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Biomedical subjects

W Swoboda

Publications and source records attributed to W Swoboda.

At least 19 recordsLinked to original sources
PubMed2001

LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Adaptor Proteins, Signal Transducing↗
PubMed2001

First results from an intensified monitoring system to estimate drug related hospital admissions.

AIMS: An intensified monitoring system was set up to identify drug related hospital admissions and estimate population-based incidences for commonly prescribed medications. METHODS: Pharmacovigilance-centres systematically screened nonelective admissions to emergency rooms or departments of internal medicine for drug related hospitalizations (DRH). Clinical pharmacologists used standardized causality assessment. Service areas of each acute care hospital were defined by 5 digit postal codes that covered 60% of all admissions. Drug dispensing information was available through claims processed by regional pharmacy computing centres. Quarterly incidences were estimated by dividing the number of events by the number of treated patients. RESULTS: 435 DRHs were reported during five quarters. The incidence of ADRs leading to admissions varied for specific drug groups from 1.5/10 000 treated patients to 24/10 000. Quarterly variation of incidences was moderate except for insulin and calcium antagonists. 95% confidence intervals overlap for all quarters within each group. Incidences are sensitive to changes in the definition of the source population. CONCLUSIONS: Our pharmacovigilance monitoring system allows comparisons of population-based incidences of drug-related hospitalizations among drugs and over time. It provides important information for risk management and monitoring outcomes of pharmaceutical quality management programmes.

Adverse Drug Reaction Reporting Systems↗
PubMed1996

Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13.

Osteoporosis-pseudoglioma syndrome (OPS) is an autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or juvenile-onset blindness. The pathogenic mechanism is not known. Clinical, biochemical, and microscopic analyses suggest that OPS may be a disorder of matrix homeostasis rather than a disorder of matrix structure. Consequently, identification of the OPS gene and its protein product could provide insights regarding common osteoporotic conditions, such as postmenopausal and senile osteoporosis. As a first step toward determining the cause of OPS, we utilized a combination of traditional linkage analysis and homozygosity mapping to assign the OPS locus to chromosome region 11q12-13. Mapping was accomplished by analyzing 16 DNA samples (seven affected individuals) from three different consanguineous kindreds. Studies in 10 additional families narrowed the candidate region, supported locus homogeneity, and did not detect founder effects. The OPS locus maps to a 13-cM interval between D11S1298 and D11S971 and most likely lies in a 3-cM region between GSTP1 and D11S1296. At present, no strong candidate genes colocalize with OPS.

Alleles↗
PubMed1992

[The mid-growth spurt--a pre-puberty growth spurt. Review of its significance and biological correlations].

The MGS is a growth phenomenon during early childhood, expressed by a mild transitory acceleration of growth velocity between five and eight years of age. It appears to be more pronounced in boys than in girls. It is probably caused by the functional maturation of the adrenals ("adrenarche") which leads to an increased androgen production during this age. Interactions with the pituitary growth hormone, also presenting with increased secretion rates at this particular period, are very probable. A hypothesis is offered for the explanation of individual differences and distinctness of the MGS. Although the MGS cannot be interpreted as a very first step of puberty, some additional biochemical facts suggest fundamental changes in the organism. Therefore, the MGS could be regarded as a "marker" within the biological development of the child.

Adrenal Cortex↗
PubMed1989

A computer program for drawing structure formulas of the hormonal steroids used most frequently in endocrinology.

A BASIC program has been developed for plotting planar structure formulas of steroid hormones. The structure formulas can be designed either by selecting distinct root-molecule shapes for further figuration of the wanted formula, i.e. androstane, 4-androstene, estrogen, cholestane, pregnane or 4-pregnene structures, or by editing detailed information concerning the molecule to be designed, starting with the number of carbon atoms, etc. The position of hydroxy and/or keto groups, as well as some stereochemical details, are also freely selectable according to the systematic steroid name. Graphs are displayed on the screen and can be printed. The program is supported by most of the conventional BASIC versions running on personal computers with graphic abilities, since graphic symbols are predominantly used for drawing the structure formulas instead of lettering the symbols.

Chemical Phenomena↗
PubMed1988

The osteoporosis pseudoglioma syndrome. Update and report on two affected siblings.

