Background: Glucocorticoids (GCs) are commonly used for long-term medication in immunosuppressive and anti-inflammatory therapy. However, the data describing gluco-and mineralo-corticoid (MC) properties of widely applied synthetic GCs are often based on diverse clinical observations and on a variety of in vitro tests under various conditions, which makes a quantitative comparison questionable. Method: We compared MC and GC properties of different steroids, often used in clinical practice, in the same in vitro test system (luciferase transactivation assay in CV-1 cells transfected with either hMR or hGRa expression vectors) complemented by a system to test the steroid binding affinities at the hMR (protein expression in T7-coupled rabbit reticulocyte lysate). Results and Conclusions: While the potency of a GC is increased by an 11-hydroxy group, both its potency and its selectivity are increased by the D1-dehydro-configuration and a hydrophobic residue in position 16 (16-methylene, 16a-methyl or 16b-methyl group). Almost ideal GCs in terms of missing MC effects, as defined by our in vitro assay, are therefore prednylidene, budesonide, beclomethasone and betamethasone. The MC potency of a steroid is increased by a 9a-or a 6a-fluoro substituent. A hydrophilic substituent in position 16 (like 16-hydroxylation in triamcinolone) decreases both MC and GC properties. As no substituent that leads to an isolated reduction of GC activity could be characterized in our experiments, 9a-fluorocortisol, the most frequently used steroid for MC substitution, seems to be the best choice of available steroids for this purpose.
The S810L mutation within the human mineralocorticoid receptor (MR S810L) induces severe hypertension and switches progesterone from antagonist to agonist. Here we report the crystal structures of the ligand-binding domain of MR S810L in complex with progesterone and deoxycorticosterone, an agonist of both wild-type and mutant MRs. These structures, the first for MR, identify the specific contacts created by Leu810 and clarify the mechanism of activation of MR S810L.
The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) system plays a pivotal role in glucocorticoid (GC) and mineralocorticoid (MC) action. Although 11beta-HSD activities are important determinants for the efficacy of synthetic MCs and GCs, corresponding pharmacokinetic data are scanty. Therefore, we characterized 11beta-HSD profiles for a wide range of steroids often used in clinical practice. 11beta-HSD1 and 11beta-HSD2 were selectively examined in 1) human liver and kidney cortex microsomes, and 2) Chinese hamster ovarian cells stably transfected with 11beta-HSD1 or 11beta-HSD2 expression vectors. Both systems produced concordant evidence for the following conclusions. Oxidation of steroids by 11beta-HSD2 is diminished if they are fluorinated in position 6alpha or 9alpha (e.g. in dexamethasone) or methylated at 2alpha or 6alpha (in methylprednisolone) or 16alpha or 16beta, by a methylene group at 16 (in prednylidene), methyloxazoline at 16, 17 (in deflazacort), or a 2-chlor configuration. Whereas the methyl groups also decrease reductase activity (steric effects), fluorination increases reductase activity (negative inductive effect), leading to a shift to reductase activity. This may explain the strong MC activity of 9alpha-fluorocortisol and should be considered in GC therapy directed to 11beta-HSD2-expressing tissues (kidney, colon, and placentofetal unit). 11beta-HSD2 oxidation of prednisolone is more effective than that of cortisol, explaining the reduced MC activity of prednisolone compared with cortisol. Reduction by 11beta-HSD1 is diminished by 16alpha-methyl, 16beta-methyl, 2alpha-methyl, and 2-chlor substitution, whereas it is increased by the Delta(1)-dehydro configuration in prednisone, resulting in higher hepatic first pass activation of prednisone compared with cortisone. To characterize a GC or a MC as substrate for the different 11betaHSDs may be essential for an optimized steroid therapy.
Circulating cell-free DNA opens up an interesting field for therapy monitoring, in particular during multimodal therapy protocols. The objective of this proof of principle study was to evaluate whether the amount of circulating plasma DNA has the potential to serve as a marker for therapy monitoring during the treatment course of locally advanced rectal cancer patients. We especially focused on kinetics of circulating DNA to assess whether variances in kinetics have the potential to discriminate between therapy responders and nonresponders.The amount of circulating DNA in plasma of rectal cancer patients undergoing preoperative chemoradiation was determined using real-time PCR before chemoradiation, after the end of chemoradiation and at the end of treatment. The study population was divided into responders (ypT0-T2 stage) and nonresponders (ypT3-T4 stage). Both groups showed comparable median plasma DNA values before and after the end of chemoradiation. At the end of treatment responders showed a further decrease in circulating DNA, whereas in nonresponders the circulating DNA manifestly increased (P = 0.006).This study demonstrates that circulating DNA in plasma of rectal cancer patients undergoing preoperative chemoradiation might serve as a surrogate marker to discriminate between responders and nonresponders. Therefore, we hypothesize that quantification of plasma DNA could be of use as an easily accessible tool for therapy monitoring in these patients.
