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Biomedical subjects

M R Johnson

Publications and source records attributed to M R Johnson.

At least 163 records · Page 9Linked to original sources
PubMed1994

The regulation of plasma relaxin levels during human pregnancy.

The factors that determine the circulating levels of relaxin during pregnancy have been investigated by comparing the plasma levels of relaxin throughout pregnancy in women who became pregnant spontaneously (singleton, n = 240) or following superovulation (singleton and multifetal pregnancies (two to ten conceptuses), n = 83). Some of the women with multifetal pregnancies underwent selective fetal reduction to twin pregnancies. Relaxin levels were higher at 7-34 weeks of gestation in singleton pregnancies achieved following superovulation when compared with levels in spontaneously conceived singleton pregnancies (p < 0.05-0.001). In samples obtained between 10 and 12 weeks of gestation (before fetal reduction for the multifetal pregnancies), plasma relaxin levels correlated with fetal number (r = 0.526, P = 0.0001). Reduction in fetal number to a twin pregnancy did not alter relaxin levels. These data suggest that the circulating levels of relaxin throughout pregnancy are determined during the cycle of conception by gonadotrophin stimulation, and within the first 10 weeks of pregnancy by the luteotrophic stimulus from the conceptus. Furthermore, once corpus luteum synthesis of relaxin is established, then reduction in the luteotrophic stimulus does not appear to affect it.

Adult↗
PubMed1994

Maternal plasma levels of human chorionic gonadotrophin, oestradiol and progesterone in multifetal pregnancies before and after fetal reduction.

The aim of the study was to investigate the circulating levels of human chorionic gonadotrophin (hCG), oestradiol (OE2) and progesterone in multifetal pregnancies before and after embryo reduction. The levels of hCG, OE2 and progesterone were measured in plasma samples obtained from two groups of pregnant women: (i) singleton (n = 17), twin (n = 15) and triplet (n = 5) pregnancies achieved following superovulation; and (ii) multifetal pregnancies (three to ten embryos) undergoing fetal reduction to twin pregnancies (n = 31). The median value for each analyte at each gestational age in twin pregnancies was defined and used to derive multiples of the median (MoMs) for each analyte in samples obtained from multifetal pregnancies before and after reduction. The levels of hCG, OE2 and progesterone were significantly associated with the number of fetuses. Prior to reduction, the median MoMs for hCG, OE2 and progesterone were 1.54, 0.99 and 1.11 respectively. After reduction to twins the median MoMs decreased to 0.84 for hCG, 0.37 for progesterone and 0.51 for OE2. These data suggest that (i) the circulating levels of hCG, OE2 and progesterone increase with conceptus number; (ii) placental tissue does not remain active following fetal reduction; and (iii) the rate of steroid metabolism is increased in multiple pregnancy and remains elevated following fetal reduction.

Chorionic Gonadotropin↗
PubMed1994

Serologic investigations of canine parvovirus and canine distemper in relation to wolf (Canis lupus) pup mortalities.

Twenty-one serum samples from 18 wolves (Canis lupus) were collected from 1985 to 1990 from northwestern Montana (USA) and southeastern British Columbia, Canada, and evaluated for antibodies to canine parvovirus (CPV), canine distemper (CD), infectious canine hepatitis, and Lyme disease; we found prevalences of 13 (65%) of 19, five (29%) of 17, seven (36%) of 19, and 0 of 20 wolves for these diseases, respectively. Pups died or disappeared in three of the eight packs studied. In these three packs, adult pack members had CPV titers > or = 1,600 or CD titers > or = 1,250. In packs that successfully raised pups, CPV and CD titers were low. We propose that CPV or CD may have caused some pup mortalities.

Animals↗
PubMed1994

Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid.