Two siblings (male, 29 years, and female, 13 years) with the rate autosomal recessive osteoporosis pseudoglioma syndrome are reported in detail. All essential signs and symptoms of the full clinical picture were present and are documented by impressive X-ray pictures. Some aspects of our patients are compared with relevant findings of previous reports. Collagen studies (skin biopsies) failed to reveal any significant disorder of the main collagen types composition. Striking similarities with established genetic disorders of collagen (like the osteogenesis imperfecta group and the Ehlers-Danlos syndrome) suggest, however, that the OPS could be a primary collagen disorder. Genetic counselling and devoted socio-medical care for these handicapped children is presently the only help which can be offered.

Adolescent↗
PubMed1988

Familial pseudohypoaldosteronism.

The clinical course of two siblings with a severe form of pseudohypoaldosteronism was followed over a period of seven and five years respectively. Both children persistently had a high sodium-potassium excretion ratio in the urine, sweat, saliva, and stools as well as high serum concentrations of aldosterone and renin and an increased urinary excretion of tetrahydroaldosterone. Despite sustained treatment with sodium chloride (10-40 mmol/kg/d) and cation exchange resin (sodium polystyrole sulfonate 0.5-2 g/kg/d) they repeatedly developed episodes of salt wasting and hyperkalemia which occurred mainly during uncomplicated respiratory tract infections. Aldosterone receptor characteristics were studied in the cytosol of the rectal mucosa at ages 2.5 years and 6 months respectively. Compared to age matched controls there was a decreased affinity for aldosterone at the low affinity binding site. Among the members of the family, the father and one of his sisters had high concentrations of sodium in the sweat and an increased urinary excretion of tetrahydroaldosterone.

Adult↗
PubMed1987

Radio gas chromatography for evaluation of sub-cellular hormone synthesis in the androgen insensitivity syndrome.

This paper gives a description of a radio gas-liquid chromatographic method for the evaluation of androgen hormone synthesis patterns in the testicular tissue of a patient suffering from the androgen insensitivity syndrome (AIS). A modified dual-column gas chromatography system, equipped with column switching facilities and a radioactivity monitor run parallel to a flame ionisation detector, enables the monitoring of radioactive intermediates of testosterone anabolism and catabolism, generated from a labelled precursor. Tissue preparations were incubated with tritiated pregnenolone for 45 min at 37 degrees C. Steroid hormones were stripped from the aqueous phase by solvent extraction and analysed by gas chromatography as methoxitrimethylsilyl (MO-TMS) derivatives on a 15 m X 0.32 mm I.D. fused-silica capillary column coated with DB-5. The results reveal abnormal enzyme kinetics due to accelerated precursor utilisation. The findings reflect the pathophysiology of AIS at the sub-cellular level of the androgen hormone target organ.

Adolescent↗
PubMed1986

Molecular biology of androgen action: testosterone/dihydrotestosterone receptor and androgen 5 alpha-reductase in the human foreskin.

Receptors for testosterone (T) and dihydrotestosterone (DHT) as well as the tissue specific androgen-5 alpha-reductase (A5R) were studied in the foreskin of 52 healthy boys (ages 1-14 years), in order to gain molecular endocrinological data and information about the ontogeny and cytogeny, respectively, of androgen specific target organs. Enzyme determinations were carried out in tissue homogenates by an enzyme kinetic method for the evaluation of Km- and Vmax-values. Reactions velocities were calculated from the turn over rates of T to DHT, 5 alpha-androstane-3 alpha,17 beta-diol and 5 alpha-androstane-3,beta,17 beta-diol. The precursor (T) was used in increasing concentrations, ranging from 8 to 208 nM. Separation of reaction products was done by thin-layer chromatography and verification of specific radioactivity of metabolites by means of radio gas chromatography on capillary columns. Results of the enzyme analyses: Km = 94.9 +/- 3.5 [nM], and Vmax = 15.8 +/- 1.9 [pmol/mg.h]. Receptors were examined in the cytosolic and nuclear fractions of the tissue specimens. Saturation analyses and calculation of binding data led to specific receptors for T and DHT in the cytosolic (T: Kd = 1.56 +/- 0.12 [nM], Nmax = 122.4 +/- 11.6 [fmol/mg]; DHT: Kd = 1.9 +/- 0.1 [nM], Nmax = 493.3 +/- 77.8 [fmol/mg]) and the nuclear fractions (T: Kd = 1.43 +/- 0.13 [nM], Nmax = 28.7 +/- 3.5 [fmol/mg]; DHT: Kd = 1.37 [nM], Nmax = 196.9 +/- 22.5 [fmol/mg]), Kd-values proved to be quite homogenous (coeff. var. = 0.15-0.21), whereas maximum specific receptor binding activities (Nmax) showed age dependent fluctuations (coeff. var. = 0.35-0.45). Binding capacities of both T- and DHT-receptor, respectively, in cytosolic and nuclear fractions showed peak values in the age group 10-11 years and additional "spikes" of binding rates at age 4-5 years. It is noteworthy that Vmax-values also reached maximum levels in the latter age group. Concerning the ontogeny of the androgen receptor a change of binding properties from the cytosol to the nuclear fraction was observed with the onset of puberty. A comparison of enzyme- and receptor data lead to the theory, that subcellular hormone actions depend on interrelational regulatory mechanisms between androgen receptors (T as well as DHT) and specific enzyme systems (A5R).

