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Biomedical subjects

M C Gordon

Publications and source records attributed to M C Gordon.

At least 19 recordsLinked to original sources
PubMed2001

Single versus repeated-course antenatal corticosteroids: outcomes in singleton and multiple-gestation pregnancies.

The objectives of this study are to compare the neonatal risks and benefits of antenatal single-course versus repeated-course corticosteroids in singleton and multiple-gestation pregnancies. A comprehensive analysis was performed of the inpatient records of all neonates admitted to our center from 1 January 1994 through 31 May 1999. The primary outcome measure was survival without chronic lung disease (CLD). Secondary outcome measures included birth weight; head circumference; interval weight ratios; respiratory disease severity; intraventricular hemorrhage rate and severity; severe retinopathy of prematurity; early infection; and hospital days. All singletons 27-32 completed weeks' gestation, and multiples 26-32 weeks' gestation, whose mothers had received betamethasone before delivery, were included. One hundred and fifteen singleton and 53 multiple-gestation infants (total 168) were stratified by multiplicity, gestational-age (< or =29 or > or =30 weeks), and number of steroid courses. Repeated courses of antenatal betamethasone were not associated with greater survival without CLD, in either singleton- or multiple-gestation infants. In singletons there was no difference in any outcome measure between groups. In multiples, the only difference was greater postnatal weight gain in the lower gestation group. Mean birth head circumference was smaller in repetitively-treated singletons < or =29 weeks. There are no clinically significant neonatal benefits of repeated-course antenatal steroids in singletons > or =27 weeks estimated gestational age (EGA) or multiple-gestation infants > or =26 weeks EGA. Prospective randomized trials of single-course versus repetitive antenatal corticosteroid therapy are warranted.

Adult↗
PubMed2000

Adrenal suppression induced by betamethasone in women at risk for premature delivery.

OBJECTIVE: To determine whether betamethasone administered to women at risk of preterm delivery causes adrenal suppression. METHODS: Ten women at risk of preterm delivery had three weekly low-dose (1 microg) ACTH stimulation tests with the first one between 24 and 25 weeks' gestation. Immediately after the first and second ACTH stimulation tests, we gave each woman a 12-mg betamethasone dose intramuscularly and repeated it 24 hours later. The third ACTH stimulation test was 1 week after the second course of betamethasone. Serum cortisol levels were measured before (baseline) and 30 minutes after ACTH administration. RESULTS: All subjects had normal baseline and stimulated cortisol levels for the first ACTH stimulation test. Mean baseline serum cortisol levels decreased with each ACTH stimulation test, from 25.4 +/- 4.8 microg/dL (before betamethasone) to 4.3 +/- 4.0 microg/dL (1 week after the second course of betamethasone) (P <.001). The mean stimulated cortisol levels also decreased from 33.0 +/- 4.3 microg/dL (before betamethasone) to 11.8 +/- 6.4 microg/dL (1 week after the second course of betamethasone) (P <.001). Compared with initial ACTH stimulation tests, laboratory evidence of adrenal suppression occurred in four patients 1 week after the first course of betamethasone and in seven patients after the second course. No signs or symptoms of Addisonian crisis occurred antepartum or intrapartum. CONCLUSION: Antenatal administration of betamethasone produced measurable adrenal suppression in women at risk of preterm delivery. The number of women with adrenal suppression increased each week that antenatal betamethasone was repeated. (Obstet Gynecol 2000;96:287-90.)

Adrenal Cortex↗
PubMed1998

Mutations within the cholecystokinin-B/gastrin receptor ligand 'pocket' interconvert the functions of nonpeptide agonists and antagonists.