The cannabinoid receptor in brain (CB1) specifically binds delta 9-tetrahydrocannabinol, the predominant central nervous system-active component of marijuana. An eicosanoid found in brain, N-(2-hydroxyethyl)arachidonylamide (anandamide), binds to CB1 with similar affinity. This report considers structure-activity requirements for a series of novel amides and rigid hairpin conformations typified by N-(2-hydroxyethyl)prostaglandin amides, assayed with phenylmethylsulfonyl fluoride inactivation of esterases/amidases. Arachidonyl esters were 30-fold less potent than N-(2-hydroxyethyl)arachidonylamide, showing a rank order of potency of methyl = ethyl > propyl = isopropyl. Within the N-(hydroxyalkyl)arachidonylamide series, a one-carbon increase in chain length increased the potency 2-fold, but continued extension decreased affinity. Substituting the amide for the N-(2-hydroxyethyl)amide function produced a 4-fold loss of affinity. The N-(propyl)-, N-(butyl)-, and N-(benzyl)arachidonylamide derivatives exhibited a 3-fold increase, no change, and a 5-fold decrease, respectively, in affinity, compared with N-(2-hydroxyethyl)arachidonylamide. Both the methoxy ether and the formamide derivatives suffered > 20-fold loss of potency, compared with N-(2-hydroxyethyl)arachidonylamide. N-(2-Aminoethyl)arachidonylamide interacted poorly with CB1. At 100 microM, N-(2-hydroxyethyl)amide analogs of prostaglandin E2, A2, B2, and B1 failed to alter [3H]CP55940 binding to CB1. N-(2-Hydroxyethyl)arachidonylamide inhibited adenylate cyclase with lesser potency but with similar efficacy, compared with desacetyllevonantradol. Extending the length of the hydroxyalkyl moiety by one carbon increased the apparent potency by 1 order of magnitude. The N-(propyl) derivative exhibited a 5-fold greater potency than did the N-(2-hydroxyethyl) analog. It appears that the bulk and length of the moiety appended to arachidonic acid are more important determinants of affinity for CB1 than is hydrogen-bonding capability.

Adenylyl Cyclase Inhibitors↗
PubMed1994

The role of relaxin in the development of the uteroplacental circulation in early pregnancy.

OBJECTIVE: To evaluate the relation between the development of the uteroplacental circulation as assessed by Doppler velocimetry and the maternal blood relaxin concentration. METHODS: Transvaginal color Doppler investigation of the uteroplacental circulation was performed in 42 healthy women at 6-15 weeks' gestation before termination of pregnancy for psychosocial reasons. The resistance index (RI), pulsatility index (PI), and maximum peak velocity were recorded at the level of the main uterine artery, and the presence of intervillous flow was noted. Relaxin, hCG, 17 beta-estradiol (E2), and progesterone levels were measured in maternal venous blood. RESULTS: Limited intervillous flow was noted from 10 weeks' gestation and continuous intervillous flow from 12 weeks. An inverse relation was observed between the circulating levels of both E2 and progesterone and uterine artery RI and PI, whereas the relaxin level correlated positively with uterine RI and PI. Estradiol and progesterone levels also correlated positively with uterine peak systolic velocity and intervillous blood flow. Multiple linear regression analysis indicated that both hormones contributed to the decrease in downstream resistance to uterine blood flow with advancing gestational age, as assessed by uterine RI. In addition, relaxin contributed to the uterine RI and PI and to the intervillous blood flow. CONCLUSION: These data suggest that relaxin, E2, and progesterone may influence the changes in uterine blood flow that occur in early pregnancy. The role played by E2 and progesterone in the development of the uteroplacental circulation may be modulated by relaxin, constituting a novel function for this ovarian peptide.

Blood Flow Velocity↗
PubMed1994

Endogenous cannabinoid receptor binding activity released from rat brain slices by depolarization.

As previously reported by this laboratory, an endogenous factor capable of inhibiting the specific binding of the radiolabeled cannabinoid agonist [3H]CP-55940 to its receptor can be released from nerve terminals in response to an influx of Ca++ induced by an ionophore (Evans et al., 1992). In the present report, we provide evidence that the endogenous ligand for the cannabinoid receptor can be released in response to a depolarizing stimulus (75 mM K+) in the presence of extracellular Ca++. K(+)-evoked release was not observed in the absence of extra-cellular Ca++ and was reduced by the specific calcium channel blockers verapamil and omega-conotoxin. The efflux of cannabinoid receptor binding activity is greatest within 2 min of stimulation with the Ca++ ionophore A23187. Within this period of time, the cannabinoid receptor binding activity was enhanced by the presence of a cocktail of peptidase inhibitors. Examination of the contribution of individual inhibitors for enhancing high K(+)-released material revealed a selectivity for captopril and thiorphan. The specificity of the released factor for the cannabinoid receptor was corroborated by its ability to compete with the aminoalkylindole radioligand [3H]WIN-55212 for binding to this receptor. Fractions from a semi-purified sample of the effluent demonstrated binding to the cannabinoid receptor and behaved as agonists in that these fractions could inhibit adenylate cyclase activity in neuroblastoma membrane preparations.

