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Biomedical subjects

J S Winter

Publications and source records attributed to J S Winter.

At least 37 records · Page 2Linked to original sources
PubMed1989

The effect of leg position on knemometric measurements of lower leg length.

Using the Valk knemometer, lower leg length (LLL) was assessed relative to changes in the positioning of the upper leg. Lowering the chair height of the knemometer resulted in a more acute angle between the upper and lower leg and a decrease in LLL. This decrease in measurement was attributed to changes in the anatomical surface of the knee underlying the measuring platform as a result of increasing the acuity of the leg angle. Based on four different leg positions, the average change in LLL per centimeter change in chair height was 0.607 mm in a child sample of 50, and 0.655 mm in an adult sample of 20. The difference in chair height with the leg angle at 90 degrees and the lowest chair height possible, ranged from 12.3 to 30.3 mm, relative to lower leg length. This meant the longest leg in the study had a LLL measurement differing by 19.8 mm between these two positions. Due to the effect of leg position, we advised the use of a standard method of measuring LLL with respect to leg angle. Given the difficulties in accurately measuring leg angle with current available tools, we advise the most acute angle.

Adolescent↗
PubMed1988

Structural characterization of normal and mutant human steroid 17 alpha-hydroxylase genes: molecular basis of one example of combined 17 alpha-hydroxylase/17,20 lyase deficiency.

Steroid 17 alpha-hydroxylase (cytochrome P-450 17 alpha) catalyzes both 17 alpha-hydroxylation of pregnenolone and progesterone and 17,20-lysis of 17 alpha-hydroxypregnenolone and 17 alpha-hydroxyprogesterone. In the course of undertaking detailed investigation of the structure-function relationships which exist within this enzyme we have begun to elucidate the molecular basis of human deficiencies in either or both of these activities. Consequently we have determined the exonic structure of the human P-450 17 alpha gene as well as the sequences at the exon/intron boundaries and at the site of initiation of transcription. A single gene in the human genome encodes this protein, being the sole member of a unique gene family (P450XVII) within the P-450 supergene family. A protocol for exonic sequencing of the P-450 17 alpha gene has been established which permits structural analysis of the gene from patients having 17 alpha-hydroxylase and/or 17,20-lyase deficiency. This procedure has been applied to the mutant gene from one individual having combined 17 alpha-hydroxylase/17,20-lyase deficiencies. A four-base duplication is found in exon 8 producing a protein with an altered C-terminal amino acid sequence which results in loss of both enzymatic activities.

Adrenal Hyperplasia, Congenital↗
PubMed1987

Kinetic analysis of inhibition of human adrenal steroidogenesis by ketoconazole.

The kinetics of the inhibitory effects of the imidazole antimicrobial ketoconazole on the activities of the steroidogenic enzymes distal to cholesterol side-chain cleavage were studied in human adrenal microsomal and mitochondrial suspensions. Although ketoconazole was a competitive inhibitor of all five enzyme reactions, the effects on 17-hydroxylase, 17,20-desmolase, and 11-hydroxylase activities (Ki = 10(-8) M) were considerably greater than those on 21-hydroxylase and 3 beta-hydroxysteroid dehydrogenase/isomerase activities (Ki = 10(-4) M). These findings explain the clinical endocrine effects of ketoconazole in the usual therapeutic doses, which include inhibition of cortisol and androgen secretion, compensatory ACTH-mediated secretion of 17-desoxysteroids such as progesterone and aldosterone, and suppression of PRA.

3-Hydroxysteroid Dehydrogenases↗
PubMed1987

The role of gonadal steroids in feedback regulation of gonadotropin secretion at different stages of primate development.

