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Biomedical subjects

M R Johnson

Publications and source records attributed to M R Johnson.

At least 181 records · Page 10Linked to original sources
PubMed1993

Serum placental protein 14 concentrations in the first trimester of ovum donation pregnancies.

The concentration of the endometrial glycoprotein placental protein 14 (PP14) has been measured at weekly intervals during the first trimester in serum obtained from women who had become pregnant naturally (n = 15, all singleton) or following ovum donation (n = 16, 15 singleton and one twin) after ovarian failure (n = 13), Turner's syndrome (n = 2) or post-chemotherapy (n = 1). The concentration of PP14 failed to rise in ovum donation pregnancies, and was significantly reduced compared to the concentration in natural conceptions from 5 to 13 weeks gestation (P < 0.05-0.01). These findings demonstrate that the corpus luteum is essential for the normal increase in serum PP14 in the first trimester. Furthermore, they suggest that progesterone is not the major stimulus to PP14 synthesis in early pregnancy.

Female↗
PubMed1993

Corpus luteum failure in ectopic pregnancy.

The endocrinology of ectopic pregnancy was studied in order to investigate the origin of the discordance in the circulating amounts of human chorionic gonadotrophin (HCG) and those of oestradiol and progesterone. Serial maternal blood samples were obtained at 4-9 weeks gestation from 93 patients who became pregnant following in-vitro fertilization and embryo transfer including 10 ectopic, 21 anembryonic and 62 normal singleton pregnancies. The samples were analysed for HCG, Schwangerschaft protein-1 (SP-1), pregnancy-associated plasma protein-A (PAPP-A), progesterone and oestradiol. In ectopic pregnancies, concentrations of all substances analysed were significantly reduced compared to singleton pregnancies from 5 weeks gestation (P < 0.05-0.001) but they were not significantly different from those of anembryonic pregnancies. In ectopic pregnancies, associations were found between the concentration of both HCG and SP-1 and those of progesterone and oestradiol. No associations were found between PAPP-A and any other substances analysed. This may be due to insensitivity of the PAPP-A assay; alternatively PAPP-A concentrations may be differentially reduced in ectopic pregnancy. These findings suggest that progesterone and oestradiol are derived from the corpus luteum in early ectopic pregnancy but that the corpus luteum fails rapidly and the dominant source of both hormones becomes the trophoblast as early as 5 weeks.

Chorionic Gonadotropin↗
PubMed1993

Interactions between the embryo and corpus luteum.

A total of 102 patients who had become pregnant following in-vitro fertilization (IVF) and embryo transfer were studied at weekly intervals between 4 and 14 weeks gestation. The pregnancies were classified as follows: (i) normal singleton, n = 52; (ii) normal twin, n = 24; (iii) heterotopic, n = 4 (weeks 4-8 only); and (iv) anembryonic with a viable intra-uterine singleton, n = 22. The serum concentrations of human chorionic gonadotrophin (hCG), Schwangerschaft protein-1 (SP-1) and pregnancy-associated plasma protein-A (PAPP-A), oestradiol and progesterone were measured. The mean serum concentrations of HCG, SP-1 and PAPP-A were significantly less in heterotopic than in singleton, singleton/anembryonic or twin pregnancies (P < 0.01-0.05), while those of progesterone and oestradiol were not different at any time. There were no significant differences between the serum concentrations of any of the substances analysed in singleton/anembryonic and singleton pregnancies, but the concentrations of all the substances analysed were significantly greater in twin pregnancies from as early as 7 weeks (P < 0.01-0.05). These data show that in heterotopic pregnancies trophoblast function is reduced, as suggested by the lower concentrations of the placental proteins. Despite this the concentrations of oestradiol and progesterone, derived predominantly from the corpus luteum between 4 and 8 weeks, are equivalent to those found in twin pregnancies, and greater than those found in singleton and singleton/anembryonic pregnancies. These findings support the notion that although HCG may rescue the corpus luteum it does not subsequently have a direct effect on its function, and suggest that the embryo may influence corpus luteum function.

Chorionic Gonadotropin↗
PubMed1993

Age, pregnancy and miscarriage: uterine versus ovarian factors.