Animals↗
PubMed1993

Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group.

Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy. Our large multicentre study aimed to find out whether metoprolol improves overall survival and morbidity in this disorder. 383 subjects with heart failure from idiopathic dilated cardiomyopathy (ejection fraction < 0.40) were randomly assigned placebo or metoprolol. 94% were in New York Heart Association functional classes II and III, and 80% were receiving background treatment. A test dose of metoprolol (5 mg twice daily) was given for 2-7 days; those tolerating this dose (96%) entered randomisation. Study medication was increased slowly from 10 mg to 100-150 mg daily. There were 34% (95% CI -6 to 62%, p = 0.058) fewer primary endpoints in the metoprolol than the placebo group; 2 and 19 patients, respectively, deteriorated to the point of needing transplantation and 23 and 19 died. The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo (0.13 vs 0.06, p < 0.0001). Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo (5 vs 2 mm Hg, p = 0.06). Exercise time at 12 months was significantly greater (p = 0.046) in metoprolol-treated than in placebo-treated patients. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol prevented clinical deterioration, improved symptoms and cardiac function, and was well tolerated.

Adolescent↗
PubMed1993

Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras.

The NF1 gene, which is altered in patients with type 1 neurofibromatosis, encodes neurofibromin, a protein whose GTPase-activating function can negatively regulate GTP-Ras by accelerating its conversion to inactive GDP-Ras. In schwannoma cell lines from patients with neurofibromatosis, loss of neurofibromin was previously shown to be associated with impaired regulation of GTP-Ras. Our analysis of other neural crest-derived tumor cell lines has shown that some melanoma and neuroblastoma cell lines established from tumors occurring in patients without neurofibromatosis contain reduced or undetectable levels of neurofibromin, with concomitant genetic abnormalities of the NF1 locus. In contrast to the schwannoma cell lines, GTP-Ras was appropriately regulated in the melanoma and neuroblastoma lines that were deficient in neurofibromin, even when c-H-ras was overexpressed in the lines. These results demonstrate that some neural crest tumors not associated with neurofibromatosis have acquired somatically inactivated NF1 genes and suggest a tumor-suppressor function for neurofibromin that is independent of Ras GTPase activation.

Blotting, Northern↗
PubMed1993

Transient impairment in P50 auditory sensory gating induced by a cold-pressor test.

Diminished gating of the auditory evoked response to repeated stimuli is a psychophysiological defect associated with schizophrenia and several other psychiatric illnesses. The P50 wave of the auditory evoked response to the second of paired stimuli is decreased in most normal subjects, whereas many psychotic subjects show significantly less decrement. The aim of this experiment was to test whether the cold-pressor test, which causes transient distress and pain accompanied by increased sympathetic activity, also causes a transient impairment in P50 auditory sensory gating in normal control subjects. Ten normal control subjects with normal gating of the P50 response immersed their hands in an ice water bath for 2 min. This cold-pressor test diminished P50 auditory gating in nine of these subjects, although the degree of impairment was highly variable among subjects. The impairment in gating was transient, with partial resolution by 30 min. The cold-pressor test was subjectively viewed as painful and also caused blood pressure to increase. Thus, a transient stressor can impair P50 auditory gating in some subjects.

Acoustic Stimulation↗
PubMed1993

Validation by high-frequency epicardial echocardiography of a new method of analyzing coronary angiography quantitatively in coronary artery disease.

In coronary atherosclerosis, the arterial lumen size and shape can be markedly irregular, eccentric and variable. Traditional angiographic interpretation, emphasizing percent diameter stenosis, has been criticized as an inadequate descriptor of such diseased arteries. Computerized quantitative angiographic technologies, yielding a true lumen area measurement, may be superior. High-frequency epicardial echocardiography (HFEE) is a technique that allows on-line evaluation of coronary arterial wall and lumen at the time of cardiac surgery. It has been extensively validated and yields accurate measurements of normal and diseased coronary lumen areas. This study compares quantitative coronary angiography (QCA) estimates of lumen area to those obtained by HFEE to determine if the computerized angiographic method more accurately predicts residual luminal area than traditional angiographic percent diameter stenosis measurements. Although actual luminal morphology was quite variable, there was a good correlation between lumen areas determined by HFEE versus QCA: r = 0.85, n = 67, HFEE = 0.8 QCA - 0.1 (HFEE 4.0 +/- 0.30 mm2, mean +/- SEM range 0.3 to 14.0; QCA 5.1 +/- 0.40 mm2, range 0.7 to 11.8). Percent diameter stenosis determined from the angiograms did not correlate well with HFEE or QCA measurements of residual luminal area. Separation of "normal" arterial segments (defined as < 25% diameter stenosis) from "abnormal" segments (> 50% diameter stenosis) by angiography did not agree with lumen areas as defined by either HFEE or QCA. Better separation occurred when QCA-determined luminal areas were used to separate normal from abnormal arterial segments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Cell transformation by ras and regulation of its protein product.