The serum gonadotropin response to castration was assessed in 8 foetal, 2 neonatal, 30 juvenile, and 2 adult rhesus monkeys (M. mulatta). In the 30 castrated juvenile monkeys and 8 sham-operated controls, concentrations of oestrone, oestradiol, androstenedione, dihydrotestosterone, testosterone and 17OH-progesterone were measured in 10 ml serum pools before, one month after, and one year after the surgical procedure. Castration during foetal life (83-137 days gestation) was followed within 48-72 h by a significant rise in serum FSH levels in males, but had no effect on the already high levels in females. Similarly, castration of males during the first post-natal month raised serum FSH and LH into the adult castrate range; however, after 3 months of age serum gonadotropin levels again declined to the normal juvenile range in spite of the open feedback loop. Orchiectomy of prepubertal juvenile monkeys (age 3 month-2 8/12 years) had no immediate effect on serum gonadotropins, but was followed by a delayed rise in FSH (at age 2 3/12-4 3/12 years) and LH (at age 2 7/12-4 4/12 years) to adult castrate levels. Orchiectomy of older prepubertal (by serum testosterone) or adult males resulted within a few days in a progressive and sustained rise in serum FSH and a more gradual rise in LH. Prepubertal gonadotropin regulation appeared to be sexually dimorphic, since ovariectomy in juvenile females (age 3 months-1 5/12 years) was followed by generally elevated, if somewhat erratic, serum FSH values, with a secondary rise in both FSH and LH levels at 2-2 1/12 years. In both sexes, prepubertal castration caused a significant and sustained decline in serum concentrations of oestradiol; castrated males also showed a decline in serum testosterone levels. Although prepubertal castration also caused in both sexes a slight decline in serum oestrone, and ovariectomy a decline in serum androstenedione and dihydrotestosterone, these effects were not sustained one year later, and values were not significantly different from sham-operated controls. Taken together, these data lend support to a model of primate sexual maturation in which the primary regulator of gonadotropin secretion in both sexes during the prolonged juvenile phase is central inhibition of the hypothalamic GnRH regulator. However, during foetal and neonatal life, and again following the onset of puberty, the major modulator of gonadotropin secretion becomes sex steroid-mediated feedback inhibition.

Age Factors↗
PubMed1987

Inactive renin and aldosterone in Bartter's syndrome.

Studies of plasma samples of 3 subjects with Bartter's syndrome were compared to 8 subjects with other conditions. Despite high levels of active renin initially, with low levels of inactive renin, addition of either human nephrectomized plasma or sheep substrate not only increased active renin (by at least 3-fold) but also led to the appearance of large quantities of inactive renin (10-20 times the concentration originally present, much greater than the small increase seen with other plasmas). The activated inactive renin after substrate addition possibly had a larger and more variable molecular size (42,000-48,000) than normal inactive renin (42,500-44,500). Renin substrate in Bartter's plasma was present in similar amounts and had a normal or supranormal angiotensin generation rate with exogenous human renin. Bartter's substrate had a similar molecular weight (55,000) to that found in normal human plasma. The agent in the exogenous substrate preparations causing the increase in apparent active and inactive renin was not ultrafiltrable. However, an acidification procedure that destroyed exogenous substrate also removed the renin-increasing effect. Captopril increased renin but not aldosterone, while amiloride increased aldosterone but not renin. Neither agent improved serum potassium significantly in these patients on indomethacin.

Adolescent↗
PubMed1986

Growth hormone deficiency in patients with histiocytosis X.

Twenty-two patients with biopsy proved histiocytosis X, aged 10 months to 14 years (median 2 years) at the time of diagnosis, were observed for 6 months to 13 years (median 4 years). One patient who had received 3000 rads irradiation directly to the hypothalamic-pituitary area had clinical and biochemical evidence of growth hormone deficiency and responded to GH therapy. Thirteen patients had normal stature, normal growth velocity, and no diabetes insipidus. The GH response to insulin-induced hypoglycemia was studied in three of these 13 patients (group 1), in three children with short stature and no diabetes insipidus (group 2), and in five patients with diabetes insipidus but normal stature and growth velocity (group 3). Peak GH responses were normal (greater than 5 micrograms/L) in all patients in groups 1 and 2, but three of the five patients in group 3 had subnormal GH responses to insulin-induced hypoglycemia and to arginine, L-DOPA/propranolol, and exercise. Their growth rates continue to be normal over 6 to 14 years follow-up. Thus, although impaired GH responses were observed in four of the 12 patients tested, true growth failure occurred only in association with direct hypothalamic-pituitary irradiation. This experience and the observation that GH deficiency was diagnosed in fewer than 1% of children with histiocytosis in Canada during a 15-year period (accounting for less than 1% of all children with GH deficiency) suggest that classic GH deficiency is not a common complication of histiocytosis unless direct hypothalamic-pituitary irradiation has been given.

Child↗
PubMed1986

Steroid inhibitory effects upon human adrenal 3 beta-hydroxysteroid dehydrogenase activity.

