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Biomedical subjects

C A Winkel

Publications and source records attributed to C A Winkel.

At least 37 records · Page 2Linked to original sources
PubMed1988

Modulation of hepatic cholesterol metabolism by ethinyl estradiol and norgestrel.

Previous investigators reported that certain combination oral contraceptives are associated with significant alterations in serum lipid concentrations, namely a decrease in high density lipoprotein and increase in low density lipoprotein fractions. The mechanism(s) responsible for these changes remain unclear. In the present study we sought to determine the effect of the oral contraceptive components, ethinyl estradiol (EE) and norgestrel (N) on hepatic cholesterol metabolism, specifically on 3-hydroxy-3-methylglutaryl coenzyme A (HMG) reductase. Forty-eight cycling female Sprague-Dawley rats were divided into six groups and treated daily with either 0.1 mg or 1.0 mg EE daily, 1.0 mg or 10.0 mg N daily, or 0.1/1.0 mg or 1.0/10.0 mg EE/N in combination daily. Twelve age- and weight-matched animals served as controls. No significant changes in hepatic HMG reductase activity were observed between those groups treated with either EE or N alone and the control group. However, hepatic HMG reductase activity was increased significantly in both EE/N combination-treated groups when compared to controls, the EE-treated groups and the N-treated groups. These results are suggestive that the changes in serum lipids noted clinically in association with oral contraceptive use may be related to the induction specifically of hepatic HMG reductase activity and subsequent changes in cellular cholesterol synthesis or metabolism.

Animals↗
PubMed1987

Mineralocorticosteroids and pregnancy: regulation of extra-adrenal deoxycorticosterone production by estrogen.

During pregnancy, deoxycorticosterone (DOC) in maternal plasma is produced principally by 21-hydroxylation of circulating progesterone in a number of extra-adrenal tissues. Estrogen acts, directly or indirectly, to increase the transfer constant of conversion of progesterone to DOC. In this study, we evaluated the regulation of DOC production during pregnancy by considering the plasma levels of progesterone, the kinetics of extra-adrenal steroid 21-hydroxylase, and the stimulation of the conversion of progesterone to DOC by estrogen.

Anencephaly↗
PubMed1987

Leukocyte esterase activity in human amniotic fluid for the rapid detection of chorioamnionitis.

Chorioamnionitis plays an important role in perinatal morbidity and mortality. Fast and accurate diagnosis poses a major problem. A prospective study was performed to assess the value of positive leukocyte esterase test (Chemstrip 9) for the diagnosis of chorioamnionitis during labor. We evaluated 21 patients with chorioamnionitis in labor at term and used 21 matched control subjects. The sensitivity and specificity of leukocyte esterase activity were compared with those of amniotic fluid cultures, Gram stains, maternal pyrexia and leukocytosis, and fetal tachycardia. The sensitivity in diagnosing chorioamnionitis was 91% and the specificity was 95%. The use of this test strip could provide a rapid, inexpensive screening test for chorioamnionitis.

Amniotic Fluid↗
PubMed1987

Effects of alterations of zinc-to-phosphorus ratios and meconium content on group B Streptococcus growth in human amniotic fluid in vitro.

Several authors have described the bacterial growth-altering properties of amniotic fluid. We examined Group B Streptococcus growth in aseptically obtained amniotic fluid in vitro after altering its zinc, phosphorus, and meconium contents. Zinc and phosphorus levels were calculated in amniotic fluid and in meconium. Separate solutions of zinc and phosphorus were added to yield concentrations of 0.7, 7.0, 70, and 700 mumol. The solutions were incubated with Group B Streptococcus III 893 and Escherichia coli C5 strains, and 24-hour growth curves were plotted. Meconium, 0.5 mg/ml, was added to each amniotic fluid + zinc and amniotic fluid + phosphorus solution, and growth curves were plotted. The rate of proliferation of Group B Streptococcus varied directly with the zinc concentration (700 = 70 greater than 7 greater than 0.7 mumol) and inversely with the phosphorus content (700 less than 70 less than 7 = 0.7 mumol). Meconium enhanced the proliferative effect of zinc and hindered the inhibitory effect of phosphorus. Thus one possible mechanism whereby meconium enhances bacterial growth in amniotic fluid may be by alteration of zinc-to-phosphorus ratios.