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1986

The subcellular defects in the androgen insensitivity syndrome.

The androgen insensitivity syndrome (AIS) was studied with consideration of the complexity of mechanisms involved on the intracellular level: testosterone (T) and dihydrotestosterone (DHT) receptors and the androgen-5 alpha-reductase (A5R). Five children with "normal" female external genitalia (group A) and three patients with variable forms of ambiguity (group B), ages 1 to 18 years, were studied. Tissue specimens from genital skin were analysed for the Kd- and N max-values of the cytosolic and nuclear T- and DHT-receptors, as well as for the Km- and Vmax-data of the tissue specific A5R. The enzyme analyses were performed with a kinetic method. Results show that patients from group A mainly lack action of the nuclear DHT receptor, combined with reduces binding capacity in the cytosol. T binding was poor in both, cytosolic and nuclear fractions, respectively. Results of group B proved to be more inhomogeneous, ranging from total absence of a DHT receptor to normal binding capacities in the nuclear fractions, accompanied by decreased cytosolic N max values for that ligand. T binding was poor in all patients of group B in the cytosolic and nuclear fractions, respectively. A5R was qualitatively normal in all patients examined, except one, but decreased enzyme activities could be observed in a wide range. In summary, the study confirms the complex mechanisms, presenting as AIS clinically. Moreover a close relationship between abnormalities of androgen receptor function and changes in A5R activity could be evaluated, thus confirming the recent theories about intracellular androgen action.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1985

Analysis of androgen-5 alpha-reductase by an enzyme kinetic method.

Analysis of androgen-5 alpha-reductase (A-5 alpha-R) is commonly done by measuring distinct testosterone (T) metabolites after tissue incubation. In the present study, A-5 alpha-R analysis was performed according to the principles of Michaelis-Menten, i.e. by evaluation of KM and Vmax data of the enzyme. 48 tissue samples (foreskin) of healthy boys in the age group 6 months to 8 years were examined. Incubation was carried out using increasing concentrations of 3H-T (8-208 nM) as substrate, followed by extraction and thin layer chromatography (TLC) of the reaction products. Zone detection and quantitation of radioactivity was done by a computing TLC scanner. The specific radioactivity of the metabolites was evaluated by high resolution radio gas chromatography. KM values ranged from 81.8 to 118.1 nM and Vmax from 8.9 to 30.1 pmol/mg . h. Coefficient of variation was smaller for KM (0.1) than for Vmax (0.38). It is recommended to do A-5 alpha-R analysis by evaluation of the enzyme kinetics as this is a reproducible method giving accurate biochemical data of the qualitative and quantitative characteristics of the enzyme.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1984

Explanation of the pseudohypoaldosteronism (PHA)-stress syndrome with an artificial aldosterone receptor model.

