be the time of appearance of the tumour. Additionally, the data support the conclusion that a desmoplastic medulloblastoma should be considered as a histological variant without clinical relevance.     

Radionuclide Studies of Posterior Fossa Lesions in Children

A series of 480 children was investigated by scintiscanning between 1966 and 1975 by rectilinear scanning or by gamma camera imaging. Of this group 39 were reported abnormal in the posterior fossa region–10 were reported as normal but were found subsequently by other investigations or by operation to have a lesion in this region. Of the 39 reported abnormal 37 were subsequently found to have a lesion, either benign or malignant. There were 2 false positives. The overall accuracy of diagnosis in the posterior fossa was 75.5%. The value of cerebral radionuclide imaging in the study of posterior fossa lesions in children has been upheld. The investigation is non invasive, safe and reasonably accurate and is an important screening test in this area.     

The application of Lienert's “configuration frequency analysis” in psychiatric epidemiology

Summary In psychiatric epidemiology it is necessary to analyze total or partial associations between categories of properties. For the analysis of associations between two properties statistical procedures are available based on correlation analysis. For the analysis of multidimensional contingency tables these procedures are inadequate. In order to solve this problem Krauth and Lienert (1973) developed the analysis of configuration frequency (CFA). The theoretical implications of this method are discussed, and illustrated by means of a five-dimensional contingency-table. Problems of interpreting the non-hierarchical CFA and the hierarchical CFA are discussed. A program written in FORTRAN IV may be obtained from the authors.This investigation was supported entirely by the Deutsche Forschungsgemeinschaft, and was conducted as part of the Sonderforschungsbereich 116 of the University of Heidelberg.