Amniotic Fluid↗
PubMed1986

Long-acting gonadotropin hormone-releasing hormone analog used to treat uteri.

Because the size of leiomyomata uteri often decreases significantly after menopause, the authors elected to employ a long-acting gonadotropin hormone-releasing hormone analog (GnRH-alpha) (imbzl-D-His6-Pro9-Net-GnRH) to create a state of pseudomenopause in six patients with leiomyomata uteri diagnosed on the basis of pelvic examination and confirmed by pelvic ultrasonography. Patients received daily, subcutaneous injections of GnRH-alpha (4 micrograms X kg-1 X 24 hour-1) for 6 months. Uterine size (13.8 +/- 4 weeks [mean +/- standard deviation (SD), n = 6]) was determined by pelvic examination and uterine volume (533.9 +/- 394 ml [mean +/- SD, n = 6]) was determined by pelvic ultrasonography before medical therapy was begun. They observed a decrease in uterine size by pelvic examination within 4 weeks of the initiation of therapy, and all patients experienced a decrease in uterine size (9.5 +/- 4 weeks [mean +/- SD, n = 6]) (P less than 0.05) within 8 weeks of initiation of therapy. After 6 months of therapy, uterine size was 229.5 +/- 145 ml (mean +/- SD, n = 6). During treatment, plasma estrogen concentrations were assessed intermittently (every 1 to 4 weeks) and remained less than 4 pg X ml-1 throughout the period of therapy. All six patients have discontinued therapy. There has been no increase in uterine size in these patients for a period from 3 to 7 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Plasma and amniotic fluid concentrations of fibronectin during normal pregnancy.

To ascertain the influence of pregnancy on plasma concentrations of fibronectin, we quantified plasma concentrations of fibronectin in 22 normal, pregnant women during the first, second, and third trimesters; at the time of delivery; and at six weeks and eight months postpartum, using a rapid, immunoturbidimetric procedure. Mean plasma concentrations of fibronectin rose significantly throughout pregnancy, and were significantly greater than umbilical cord plasma concentrations. Maternal plasma concentrations of fibronectin at six weeks postpartum were similar to those observed at the time of delivery, but returned to concentrations observed in nonpregnant women by eight months postpartum. No significant differences between concentrations of fibronectin in amniotic fluid obtained during the second and third trimesters of pregnancy were observed. Six-week postpartum values appeared to depend upon the type of infant feeding as values rose in bottle feeding but fell in breast-feeding mothers.

Adolescent↗
PubMed1984

Umbilical cord plasma concentrations of deoxycorticosterone sulfate in anencephalic fetuses.

In the present investigation, we determined the levels of deoxycorticosterone sulfate in mixed umbilical cord plasma of anencephalic abortuses and newborn infants. The anencephalic fetus is an interesting model with respect to the production of deoxycorticosterone and deoxycorticosterone sulfate on several accounts. There is profound adrenal atrophy in most such fesuses, and, in consequence, there also is relatively profound hypoestrogenism. This is an important consideration in the formation of deoxycorticosterone and deoxycorticosterone sulfate since it is known that estrogen acts to stimulate extra-adrenal steroid 21-hydroxylase and 21-hydroxysteroid sulfotransferase activities. The plasma levels of deoxycorticosterone sulfate in 22 anencephalic abortuses and newborn infants delivered between 21.5 and 45.5 weeks of gestation ranged from 1.8 to 30.3 ng/ml. The concentrations of deoxycorticosterone sulfate in umbilical cord plasma of anencephalic fetuses and newborn infants were not related to gestational age or method of delivery and, at term, were less than 13% of those in umbilical cord plasma of normal newborn infants. These data can be interpreted to indicate (1) that deoxycorticosterone sulfate normally is secreted directly by the fetal adrenal or (2) that placental estrogen normally derived largely from fetal adrenal dehydroisoandrosterone sulfate is essential for the maintenance of plasma deoxycorticosterone sulfate levels in the fetus by stimulating extra-adrenal deoxycorticosterone sulfate production from plasma progesterone, or both.