This study was performed to evaluate the relative contribution of oocyte and uterine factors to the age-related reduction in fecundity. The pregnancy and miscarriage rates in women receiving donated oocytes were compared to those in women using their own oocytes in in-vitro fertilization (IVF) and gamete intra-Fallopian transfer (GIFT) procedures. Oocyte donation with embryo transfer was performed on 241 women in 371 cycles; 116 of these women became pregnant (48% per patient and 31.5% per cycle) of whom 40 (35%) miscarried, giving a live birth rate of 20.5%. Assisted conception, in the form of IVF/GIFT procedures, was performed on 1331 women using their own oocytes in 2194 cycles; 627 of these women became pregnant (47% per patient and 28.7% per cycle), of whom 228 (36%) miscarried, giving a live birth rate of 18.2%. Neither the age of the donor nor the age of the recipient was related to pregnancy rate. The age of the donor, however, was directly related to the miscarriage rate. On the other hand, the age of patients undergoing IVF/GIFT was inversely related to the pregnancy rate and directly related to the miscarriage rate. In women of 40 years or over, the overall pregnancy and live birth rates were significantly higher and the miscarriage rate was significantly lower in the group receiving donated oocytes compared to the group using their own oocytes. In summary, we suggest that the age-related decline in fecundity is associated with the age of the oocytes rather than the age of the uterus.

Abortion, Spontaneous↗
PubMed1993

The role of trophoblast dysfunction in the aetiology of miscarriage.

OBJECTIVE: To investigate the endocrine changes associated with spontaneous miscarriage after fetal heart activity has been demonstrated. DESIGN: Prospective study during the first trimester of pregnancy comparing the circulating levels of human chorionic gonadotrophin (hCG), Schwangerschaft protein 1 (SP-1), pregnancy-associated plasma protein A (PAPP-A), oestradiol (E2), and progesterone (P), and fetal growth (crown-rump length [CRL] and gestational sac volume [GSV]) in women who miscarried after the identification of fetal heart activity with those of normal singleton and twin pregnancies achieved following in vitro fertilisation (IVF) and embryo transfer (ET). SETTING: The Assisted Conception Unit of King's College Hospital, London. SUBJECTS: Nine women who miscarried after demonstration of fetal heart activity, 52 normal singleton and 22 normal twin pregnancies. INTERVENTIONS: Weekly blood tests and ultrasound assessments of CRL and GSV. RESULTS: Four fetuses (all singleton) died between 9 and 12 weeks gestation (Group 1), and seven (three singleton and two twin) died between 16 and 20 weeks gestation (Group 2). In Group 1, both fetal growth and placental function, as assessed by serial measurements of CRL and GSV, and of serum levels of PAPP-A, SP-1 and hCG respectively, were reduced before fetal death. In Group 2, while fetal growth was maintained in all but one case, placental function was reduced in 4 of 5 women. CONCLUSION: These findings suggest that there may be a relationship between trophoblast dysfunction and some forms of miscarriage. Furthermore, the pattern of the reduction in the circulating levels of the placental proteins in later miscarriages suggests that the function of specific cell types may be impaired.

Abortion, Spontaneous↗
PubMed1993

Functional role of GTPase-activating protein in cell transformation by pp60v-src.

Morphological transformation of NIH 3T3 cells was observed following coexpression of a portion of the ras GTPase-activating protein (GAP) comprising the amino terminus (GAP-N) and a mutant of v-src (MDSRC) lacking the membrane-localizing sequence. Cells expressing either of these genes alone remained nontransformed. Coexpression of GAP-N with MDSRC did not alter the subcellular localization, kinase activity, or pattern of cellular substrates phosphorylated by the MDSRC product. In contrast to SHC, phospholipase C-gamma 1, and the p85 alpha phosphatidylinositol 3'-kinase subunit, the endogenous GAP product (p120GAP) was highly tyrosine-phosphorylated only in cells transformed by wild-type v-src. Furthermore, for transformation induced by wild-type v-src as well as by coexpression of MDSRC and GAP-N, a strict correlation was observed between cell transformation, elevated tyrosine phosphorylation of p62, p190, and a novel protein of 150 kDa, and complex formation between these proteins and p120GAP. As with cells transformed by wild-type v-src, the MDSRC plus GAP-N transformants remained dependent on endogenous Ras. The results suggest that tyrosine phosphorylation and complex formation involving p120GAP represent critical elements of cell transformation by v-src and that complementation of the cytosolic v-src mutant by GAP-N results, at least in part, from the formation of these complexes.

3T3 Cells↗
PubMed1993

Mechanism of glucocorticoid induction of the rat plasminogen activator inhibitor-1 gene in HTC rat hepatoma cells: identification of cis-acting regulatory elements.