Auditory evoked potentials and in this context especially five waves in the first 10 ms (early auditory evoked potentials = EAEP) are a diagnostic aid in topodiagnosis of posterior fossa diseases. This is due to waves I to V which arise along the acoustic nerve and in brain stem structures such as medulla, pons and mid-brain. Besides an indication about the site of a lesion in the posterior fossa, wave V allows an objective threshold determination. The present results were gained in normal children aged 1-3 years and in children with neuropaediatric and audiologic disorders.
Delayed Intracranial Hemorrhage in a Newborn with Alloimmune Thrombocytopenia after Intensive Prenatal Treatment with Serial Platelet Transfusions Background: Fetal alloimmune thrombocytopenia (FAIT) is caused by maternal immunization against a fetal platelet antigen, most frequently HPA-1a (Zwa, Pl A1), and subsequent transplacental transfer of maternal IgG antibodies into the fetal circulation. The fetus and the neonate are threatened by severe bleeding, particularly intracranial hemorrhage (ICH), which occurs in 10–20% of all cases. We describe a case of FAIT due to immunization against HPA-1a. Patients, Materials and Methods: At the beginning of pregnancy, the previously diagnosed HPA-1a antibody was confirmed by monoclonal antibody-specific immobilization of platelet antigen (MAIPA). Fetal blood specimens were obtained by umbilical venipuncture. Fetal platelet counting and umbilical blood sampling, first in the 22nd week of gestation, were combined with intrauterine platelet transfusion of HPA-1a-negative platelet concentrates of maternal or high-dose donor platelet concentrates. The thrombocytopenic fetus was treated by nearly weekly intrauterine platelet transfusions of maternal or donor platelet concentrates and delivered by caesarean section in the 35th week of gestation. Results: Our observations suggest that frequent platelet transfusions in short intervals may be necessary to increase platelet counts in thrombocytopenic fetuses. The platelet count at birth was 145,000/µl. The newborn did not show any signs of cutaneous bleeding. Postpartal ultrasonic examination of the child’s head revealed no signs of ICH. The platelet counts were examined daily during a 14-day period. Platelet counts reached a nadir of 70,000/µl at day 4. The child was discharged at day 14 with 150,000 platelets/µl and without any hemorrhagic symptoms. Neurologic examination at the age of 6 months revealed subtle signs of a developmental disturbance. Upon ultrasonic examination a parieto-occipital posthemorragic cyst was detected. Conclusion: Delayed ICH may occur in newborns with FAIT. It remains to be elucidated whether this complication is a specific problem in children who had been treated with serial intrauterine platelet transfusions for FAIT. However, for the early recognition of such delayed ICH, short-term postpartal examinations during the first months of life are necessary.
Inborn errors of metabolism in 40 children have been investigated by computed tomography to obtain data on the degree of cerebral involvement in neurodegenerative and storage disorders: 20 children had various mucopolysaccharidoses, 8 sphingolipidoses , 3 mucolipidoses, 2 oligosaccharidoses , 3 ceroidlipofuscinoses and 4 had various leucodystrophies . Diagnosis in all patients except Alexander's disease was established by biochemical or histological means. The main findings on CT were cerebral atrophy with enlargement of the ventricles and the subarachnoid spaces and hypodensity of the white matter. The degree of cerebral atrophy seemed to develop according to the age of the patients, as could be seen from the patients with mucopolysaccharidosis III, metachromatic leucodystrophy and GM1-gangliosidosis. Hypodensity of the white matter was found in mucopolysaccharidosis I-H, II-B, VI, in mucolipidosis II and in patients with leucodystrophies . On the other hand, there was great variability in these CT findings even in siblings, as seen in four patients with mucopolysaccharidosis VI. Among the series there were several patients who did not show any abnormalities in CT, so that a negative CT did not exclude these disorders, even the leucodystrophies . CT features such as cerebral atrophy or hypodensity were helpful in the evaluation of these disorders, though a diagnosis could not be made by CT alone.
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