We are studying the biological activity and regulation of mammalian Ras protein in tumours and in physiological signalling. We have shown that GAP (the GTPase-activating protein) is a potent negative regulator of normal Ras in cells. Reduction or loss of the NF1 gene product neurofibromin, in association with genetic abnormalities of the NF1 locus, has been identified in schwannoma cell lines from patients with neurofibromatosis and in melanoma and neuroblastoma lines from patients without neurofibromatosis. Although loss of neurofibromin in the schwannoma lines was associated with a high proportion of normal Ras protein in the active GTP-bound state, Ras-GTP appeared to be appropriately regulated in the melanoma and neuroblastoma lines, which contain normal levels of GAP. Therefore the GTPase-activating activity of neurofibromin is not essential for negative regulation of Ras in some cell types and the putative tumour suppressor function of neurofibromin in such cell types is independent of its GTPase-activating activity. Mitogen activation of Ras in fibroblasts is mediated primarily by exchange factors, which probably interact with a region on the Ras protein distinct from the region required for interaction with GAP. Multiple full-length cDNAs have identified a mouse gene whose products are related to yeast CDC25 guanine nucleotide exchange factor.

Animals↗
PubMed1993

High-risk cardiac operation: a viable alternative to heart transplantation.

To determine if high-risk heart operation with circulatory support standby is an acceptable alternative to direct heart transplantation, we reviewed 21 patients who were accepted as heart transplant candidates but offered a heart operation because of the availability of circulatory support. Preoperative left ventricular ejection fraction was 0.25 +/- 0.08 (mean +/- standard deviation), and New York Heart Association functional class was 3.4 +/- 0.7. The patients underwent 16 bypass graft operations, 4 mitral and 2 aortic valve replacements, and 4 defibrillator implantations (combined procedures in 5 patients). An intraaortic balloon pump was placed in 12 patients. One patient required biventricular assist device support but was weaned in 11 days. Twenty patients were discharged 14.8 +/- 11.5 days postoperatively. One patient died 15 days postoperatively of amiodarone-induced respiratory failure, and 1 died suddenly 2 months postoperatively. At 10.5 +/- 6 months postoperatively, 19 patients (90%) are alive. Mean functional class is 1.9 +/- 0.9. None of the patients has undergone transplantation, but 2 are awaiting donor organs. We conclude that in selected heart transplant candidates high-risk heart operation is a viable alternative to direct heart transplantation.

Actuarial Analysis↗
PubMed1993

Placental and ovarian hormones in anembryonic pregnancy.

The circulating levels of human chorionic gonadotrophin (HCG), pregnancy-associated plasma protein-A (PAPP-A), Schwangerschaft protein 1 (SP-1), oestradiol and progesterone were measured in 81 pregnant patients between 4 and 11 weeks gestation, following in-vitro fertilization and embryo transfer. The patients were divided as follows: singleton anembryonic pregnancies, n = 22; singleton pregnancies which spontaneously aborted following the demonstration of fetal heart activity, n = 7; and normal singleton pregnancies, n = 52. The levels of all substances measured were significantly reduced in women with anembryonic compared to those with singleton pregnancies which proceeded to term. The serum levels of SP-1, weeks 6-8 (P < 0.01); HCG, weeks 6-8 (P < 0.05); oestradiol, weeks 5-8 (P < 0.05) and progesterone, weeks 6-8 (P < 0.05), were lower in anembryonic pregnancies than in those of pregnancies which spontaneously aborted. These differences may be a reflection of the fact that miscarriage, after the demonstration of fetal heart activity, represents fetal demise at a later stage in pregnancy. In anembryonic pregnancies, significant associations were found between HCG and both oestradiol and progesterone levels from weeks 6 and 8, suggesting that in the absence of an embryo, HCG is the prime determinant of steroid synthesis by the corpus luteum.