The inhibitory effects of varying concentrations of steroids upon 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) kinetics were studied in human adrenal microsomes. Each enzyme assay was conducted in triplicate at five different concentrations of three substrates (dehydroepiandrosterone, pregnenolone, and 17OH-pregnenolone), using microsomes from at least three donors. Each steroid was screened for possible inhibition at concentrations of 10(-8) and 10(-6) M and then studied in more detail at five different concentrations. The type of inhibition and the inhibition constant (Ki) were determined by analysis of Lineweaver-Burk and Dixon plots, together with replots of the slopes from the Dixon plots. The mean Km (Michaelis-Menten constant) for the three substrates was 0.42 +/- 0.04 (SE) mumol/liter (n = 73). Each steroid tested, including delta 5-3 beta-hydroxysteroids, estrogens, and several delta 4-3-ketosteroids, with the exception of cortisol, caused significant inhibition of 3 beta-HSD activity, and in each case the steroid appeared to behave as a competitive inhibitor. In most cases the Ki value was approximately 10(-7) M. At micromolar concentrations several steroids, notably estrone and estradiol, caused almost total inhibition of adrenal 3 beta-HSD activity. Comparison of the calculated Ki values with available data concerning changes in intra-adrenal steroid concentrations during childhood suggests that these changes would be sufficient to cause a relative decline in 3 beta-HSD activity during adrenarche. Although postnatal circulating steroid concentrations would appear to be insufficient to influence adrenal steroidogenesis, the high serum levels of placental steroids during fetal life would be expected to cause marked 3 beta-HSD inhibition.

3-Hydroxysteroid Dehydrogenases↗
PubMed1986

Regulation of the activities of 17-hydroxylase and 17,20-desmolase in the human adrenal cortex: kinetic analysis and inhibition by endogenous steroids.

Kinetic analyses of 17-hydroxylase and 17,20-desmolase activities have been performed on human adrenal microsomes from 12 individuals, aged 1-60 yr. The median Michaelis constant of 17-hydroxylase for the substrate pregnenolone was 0.09 microM, and that of 17,20-desmolase for the substrate 17-hydroxypregnenolone was 0.12 microM. The median maximum velocity of 17-hydroxylase (0.25 nmol/mg X min) was significantly greater than that of the desmolase (0.13 nmol/mg X min). There was no significant correlation between the age of the adrenal donor and the Michaelis constant, but the maximum velocity for both activities in the single infant donor was lower than the values in older individuals. The inhibitory effects of various steroids on both enzyme activities also were studied. All steroids examined, except cortisol, competitively inhibited both enzymes. In each case the inhibition constant was higher for 17-hydroxylase than for 17,20-desmolase, indicating that C21 side-chain cleavage would be more sensitive to inhibition by endogenous steroids. The results, taken together with those of similar studies of 3 beta-hydroxysteroid dehydrogenase kinetics, are compatible with the suggestion that increased enzyme synthesis mediated by ACTH and differential inhibition by endogenous steroids may, in part, account for developmental changes in adrenal hormone secretion.

Adolescent↗
PubMed1986

An autosomal dominant form of adolescent multinodular goiter.

Eighteen members of an extended pedigree have been found to have a form of euthyroid adolescent multinodular goiter. Histological examination showed multiple adenomata with areas of epithelial hyperplasia, hemorrhage, and calcification. In two subjects there were focal areas of epithelial hyperplasia reminiscent of low-grade papillary carcinoma, but capsular and vascular invasion was not found. The pattern of inheritance appeared to be autosomal dominant, with diminished penetrance in males. Although the patients were euthyroid, the likely basis for this disorder is an abnormality in thyroglobulin structure and function.

Adolescent↗
PubMed1985

Postpartum disappearance of chorionic gonadotropin from the maternal and neonatal circulations.

The disappearance of chorionic gonadotropin from the circulation was studied in a group of 10 healthy mothers and their offspring following vaginal delivery. Kinetic analysis revealed the following biexponential clearance characteristics: in mothers the rapid half-life component averaged 4.75 +/- 0.58 (SE) hours (n = 6), and the slow half-life component averaged 32.2 +/- 1.35 hours (n = 6); in neonates the respective overall means were 1.32 and 55.2 hours. Total elimination of chorionic gonadotropin (less than 0.005 IU/ml) occurred at a median time of 14 days following birth (range, 8 to 24 days) in mothers and at 1.5 days (range, 0 to 4 days) in neonates.

Chorionic Gonadotropin↗
PubMed1985

Absent factor VIII response to synthetic vasopressin analogue (DDAVP) in nephrogenic diabetes insipidus.

To study the effect of 1-deamino-8D-arginine vasopressin (DDAVP) on the factor VIII response in nephrogenic diabetes insipidus (NDI), 0.30 microgram/kg DDAVP was given to 2 unrelated NDI patients, 3 obligate carriers, and 20 controls. Factor VIII coagulant activity (FVIIIC) and factor VIII related antigen (FVIIIR:Ag) responses were absent in both NDI patients and were decreased by approximately 50% in the carriers by comparison with controls. These results show that the vasopressin receptor defect in NDI is not confined to the kidney but is equally expressed in other tissues including the vascular endothelium and hepatic sinusoids, the respective sites of FVIIIR:Ag and FVIIIC production. A decreased factor VIII response may help in identifying carriers in families at risk.

Adolescent↗
PubMed1985

Congenital 11 beta-hydroxysteroid dehydrogenase deficiency associated with juvenile hypertension: corticosteroid metabolite profiles of four patients and their families.