Abnormalities, Multiple↗
PubMed1984

Conversion of plasma progesterone to deoxycorticosterone in nonpregnant Macaca mulatta: an animal model for the study of extraadrenal steroid 21-hydroxylase activity.

We have reported previously that during the third trimester of pregnancy a significant portion of DOC in the maternal compartment arises by extraadrenal, 21-hydroxylation of maternal plasma progesterone. Moreover, the increase in DOC observed in plasma of women during the luteal phase of the ovarian cycle, when plasma concentrations of progesterone are elevated, can be attributed to increased DOC formation in extraadrenal sites. In the present study, we sought to ascertain if progesterone is converted to DOC in adult, nonpregnant, female rhesus monkeys to establish this species as an animal model for further investigation of extraadrenal mineralocorticosteroid biosynthesis. We measured the transfer constant of conversion of progesterone to DOC in plasma [( rho]P-DOCBB) from the 3H: 14C ratio of DOC in plasma after a 4 h infusion of [3H]progesterone and [14C] DOC into anesthetized monkeys. The [rho]P-DOCBB was 0.014 +/- 0.004 (mean +/- SEM, N = 7) in the animals studied. The values obtained for [rho]P-DOCBB ranged from 0.006 to 0.04 among the animals studied, a range of values similar to that observed in pregnant and nonpregnant women, men, and adrenalectomized persons. On the basis of these data, we conclude that the rhesus monkey may be an appropriate animal model for further study of extraadrenal steroid 21-hydroxylase activity.

Adrenal Glands↗
PubMed1984

The origin of and metabolic fate of deoxycorticosterone and deoxycorticosterone sulfate in pregnant women and their fetuses.

DOC and DOC-SO4, which are present in large amounts in the blood of pregnant women, are derived from sources other than maternal adrenal. Other investigators demonstrated that treatment of near-term pregnant women with ACTH or dexamethasone did not cause alterations in the blood levels of DOC. To define the source(s) of DOC and DOC-SO4 in plasma of pregnant women, we evaluated the conversion of plasma progesterone (P) to DOC in extraadrenal sites. DOC is formed from plasma P and, provided that the pregnancy is one characterized by the usual large production of estrogen, DOC production in a given woman is proportional to the level of P in plasma. Unlike other steroid conversions or interconversions, however, the fractional conversion of P to DOC among apparently normal persons varied widely 0.011 +/- 0.003 (mean +/- SEM, n = 40, range = 0.001 to 0.030). In women pregnant with a normal living fetus, the product of the production rate of P and the fractional conversion of P to DOC is sufficient to account for the majority of DOC produced in the mother. There may be a second source of DOC, i.e. the transfer of DOC from the fetal to the maternal compartment in a manner that involves (a) direct transfer of DOC by way of trophoblast and (b) by desulfurylation of DOC-SO4 from fetal umbilical arterial plasma in trophoblast and thence transfer of DOC liberated in trophoblast to the maternal compartment. Presently, it is clear that DOC-SO4 in blood of pregnant women is not derived from plasma DOC; and there is little or no evidence in support of the proposition that DOC-SO4 (as a sulfoconjugate) is transferred from the fetal to the maternal compartment because of placental hydrolysis to DOC. Among the extraadrenal tissue sites identified as those in which 21-hydroxylation of plasma P could be effected are some also believed to be tissue sites of mineralocorticosteroid action, viz, kidney, aorta, thymus, and spleen. Quantitatively, the origin of DOC in the fetus is not as clear as in the maternal compartment; yet, many tissues of the fetus have been identified in which both steroid 21-hydroxylase and 21-hydroxysteroid sulfotransferase activity are present. Thus, in the human fetus, extraadrenal as well as adrenal production of DOC and DOC-SO4 are possible.

Adrenocorticotropic Hormone↗
PubMed1983

Pharmacokinetics of cefoxitin in patients at term gestation: lavage versus intravenous administration.

