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BACKGROUND: The bladder exstrophy-epispadias complex represents a spectrum of urogenital anomalies in which part or all of the distal urinary tract fail to close and are exposed on the outer abdominal wall. Previous studies are suggestive of an underlying multifactorial mode of inheritance. However, no genetic or nongenetic factor has been identified so far. In this study, we sought risk loci by parametric and nonparametric linkage analysis, searching for homozygous segments, and more complex inherited loci, respectively. METHODS: Two pedigrees, Spanish and German, each comprising two members affected with classical bladder exstrophy, were analyzed by genome-wide linkage scan. RESULTS: Evidence for possible risk/modifying loci on chromosomes 2p22.1-p21, 2p25.2-p25.1, 4q23-q32.3, 7q21.3-q33, 7q34-q36.1, 14q31.1-q32.2, and 19q13.33-q13.43 (LOD scores >1.50) was obtained. CONCLUSIONS: This study was the first positional approach to identify chromosomal candidate regions causally related to bladder exstrophy-epispadias complex. Our results suggest the presence of susceptibility genes in the regions identified. These regions need to be confirmed in future studies.

Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are suggested to be important neurosteroids. We investigated steroid sulfatase (STS) in human temporal lobe biopsies in the context of possible cerebral DHEA(S) de novo biosynthesis. Formation of DHEA(S) in mature human brain tissue has not yet been studied. 17α-Hydroxylase/C17-20-lyase and hydroxysteroid sulfotransferase catalyze the formation of DHEA from pregnenolone and the subsequent sulfoconjugation, respectively. Neither their mRNA nor activity were detected, indicating that DHEA(S) are not produced within the human temporal lobe. Conversely, strong activity and mRNA expression of DHEAS desulfating STS was found, twice as high in cerebral neocortex than in subcortical white matter. Cerebral STS resembled the characteristics of the known placental enzyme. Immunohistochemistry revealed STS in adult cortical neurons as well as in fetal and adult Cajal-Retzius cells. Organic anion transporting proteins OATP-A, -B, -D, and -E showed high mRNA expression levels with distinct patterns in cerebral neocortex and subcortical white matter. Although it is not clear whether they are expressed at the blood–brain barrier and facilitate an influx rather than an efflux, they might well be involved in the transport of steroid sulfates from the blood. Therefore, we hypothesize that DHEAS and/or other sulfated 3β-hydroxysteroids might enter the human temporal lobe from the circulation where they would be readily converted via neuronal STS activity.

Dehydroepiandrosterone and its sulphate are important factors for vitality, development and functions of the CNS. They were found to be subjects to a series of enzyme-mediated conversions within the rodent CNS. In the present study, we were able to demonstrate for the first time that membrane-associated dehydroepiandrosterone 7α-hydroxylase activity occurs within the human brain. The cytochrome P450 enzyme demonstrated a sharp pH optimum between 7.5 and 8.0 and a mean KM value of 5.4 µm, corresponding with the presence of the oxysterol 7α-hydroxylase CYP7B1. Real-time RT–PCR analysis verified high levels of CYP7B1 mRNA expression in the human CNS. The additionally observed conversion of dehydroepiandrosterone via cytosolic 17β-hydroxysteroid dehydrogenase activity could be ascribed to the activity of an enzyme with a broad pH optimum and an undetectably high KM value. Subsequent experiments with cerebral neocortex and subcortical white matter specimens revealed that 7α-hydroxylase activity is significantly higher in the cerebral neocortex than in the subcortical white matter (p

Summary OBJECTIVE No satisfactory treatment for adrenocortical carcinoma (ACC) is available. We investigated the efficacy and toxicity of suramin In the treatment of metastatic ACC since suramin has been recently reported to be active as a single agent therapy for patients with ACC and prostatic carcinoma. DESIGN We collected data on 9 patients with metastatic ACC treated with suramin in four centres in Germany between 1987 and 1992. PATIENTS Nine patients (5 women, 4 men; age range 32–67 years) were included. Biochemical evidence of steroid excess was found in 6/9, in three leading to clinical symptoms (hypertension, hyperglycaemla, hirsutism, gynaecomastia). MEASUREMENTS Tumour responses were assessed by radiological and biochemical evaluation. Other investigations included regular measurements of blood cell counts, coagulation, hepatic and renal function parameters, and serum suramin concentrations. RESULTS The patients received cumulative doses ranging from.2 to 30·2 g suramin over periods of 1–15 months. 3/9 achieved a partial response, 2/9 disease stabilization and 4/9 experienced progressive disease. Tumour responses were transient. Suramin treatment was without direct influence on steroid excess. Serious side-effects included coagulopathy (6/9), thrombocytopenla (6/9), polyneuropathy (2/9) and allergic skin reactions (4/9); the death of two patients was possibly related to suramin therapy. Both toxicity and tumour response were strongly associated with serum level or cumulative dose of suramin. CONCLUSIONS (1) Suramin is of antineoplastic efficacy in the treatment of metastatic adrenocortical carcinoma. (2) The clinical use of suramln is limited by a narrow therapeutic window with the risk of serious and possibly lethal toxicity at one extreme, and loss of efficacy at the other. Strict monitoring of suramin serum levels is mandatory aiming at levels between 200 and 250mg/l. Suramin should not be considered as first-line treatment for metastatic adrenocortical carcinoma. (3) To improve treatment options in adrenocortical carcinoma as well as for further investigation on the usefulness of suramin, controlled prospective trials are urgently needed.

The highly specific and accurate technique of isotope dilution mass spectrometry has been used for the measurement of 17 alpha-ethynyloestradiol-17 beta and norethisterone in serum. Serum samples were obtained from female volunteers who received 2.5 mg lynestrenol and 50 micrograms 17 alpha-ethynyloestradiol-17 beta in two different galenical preparations. The determination of total 17 alpha-ethynyloestradiol-17 beta (conjugated and non-conjugated) was carried out by the following procedure: (1) adsorption of the steroids from 1 ml serum to Amberlite XAD-2; (2) enzyme hydrolysis of the conjugated steroid; (3) addition of 1 ng [6,7-3H2] 17 alpha-ethynyloestradiol-17 beta as internal standard; (4) column chromatography on Sephadex LH 20; (5) derivative formation with heptafluorobutyric anhydride; (6) isotope dilution mass spectrometry at m/z 474 and 478 using a glass capillary gas-liquid chromatography column. For the measurement of norethisterone, which is the major metabolite of lynestrenol, 1 ng [7-3H]norethisterone was added to 0.5 ml serum. The labelled and the non-labelled steroids were extracted and purified by column chromatography on Sephadex LH 20. The norethisterone was reacted to form the 3-enol-17 beta-trimethylsilyl ether of norethisterone and [3H]norethisterone. For isotope dilution mass spectrometry the derivative was injected into the glass capillary column which was coupled to the mass spectrometer. The instrument was adjusted to m/z 442 and 444, corresponding to the molecular ions of the ether derivatives of norethisterone and [7-3H]norethisterone. Accuracy was achieved by the use of highly specific technique of mass spectrometry and the exact control of recovery using the isotope dilution principle. The precision was 4.5% (CV) for the determination of 17 alpha-ethynyloestradiol-17 beta and 2.5% (CV) for norethisterone. The lower limit of detection was at 20 pg ml-1 for both methods.

Die Darstellung von drei siliciumorganischen Derivaten des Dimethylsulfodiimins, darunter zwei Cyclosilazane, wird beschrieben. Die Eigenschaften der neuen Verbindungen werden mitgeteilt.