Four children with 11 beta-hydroxysteroid dehydrogenase deficiency are described. All patients had severe hypertension, hypokalaemia, and low plasma aldosterone and renin activities. Two of the patients were siblings and two were unrelated. The most noticeable biochemical feature of these individuals was the extremely low excretion of cortisol metabolites containing an 11-carbonyl group compared to the excretion of the 11 beta-hydroxyl containing metabolites. Although this condition is readily diagnosed in affected individuals by urinary steroid analysis, carriers of the defect do not differ from normal in their urinary steroids. Both parents of the affected siblings had normal 11-oxo-steroid/11 beta-hydroxysteroid ratios under baseline conditions and the lesions could not be revealed by ACTH administration.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1985

Pituitary-gonadal function in Klinefelter syndrome before and during puberty.

Serum concentrations of follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol were determined at intervals before and during puberty in 40 individuals with Klinefelter syndrome (47,XXY karyotype), of whom 27 had been detected in neonatal cytogenetic screening programs. Prior to the appearance of secondary sexual changes, basal serum hormone concentrations and acute responses to stimulation with gonadotropin-releasing hormone and human chorionic gonadotropin were normal. The timing of the onset of clinical puberty was normal. Early pubertal boys showed initial testicular growth and normal serum testosterone levels, while serum follicle-stimulating hormone and estradiol concentrations were significantly elevated. By midpuberty, the Klinefelter subjects were uniformly hypergonadotropic and their testicular growth had ceased. Serum testosterone concentrations after age 15 remained in the low-normal adult range. Serum estradiol levels remained high, irrespective of the presence or absence of gynecomastia. Exaggerated responses to gonadotropin-releasing hormone are seen in pubertal subjects with elevated basal gonadotropin values.

Adolescent↗
PubMed1985

Kinetic analysis of adrenal 3 beta-hydroxysteroid dehydrogenase activity during human development.

Kinetic analyses of microsomal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity in adrenal glands from 11 individuals, aged 1-60 yr, were carried out to determine whether changes in substrate or cofactor affinity (Km) or cellular content, as reflected in maximal velocity, could explain the changes in adrenal delta 5-3 beta-hydroxysteroid secretion that occur in late childhood and puberty. The Km values for the cofactor NAD+ were similar regardless which substrate, dehydroepiandrosterone (DHA), pregnenolone, or 17-hydroxypregnenolone (17OH-delta 5P), was used. The Km values for DHA (0.3 microM), pregnenolone (0.4 microM), and 17OH-delta 5P (0.3 microM) were similar and within the intraadrenal concentration ranges for DHA and 17OH-delta 5P previously reported. Each substrate was a competitive inhibitor for the others, with close similarity between affinity and inhibition constants. These observations point to the presence of a single 3 beta-HSD, rather than several substrate-specific variants. There was no change in substrate Km with age; the maximal velocity was lower (0.1-0.6 nmol/mg X min) in a single 1-yr-old infant than in later life, but there was no significant change (mean, 2.9-4.6 nmol/mg X min for the three substrates) between values at 12 and 60 yr. This suggests that ACTH-mediated induction of 3 beta-HSD may be low in infancy and higher in adults, while in vivo studies point to a reduction in actual 3 beta-HSD activity during this period. The likely explanation for this paradox between enzyme levels and final activity is that 3 beta-HSD is progressively inhibited during late childhood and puberty by rising intraadrenal concentrations of various delta 4-3-ketosteroids.

17-alpha-Hydroxypregnenolone↗
PubMed1984

The effect of five synthetic progestational compounds on 5 alpha-reductase activity in genital skin fibroblast monolayers.

The suggestion has been made that prenatal exposure to synthetic progestogens contributes to an increased incidence of hypospadias. One potential mechanism for such an effect might be inhibition of 5 alpha-reductase, a key enzyme in normal male sexual differentiation. We have examined the effect of progesterone and of five synthetic progestogens upon 5 alpha-reductase activity in fibroblast monolayers from 12 genital skin cell lines obtained from normal newborn infants, boys with phimosis and hypospadias and a normal adult male. Basal enzyme activities ranged from 0.8-12.1 pmoles 5 alpha-reduced product/micrograms DNA/hour. Progesterone and norethindrone inhibited 5 alpha-reductase activity in a dose dependent manner to a maximum of 95% and 50% of basal levels respectively at 10(-5) M. Similar concentrations (10(-5) M) of norethynodrel, ethisterone, dl-norgestrel and d-norgestrel had little or no effect. Studies of cell viability showed that the effects of progesterone and norethindrone were specific for 5 alpha-reductase and not non-specific toxic effects.

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