We have reported previously that the transmembrane domains of the cholecystokinin-B/gastrin receptor (CCK-BR) comprise a putative ligand binding pocket. In the present study, we examined whether amino acid substitutions within the CCK-BR pocket altered the affinities and/or functional activities of L-365,260 (the prototypical nonpeptide CCK-BR antagonist) and two structural derivatives, YM022 (a higher affinity antagonist) and L-740,093S (a partial agonist). Eight amino acids that project into the CCK-BR pocket were individually replaced by alanine, using site-directed mutagenesis. Affinities for the nonpeptide molecules, as well as ligand-induced inositol phosphate production, were assessed with the wild-type and mutant receptors. For each of the nonpeptide ligands examined, a distinct series of mutations altered the affinity, suggesting that each ligand possessed a characteristic pattern of interactions within the CCK-BR pocket. Basal signaling levels and inositol phosphate formation induced by the full agonist CCK octapeptide were comparable for the wild-type receptor and all of the mutant CCK-BR forms. In contrast to the peptide agonist CCK octapeptide, the functional activities of the nonpeptide molecules were selectively altered by single point mutations within the CCK-BR pocket, resulting in interconversion of agonists and antagonists. These findings suggest that interactions between nonpeptide molecules and transmembrane domain amino acids of the CCK-BR can determine the functional activity and affinity of the ligands.

Animals↗
PubMed1997

Inter- and intraspecies polymorphisms in the cholecystokinin-B/gastrin receptor alter drug efficacy.

The brain cholecystokinin-B/gastrin receptor (CCK-BR) is a major target for drug development because of its postulated role in modulating anxiety, memory, and the perception of pain. Drug discovery efforts have resulted in the identification of small synthetic molecules that can selectively activate this receptor subtype. These drugs include the peptide-derived compound PD135,158 as well as the nonpeptide benzodiazepine-based ligand, L-740,093 (S enantiomer). We now report that the maximal level of receptor-mediated second messenger signaling that can be achieved by these compounds (drug efficacy) markedly differs among species homologs of the CCK-BR. Further analysis reveals that the observed differences in drug efficacy are in large part explained by single or double aliphatic amino acid substitutions between respective species homologs. This interspecies variability in ligand efficacy introduces the possibility of species differences in receptor-mediated function, an important consideration when selecting animal models for preclinical drug testing. The finding that even single amino acid substitutions can significantly affect drug efficacy prompted us to examine ligand-induced signaling by a known naturally occurring human CCK-BR variant (glutamic acid replaced by lysine in position 288; 288E --> K). When examined using the 288E --> K receptor, the efficacies of both PD135,158 and L-740, 093 (S) were markedly increased compared with values obtained with the wild-type human protein. These observations suggest that functional variability resulting from human receptor polymorphisms may contribute to interindividual differences in drug effects.

Animals↗
PubMed1996

Ketoacids attenuate glucose uptake in human trophoblasts isolated from first-trimester chorionic villi.

OBJECTIVE: The objective of this study was to evaluate the hypothesis that ketoacids (acetoacetic acid and beta-hydroxybutyrate) diminish glucose transport in trophoblasts cultured from first-trimester chorionic villi. STUDY DESIGN: First-trimester trophoblasts were obtained by transabdominal chorionic villus sampling for subsequent cytogenetic analysis. The cells were established as a continuous line exhibiting trophoblast characteristics. Trophoblasts were cultured in Ham's F12/Dulbecco's modified Eagle's medium (1:1) supplemented with 15% fetal bovine serum. Experiments were initiated by a 24-hour preincubation in serum-free Ham's F12/Dulbecco's modified Eagle's medium followed by incubation with ketoacids (acetoacetic acid and beta-hydroxybutyrate, 0 to 10 mmol/L) in the presence or absence of insulin-like growth factor-I (100 ng/ml). The cells were challenged with 2-deoxy-[1,2-3H]D-glucose (0.1 mmol/L) for 5 minutes and then cell-associated radioactivity was measured. Total ribonucleic acid was extracted from cells incubated with ketoacids in the presence or absence of insulin-like growth factor-I, and Northern blots were probed with a phosphorus 32-labeled complementary deoxyribonucleic acid fragment encoding the rat GLUT 1. RESULTS: Ketoacids caused a dose-dependent inhibition of glucose transport. At 5 mmol/L acetoacetic acid there was a > 50% reduction in the rate of glucose transport in both control and insulin-like growth factor-I-treated cells. The diminution in glucose uptake by trophoblasts was not due to cellular toxicity of the ketoacids because there was no significant difference in trypan blue exclusion or lactate dehydrogenase release between control and ketoacid-treated cells. Northern analysis revealed that the steady-state expression of GLUT1 messenger ribonucleic acid was diminished in ketone-treated cells, but this effect was overcome by coincubation of cultures with insulin or insulin-like growth factor-I. CONCLUSIONS: These results indicate that ketoacids can suppress the uptake of glucose into first-trimester human trophoblasts. Because ketoacidosis in pregnant women with diabetes mellitus is a frequent clinical consequence of poor metabolic control, it is possible that elevated levels of acetoacetic acid and beta-hydroxybutyrate may impair the transport of glucose across the placental trophoblast and into the fetal circulation.