Type 1 plasminogen activator inhibitor (PAI-1) is the major physiological inhibitor of plasminogen activation, inhibiting both tissue- and urokinase-type plasminogen activators. In HTC rat hepatoma cells, glucocorticoids increase PAI-1 activity, antigen and mRNA accumulation 3- to 5-fold; this increase is due solely to an increase in the rate of PAI-1 gene transcription. We have identified the cis-acting sequences in the 5'-flanking sequence of the HTC PAI-1 gene that mediate this induction. Analysis of a series of hybrid genes containing various portions of the PAI-1 5'-flanking region fused to the chloramphenicol acetyltransferase reporter gene transfected into HTC cells localized the region involved in the transcriptional regulation by glucocorticoids to between -1237 and -764. Electrophoretic mobility shift assays and DNase-I protection assays showed that a glucocorticoid response element (GRE) 15-mer located at -1212 bound the glucocorticoid receptor DNA-binding domain protein in a concentration-dependent manner. Mutations created within this GRE eliminated its ability both to confer a glucocorticoid response and to bind the glucocorticoid receptor. When placed upstream of a heterologous promoter in either orientation, this GRE conferred glucocorticoid inducibility. We, therefore, conclude that the sole cis-acting sequence required for the glucocorticoid response of the PAI-1 gene in rat HTC hepatoma cells is the GRE at -1212.

Animals↗
PubMed1993

Relationship between ovarian steroids, gonadotrophins and relaxin during the menstrual cycle.

The circulating levels of relaxin have been measured and their relationship with the plasma levels of oestradiol (E2), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) have been investigated during the normal menstrual cycle. In addition, the effect of human chorionic gonadotrophin (hCG) on plasma relaxin levels has been studied. In the first part of the study, blood samples were obtained on days 5, 10 and 15 of the follicular phase and on alternate days from the day of the LH surge (detected in early-morning urine and confirmed by circulating levels of LH) until day 6 of the following follicular phase in nine normally cycling female volunteers. In the second part of the study, a single intramuscular dose of hCG (10,000 IU) was given on day 11 of the menstrual cycle. Relaxin was detectable from the mid-luteal phase until the onset of menstruation. The plasma levels of relaxin on days 10 and 12 of the luteal phase were significantly greater than on day 6. Positive associations between the circulating levels of relaxin and E2 and negative associations between the plasma levels of FSH and those of both relaxin and E2 were found on days 8, 10 and 12 of the luteal phase. The relationship between E2 and FSH was stronger than that between relaxin and FSH. Exogenous hCG had no effect on plasma relaxin levels. The pattern of the relationship between E2 and relaxin suggests that a common mechanism may regulate their release or that plasma relaxin levels are determined by those of E2.(ABSTRACT TRUNCATED AT 250 WORDS)

Chorionic Gonadotropin↗
PubMed1993

Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs.

Cannabimimetic compounds, such as delta 9-tetrahydrocannabinol (delta 9-THC), evoke analgesia in addition to other behavioral responses in humans and animals. The cannabinoid receptor mediating this response has been characterized by its ability to bind the cannabinoid agonist [3H]CP-55,940 and to inhibit adenylyl cyclase via Gi. An investigation of structural requirements for antinociceptive activity of cannabinoid structures led to the development of a simple bicyclic cannabinoid agonist, CP-47,497, that possessed a spectrum of cannabinoid activities in animals that resembled that of delta 9-THC. The present investigation examines several series of CP-47,497 analogs for their binding affinity at the cannabinoid receptor and their ability to evoke analgesia in rodents. Analogs substituted at the C-3 alkyl side chain exhibited maximal affinity for the cannabinoid receptor with side chains of seven or eight carbons in length. Analgesic potency paralleled the receptor-binding affinity. The cyclohexyl ring was optimized as a six- or seven-membered ring structure for binding as well as analgesic activity. Cyclohexyl alkyl side chain extensions of up to four carbons in length had little influence on the affinity for the receptor or analgesic activity. Hydroxyalkyl side chains exhibited optimal binding affinity and antinociceptive activity at three or four carbon atoms in length; however, polar groups closer to the ring diminished binding to the receptor. The importance of the phenolic and cyclohexyl hydroxyl groups for binding affinity was demonstrated. In general, analgesic activity correlated well with the affinity of these analogs for the cannabinoid receptor. Exceptions could be explained by metabolic transformations likely to occur in vivo.

Adenylyl Cyclase Inhibitors↗
PubMed1993

Risk/benefit ratio of perioperative OKT3 in cardiac transplantation.