Despite the increasing popularity of antibiotic prophylaxis to reduce febrile morbidity in patients who undergo cesarean delivery, little is known of the pharmacokinetics of antibiotics in the patient at term gestation. This study was designed to elucidate the pharmacokinetics of cefoxitin when administered intravenously or by uterine and peritoneal lavage at cesarean section. Significant differences were found in the values for total body clearance area under the serum concentration-time curve (AUC), and K21 of cefoxitin administered intravenously to pregnant patients at term gestation compared to values for these parameters observed in nonpregnant patients. The concentration of cefoxitin in decidual tissue after uterine and peritoneal lavage with the antibiotic was 92.5 +/- 10.1 micrograms/gm (mean +/- SEM), whereas the concentration of cefoxitin in decidual tissue after intravenous administration of the antibiotic was 36.9 +/- 10.5 micrograms/gm (mean +/- SEM). This difference is statistically significant (p less than 0.05). We conclude that the pharmacokinetics of cefoxitin are altered in the pregnant patient as evidenced by the increased rapidity of clearance of the antibiotic (total body clearance for cefoxitin in pregnant patients, 20.41 L/hr). Moreover, uterine and peritoneal lavage results in significant tissue concentrations of antibiotic, which is of potential importance since the decidua is a presumed site of initiation of bacterial infection after cesarean section.

Cefoxitin↗
PubMed1983

Conversion of progesterone to deoxycorticosterone in the human fetus: steroid 21-hydroxylase activity in fetal tissues.

Steroid 21-hydroxylase activity was assayed in microsome-enriched fractions prepared from homogenates of a number of human fetal tissues. The activity of this enzyme was demonstrable in several tissues in addition to the adrenal, kidney, and gonads. The highest specific activities of the enzyme were found in adrenal, skin, kidney and urinary bladder. In addition, 21-hydroxylation of progesterone was demonstrated in microsome-enriched preparations of pancreas, thymus, spleen, testis and ovary. Thus a number of fetal tissues may contribute to the formation of deoxycorticosterone, which is present in high concentrations in plasma of the human fetus compared with those in men and nonpregnant women. Moreover, the potential for the in situ formation of DOC in presumed tissue sites of mineralocorticosteroid action was demonstrated.

Adrenal Glands↗
PubMed1983

Conversion of progesterone to deoxycorticosterone in guinea pig spleen: an animal model for the study of steroid 21-hydroxylase activity in extra adrenal sites.

Steroid 21-hydroxylase activity has been demonstrated, previously, in microsome-enriched fractions prepared from a number of human fetal tissues. The finding that this enzyme activity was present in thymus and spleen is suggestive of the possibility that deoxycorticosterone is important in regulation of immunological processes. In the present investigation, we characterized steroid 21-hydroxylase activity in microsome-enriched preparations of guinea pig spleen. The activity of the enzyme was linear with time for 40 min and with protein concentrations up to 4.8 mg X ml-1 incubation mixture. The apparent Km of the enzyme for progesterone was 0.405 microM. Thus, the potential exists for the biosynthesis of DOC from progesterone in the spleen of the guinea pig as well as in the spleen of the human fetus. Therefore, the guinea pig may be an appropriate animal model for the study of the regulation of steroid 21-hydroxylase activity in the spleen as well as a model for the study of the role of this enzyme in immunologic processes.

Animals↗
PubMed1983

Generation of hydrogen peroxide by Candida albicans and influence on murine polymorphonuclear leukocyte activity.

Iodide fixation by murine polymorphonuclear leukocytes (PMN) incubated with viable Candida albicans blastoconidia increases directly with yeast cell concentration up to about 3 x 10(6) cells per ml, but above this concentration bound activity declines dramatically. To understand the basis for this decline, we examined the oxidative metabolism of fungi and stimulated PMN and found some remarkable similarities between these cell types. Both produced 14CO2 when incubated with [1-14C]glucose, both reduced cytochrome c, and both fixed radiolabeled iodide, although the fungi required exogenous lactoperoxidase. In dose-response experiments, iodination by fungi with lactoperoxidase was identical to that with PMN, i.e., the maximum bound activity occurred in cultures with 10(6) to 3 x 10(6) blastoconidia per ml. Iodination by fungi with lactoperoxidase was reduced when blastoconidia were incubated at 25 degrees C or in the presence of catalase and the metabolic inhibitors rotenone, antimycin A, and 2-deoxyglucose. Results from assays for oxidation of scopoletin and o-dianisidine showed that 10(6) blastoconidia in 1.0 ml of medium released 0.5 to 0.7 nmol of H2O2 after 1 h, but 3 X 10(6) and 10(7) cells released significantly less H2O2. These results suggest that iodide fixation by PMN and low numbers of fungal cells may reflect a cooperative effort, with fungi generating some H2O2 that reacts with the myeloperoxidase released from the PMN. With high concentrations of blastoconidia, H2O2 activity appeared to be specifically inhibited, possibly to protect fungal cells from damage.