Acetoacetates↗
PubMed1996

Coronary artery disease in insulin-dependent diabetes mellitus of pregnancy (class H): a review of the literature.

Coronary heart disease and myocardial infarction are uncommon complications during pregnancy. Women with insulin-dependent diabetes mellitus (IDDM) have a much greater risk of serious coronary heart disease, but few cases of myocardial infarctions occurring during pregnancy have been reported. Significant maternal morbidity has been reported in half of these cases. This is a case of a myocardial infarction occurring at 21 weeks of gestation in a patient with class R/F IDDM and the subsequent pregnancy management as well as a review of the literature concerning Class H IDDM in pregnancy.

Adult↗
PubMed1995

Insulin and glucose modulate glucose transporter messenger ribonucleic acid expression and glucose uptake in trophoblasts isolated from first-trimester chorionic villi.

OBJECTIVE: Our purpose was to determine the effects of insulin and glucose on glucose transport and expression of GLUT1 glucose transporter messenger ribonucleic acid in first-trimester human trophoblast-like cells. STUDY DESIGN: First-trimester human trophoblast-like cells were maintained as a continuous cell line. For 2[3H]deoxy-D-glucose uptake and messenger ribonucleic acid studies the cells were incubated in the presence or absence of insulin (10(-7) to 10(-11) mol/L) or D-glucose (0 to 50 mmol/L) for 0 to 24 hours. Glucose transport was measured by incubating cells with 0.1 mmol/L 2[3H]deoxy-D-glucose for 5 minutes. Specific uptake was determined by incubating companion cultures with 10 mumol/L cytochalasin B. The cells were then solubilized with sodium hydroxide and the radioactivity counted. Data were expressed as nanomoles of 2[3H]deoxy-D-glucose transported per milligram of protein per 5 minutes and analyzed by one-way analysis of variance with post hoc testing by the method of Tukey. GLUT1 messenger ribonucleic acid was measured by Northern blotting of total ribonucleic acid samples hybridized to a phosphorus 32-labeled complementary deoxyribonucleic encoding the rat GLUT1 glucose transporter. As a control for loading efficiency, blots were stripped and rehybridized to a 40-mer phosphorus 32-labeled beta-actin oligonucleotide probe. RESULTS: Insulin treatment resulted in a dose-dependent increase in the transport of 2[3H]deoxy-D-glucose at 24 hours (p < 0.001 at 10(-7) mol/L). This change was first detected at 12 hours of incubation. These data closely paralleled the insulin-induced increase in GLUT1 messenger ribonucleic acid seen in Northern blots. In contrast to insulin, increasing concentrations of D-glucose did not change the transport of 2[3H]deoxy-D-glucose. However, when cells were incubated in low concentrations of D-glucose (0 or 1 mmol/L), an enhancement in the uptake of 2[3H]deoxy-D-glucose (p < 0.001) was observed. Kinetic studies indicated that D-glucose augmentation of 2[3H]eoxy-D-glucose uptake was significant at 9 hours (p < 0.05). The effects of D-glucose on GLUT1 messenger ribonucleic acid expression paralleled the uptake of 2[3H]deoxy-D-glucose, although the modulation of GLUT1 messenger ribonucleic acid levels by glucose was much less pronounced than in insulin-treated cells. CONCLUSION: Although it has been assumed that the placenta has a limited role in influencing glucose transport to the fetus, our in vitro data demonstrate that both insulin and glucose can modulate glucose transport at the cellular level of the placental trophoblast. Thus maternal insulin and glycemic status may influence the expression of GLUT1, the major trophoblast glucose transporter protein, therefore directly affecting first-trimester placental glucose transport. These in vitro data may help explain the association between maternal glucose abnormalities and impaired fetal development during the first trimester when placental GLUT1 messenger ribonucleic acid expression is at its peak.