Abortion, Spontaneous↗
PubMed1993

Reduced circulating placental protein concentrations during the first trimester are associated with preterm labour and low birth weight.

Serum concentrations of human chorionic gonadotrophin (HCG), Schwangerschaftsprotein 1 (SP-1), pregnancy-associated plasma protein A (PAPP-A), progesterone and oestradiol were measured at weekly intervals between the fifth (embryo transfer plus 3 weeks) and 13th week of gestation during the first trimester of pregnancies achieved following in-vitro fertilization (IVF) and embryo transfer in a group of women who delivered before (n = 8) or at term (n = 52). Those women who had a preterm delivery had significantly lower concentrations of PAPP-A (weeks 7-13; P = 0.0001-0.028) and SP-1 (weeks 6-8 and 10-12; P = 0.004-0.04). After correction of birth weight for sex and gestational age at delivery, preterm delivery was found not to be associated with growth retardation. However, comparison of the circulating concentrations of the substances analysed in mothers who delivered babies of < 85% of the 50th centile of the normal range of birth weight for a given gestational age and sex, with those who delivered babies of > 85% revealed that the concentrations of HCG (P = 0.012-0.04 on weeks 6-9) and SP-1 (P = 0.003-0.03 on weeks 7, 9-13) were significantly lower in the former group. Weak, inconsistent associations were found between the circulating concentrations of HCG, SP-1 and PAPP-A and both corrected birth weight and gestational age at delivery. Thus, both the gestational age at delivery and low birth weight may be related to impaired placental development/function during the first trimester.

Chorionic Gonadotropin↗
PubMed1993

Endocrinology of in-vitro fertilization pregnancies during the first trimester.

The endocrine function of the corpus luteum and placenta and the inter-relationships between ovarian steroids and the placental proteins in pregnancies achieved following ovarian stimulation, in-vitro fertilization and embryo transfer (IVF-ET) have been investigated. The serum concentrations of human chorionic gonadotrophin (HCG), Schwangerschaft protein-1 (SP-1), pregnancy-associated plasma protein A (PAPP-A), progesterone and oestradiol were measured at weekly intervals between the 4th (ET plus 2 weeks) and 14th week of gestation in 86 pregnancies. The mean concentrations of the placental proteins and oestradiol were significantly higher in twin than in singleton pregnancies from as early as 5 weeks gestation, but the mean concentrations of progesterone were significantly higher only at the end of the first trimester. Ranking, as demonstrated by the presence of statistically significant correlations between serum levels of each substance analysed in week 13 with those of preceding weeks, was established for progesterone and SP-1 from the 5th week, for oestradiol and PAPP-A from the 7th week and for HCG from the 8th week of gestation. The presence of statistically significant correlations between each substance analysed suggests that the placenta becomes the dominant source of oestradiol from 8 weeks gestation and of progesterone not until 12 weeks gestation, and that the placental synthesis of HCG, SP-1, PAPP-A, oestradiol and progesterone appear to be linked. There were no statistically significant correlations between the serum concentrations of HCG and either progesterone or oestradiol until the production of each had become predominantly placental.

Adult↗
PubMed1993

Circulating placental protein 14: in the first trimester of spontaneous and IVF pregnancies.

Circulating placental protein 14 (PP14) levels were measured during the first trimester in three groups of pregnant women: (i) natural conception (n = 15); (ii) pituitary desensitization with buserelin and ovarian stimulation with human menopausal gonadotrophin (HMG) followed by in-vitro fertilization and embryo transfer (IVF-ET) (n = 15); and (iii) ovarian stimulation with clomiphene citrate and HMG, followed by IVF-ET (n = 16). A 7- to 8-fold increase in serum PP14 levels was observed in normal pregnancies between weeks 4 and 10. This increase was earlier and less marked in group (ii) and absent in group (iii). These findings support the concept that endometrial function is altered in pregnancies achieved following ovarian stimulation. Alternatively, if the ovary is an important source of PP14, then these data suggest that in contrast to ovarian synthesis of steroids and the peptide relaxin, ovarian stimulation results in an impairment of PP14 synthesis, and that this is most marked when clomiphene citrate has been used.

Adult↗