Animals↗
PubMed1983

Extraadrenal steroid 21-hydroxylase activity in a woman with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency.

The 21-hydroxylation of plasma progesterone (P) has been demonstrated in pregnant, nonpregnant, and adrenalectomized women and in men. The fractional conversion of plasma progesterone to deoxycorticosterone (DOC), [rho]P-DOC BU, among those subjects was 0.009 +/- 0.001 (mean +/- SEM, n = 32). The [rho]P-DOC BU in a woman with congenital adrenal hyperplasia due to apparent adrenal steroid 21-hydroxylase deficiency was 0.010 when she was taking cortisone acetate, and the [rho]P-DOC BU determined when she was not taking cortisone acetate was 0.012. Moreover, the value computed for the fractional conversion of 17 alpha-hydroxyprogesterone to 11-deoxycortisol in this woman (0.004) was similar to that observed in a woman with normal adrenal function (0.005). Therefore, extraadrenal 21-hydroxylase activity in a woman with nonsalt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency was similar to that found in persons with normal adrenal function.

Adrenal Glands↗
PubMed1983

Hypercholesterolemia due to elevated low density lipoprotein-cholesterol in newborns with anencephaly and adrenal atrophy.

In the present investigation, we evaluated the relationship between plasma lipoprotein-cholesterol and adrenal steroid production in abortuses and newborns in whom the adrenal was expected to be atrophic, i.e. in anencephalics. We found that umbilical cord plasma levels of dehydroepiandrosterone sulfate (DS) in 23 anencephalics delivered between 13.5 and 45.5 weeks of gestation (mean +/- SE, 176 +/- 37 ng/ml) were significantly lower than those in normal newborns of similar gestational ages; the umbilical cord plasma concentrations of cortisol in many anencephalics, however, were within normal limits. The levels of total cholesterol (134 +/- 10 mg/dl) and low density lipoprotein (LDL)-cholesterol (94 +/- 8 mg/dl) were substantially higher (up to 4-fold) in umbilical cord plasma of anencephalics than in umbilical cord plasma of normal newborns. The mean level of high density lipoprotein-cholesterol in umbilical cord plasma of anencephalic abortuses and newborns (38 +/- 4 mg/dl) was approximately 50% higher than that in normal newborns. The lowest plasma cholesterol level (56 mg/dl) and a concentration of DS (480 ng/ml) that was among the highest seen in the group of anencephalics were found in an anencephalic newborn in whom adrenals were of near-normal weight. Plasma cholesterol levels were inversely correlated to adrenal weights and plasma DS levels, and plasma DS levels were correlated to adrenal weight. Whereas the estimated plasma pool of DS in normal newborns increased to over 300 micrograms during the latter part of gestation, that of anencephalic newborns was much lower (less than 1 to 26 micrograms) and did not appear to increase as a function of gestational age. Conversely, the estimated plasma pool of cholesterol in normal newborns appeared to decline slightly during the last 10 weeks of gestation (80 mg at term), whereas that of anencephalic newborns expanded greatly near term; levels (approximately 200 mg) were attained that were about 3 times those in normal newborns. We conclude that the hypercholesterolemia in anencephalic newborns, due primarily to extremely elevated plasma levels of LDL-cholesterol, is a result of decreased uptake and utilization of plasma LDL-cholesterol for steroid biosynthesis by the adrenals. Since hypercholesterolemia is apparently early in gestation in anencephalic abortuses, we speculate that in normally developing fetuses, plasma LDL-cholesterol is used as substrate for adrenal steroidogenesis early in gestation as well as near term when the rates of growth and steroid production by the adrenals accelerate markedly.

Adrenal Glands↗