Analysis of Variance↗
PubMed1995

Indomethacin.

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Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Magnesium sulfate.

Since the first American report on the use of magnesium sulfate tocolysis in 1977, its popularity as a tocolytic agent has increased progressively. Primarily because of its safety and familiarity, magnesium has become the primary tocolytic agent in the majority of U.S. centers. The exact mechanism of action is unknown, and long-term effects on neonates have not been studied. Although randomized studies show similar success compared to other tocolytic agents, no placebo-controlled study has shown neonatal improvement with magnesium sulfate tocolysis. This is similar to the studies of beta-sympathomimetic tocolytics and has led some authors (e.g., Higby) to suggest that safe dosages of magnesium sulfate are ineffective in preventing preterm birth and should not be used as a tocolytic agent. Although magnesium sulfate, like other tocolytics, has not fulfilled the initial promise of preventing preterm birth, it does appear if used correctly in a well identified population of patients to at least transiently inhibit preterm labor as well as other tocolytic agents with fewer side effects and fewer contraindications.

Clinical Trials as Topic↗
PubMed1995

Severe hemolytic disease of the newborn due to anti-Js(b).

Anti-Js(b) has not been reported to cause severe hemolytic disease of the newborn requiring intrauterine evaluation and treatment. We now report on such a patient with high-titered anti-Js(b) causing fetal hydrops with demise in one pregnancy, followed by a pregnancy treated with multiple intrauterine fetal transfusions.

Abortion, Spontaneous↗
PubMed1994

Induction of IL-8 expression in T cells uses the CD28 costimulatory pathway.

IL-8, a potent chemotactic factor for neutrophil granulocytes and lymphocytes, is a proinflammatory cytokine secreted by a variety of cell types, including T cells. Stimulation of the CD28 cell surface molecule delivers costimulatory signals essential for lymphokine production in activated T cells via a conserved sequence element found in the promoter of several lymphokine genes. Anti-CD28-stimulated T cells produced significant amounts of IL-8; additionally, costimulation with anti-CD3 and anti-CD28 Abs resulted in a synergistic induction of IL-8 secretion. Sequence homology, single nucleotide mutations, and anti-CD28 Ab stimulation studies established that the NF-kappa B-like sequence in the promoter of the IL-8 gene functioned as a CD28 response element. Furthermore, cyclosporin A, but not rapamycin, blocked the synergistic induction of IL-8 expression achieved with anti-CD3 and anti-CD28 costimulation. The involvement of a CD28 response element in the induction of IL-8 expression in activated T cells may provide new insights into the pathogenesis and persistence of immune disorders characterized by increased levels of IL-8, such as psoriasis and rheumatoid arthritis.

Base Sequence↗
PubMed1987

Correlates of sophisticated listener judgments of esophageal air intake noise.

Twenty-four laryngectomies, ranging widely in speaking ability, read a standard passage for audio recording. Four experienced voice clinicians rated the acceptability of the speakers' air intake noise. Independently, overall speech proficiency ratings were obtained for 18 of the subjects. Five objective measures of the subjects' esophageal speech were obtained using a real-time intensity display on a storage oscilloscope. Judges' reliability was determined by Pearson Product Moment Correlations. Ratings were submitted to multiple regression analysis. The means of air intake noise acceptability were the criterion variables; the objective measures and speech proficiency scores were the predictor variables. Three predictors were positively correlated (less than .01) with air intake acceptability: the number of syllables per intake, the sound intensity of the intake, and the rate of speech. Syllables per intake provided the largest share of the variance.

Air↗