A receptor for aldosterone was studied in the cytosol of rectal mucosa of two sisters (M.A., M.B.) with the clinical manifestations of pseudohypoaldosteronism (PHA). Compared to age matched controls the patients showed a decreased affinity for aldosterone (M.A. Kd1: 0.18 nM, Kd2: 4.55 nM; Nmax1: 0.185 fmol/mg cytosol protein (CP), Nmax2: 3.12 fmol/mg CP, respectively). In an attempt to find an explanation for the phenomenon of stress-induced electrolyte imbalance in PHA patients an experimental set up was designed, using aldosterone antibody material as artificial aldosterone receptor. Specific binding was evaluated in addition with and without a 25-100-fold molar excess of dexamethasone (DEX) in order to overcome the glucocorticoid affinity of the aldosterone receptor, a phenomenon proposed to be the cause for the severe consequences of stress in some patients with PHA. The aldosterone antiserum showed two binding sites, similar to the natural receptor (Kd1: 0.15 nM, Kd2: 1.30 nM; Nmax: 30 fmol/mg CP and 130 fmol/mg CP, respectively). Under the influence of DEX the high affinity binding site (Kd1) was occupied by the glucocorticoidanalogon (Kd: 1.30 nM; Nmax: 125 fmol/mg CP). In conclusion, in stress situations, with increased quantities of glucocorticoid circulating, the high affinity binding site of the aldosterone receptor might be occupied by the glucocorticoids, while the low affinity binding site in PHA patients might not have sufficient binding capacity to maintain the electrolyte balance.

Adolescent↗
PubMed1982

[Application of capillary gas chromatography to androgen excretion - analysis as diagnostic tool in paediatric endocrinology (author's transl)].

A gas-chromatographic method on glass capillary columns was developed mainly for the separation of androgens in order to diagnose endocrinopathies, especially various forms of intersexual anomalies. For this purpose the gas-chromatographic conditions were chosen in such a way as to gain a long distance (retention time interval) between the alkanes n-C24H50 and n-C28H58, because these two alkanes limit the area in which most of the androgens appear. Column: 50 m X 0.25 mm (ID), WCOT, OV 101. (Formula: see text). The steroids were analysed in 24-hour urine samples. Extraction was performed with ethyl acetate, followed by persililation to methoxim-trimethylsilyl derivatives. The application of the procedure was demonstrated in two clinical cases, whereby Hamilton's theory, according to which certain androgens as well as their metabolites reflect the psychological and physical status of a person, was evaluated. On the basis of the present results it can be stated that gas chromatography on capillary columns, as described in this paper, is a useful diagnostic tool. With this method it is easy to detect disorders in the synthesis and metabolism of steroid hormones.

Adolescent↗
PubMed1982

Gonadotropin responsiveness to luteinizing hormone releasing hormone in prepubertal and pubertal patients with growth hormone deficiency.

Gonadotropin response to 100 microgram/m2 LHRH was determined in 31 patients with growth hormone deficiency. According to their bone ages the patients were divided into a "prepubertal" (n = 18) and a "pubertal" (n = 13) group. The results were compared with the LHRH tests from 16 healthy prepubertal boys and girls and 32 healthy adult probands, respectively. The maximum increment of LH and FSH was evaluated. In the "prepubertal" group five patients had an insufficient rise of LH and FSH, four of them having additional anterior pituitary hormone deficiencies. In the "pubertal" group nine patients were found to be gonadotropin deficient, all of them had additional hormone deficiencies, TSH being the most frequently affected hormone. Only one of 14 gonadotropin-deficient patients had no other than growth hormone deficiency in addition. An isolated decreased FSH increment without LH deficiency was found in 6 male and 2 female patients and is not thought to be of diagnostic value. No influence of growth hormone treatment or growth velocity on the gonadotropin responsiveness was found. Patients with an additional thyreotropic defect could be classified as pituitary or hypothalamic disorder due to their reaction in the TRH test. These groups could not be differentiated by a single bolus LHRH test, indicating the need of prolonged stimulation to recover the pituitary hyporesponsiveness. Due to methodological problems the diagnosis of gonadotropin deficiency in an individual patient of the prepubertal age group might be questioned. However, a normal gonadotropin response to LHRH can be expected in prepubertal patients with growth hormone deficiency and may indicate a normal gonadotropin function.

Adolescent↗
PubMed1981

[Steroid treatment of adolescent gynecomastia with danazol (author's transl)].

Report on the successful treatment of pubertal gynecomastia with the synthetic steroid preparation Danazol. In 15 male adolescents, 11 to 18 years old, Danazol in an average dose of 8 to 10 mg/kg/day, administered orally over 2 to 3 months, achieved a very good or good reduction of breast tissue. 4 patients showed a palpable but insufficient regression. Side-effects of the treatment were rare and clinically negligible. The mechanism of the hormonal action of the gonadotropin inhibiting steroid Danazol in gynecomastia cannot be explained by the hormone findings available so far.

Adolescent↗