This study shows that perioperative OKT3 provides no benefit in terms of the time of onset or frequency of rejection or patient survival. However, it does result in an increased incidence of infection, particularly CMV infection. Thus, the risk/benefit ratio of perioperative OKT3 does not appear favorable. However, a multicenter, randomized trial including a larger number of patients and longer patient follow-up will be required to definitively answer the question.

Azathioprine↗
PubMed1993

Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities.

Although a receptor exists for cannabinoid drugs, it is uncertain which pharmacological actions this receptor mediates. This structure-activity relationship investigation was initiated to determine which effects might correspond to binding affinity for the cannabinoid receptor, as well as to explore the binding requirements of this site. The ability of nearly 60 cannabinoids to displace [3H]CP-55,940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-[3-hydroxy propyl] cyclohexan-1-ol] was determined before establishing correlations between receptor affinity and in vivo pharmacological potency. Analysis of [3H]CP-55,940 binding indicated a Hill coefficient of 0.97, a Bmax of 499 pM (3.3 pmol/mg of protein) and an apparent Kd of 924 pM. Closer inspection indicated the binding assay exhibited "zone B" characteristics, and use of correction equations indicated a true Kd for CP-55,940 of 675 pM. The structure-activity relationship indicated the importance of side chain structure to high-affinity binding, with the most potent analogs (K1 < 10 nM) possessing either a dimethylheptyl side-chain, a similarly complex branched side chain or a halogen substituent at the 5' position. Comparative analysis of K1 values to in vivo potency in a mouse model indicated a high degree of correlation between parameters for the depression of spontaneous locomotor activity (r = 0.91) and for the production of antinociception (r = 0.90), hypothermia (r = 0.89) and catalepsy (r = 0.85). Similarly high correlations were demonstrated between binding affinity and in vivo potency in both the rat drug discrimination model (r = 0.81) and for psychotomimetic activity in humans (r = 0.88).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Regulatory sequences and protein-binding sites involved in the expression of the rat plasminogen activator inhibitor-1 gene.

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that inhibits both tissue-type and urokinase-type plasminogen activators. Expression of PAI-1 is regulated by growth factors, cytokines, and hormones. To determine the molecular mechanisms involved in the basal expression of the rat PAI-1 gene, we have analyzed the cis-acting sequences and the trans-acting factors involved in the transcription of this gene in the HTC rat hepatoma cell line. DNase I protection analyses revealed eight regions within the first 764 base pairs of 5'-flanking sequence that interact specifically with HTC cell nuclear proteins. The proteins that bind to five of the eight footprinted sites were identified as PEA3-, Sp1-, and CTF/NF-1-like proteins using competition electrophoretic mobility shift assays. The expression of fusion genes containing progressive 5' deletions of the rat PAI-1 promoter linked to the chloramphenicol acetyltransferase reporter gene were analyzed in transient transfection experiments in HTC cells. These studies demonstrated the Sp1 and CTF/NF-1 sites to be important for transcriptional activation. Two of the footprinted sites contain the sequence 5'-TTTGn(n)TCAAT-3' and were shown in competition electrophoretic mobility shift assays to bind the same or related protein(s). Sequences containing these sites, from -764 to -628 base pairs, and from -266 to -188 base pairs, were identified in functional studies as repressor elements of transcription.

Animals↗
PubMed1992

Variable morphology of coronary atherosclerosis: characterization of atherosclerotic plaque and residual arterial lumen size and shape by epicardial echocardiography.

The purpose of this study was to evaluate the in vivo characteristics of coronary atherosclerosis by using high frequency epicardial echocardiography. High frequency epicardial echocardiography was used to evaluate residual lumen and wall morphology at the sites of maximal coronary atherosclerosis in 26 patients undergoing coronary artery bypass grafting. The maximal/minimal wall thickness ratio was 3.1 +/- 0.2 (mean +/- SEM) with a large range (1.3 to 7.5). Portions of the wall were normal in 16 of 31 lesions; the percent normal circumference ranged from 9% to 85%. Maximal/minimal lumen diameter ratio was 1.5 +/- 0.1 (range 1.1 to 2.9). The shape of the residual coronary lumen was noncircular in 16 lesions: oval in 13 and complex in 3. The residual coronary lumen was eccentrically placed within six arteries. These data emphasize the variability of residual lumen and wall geometry in atherosclerosis.

Coronary Artery Bypass↗
PubMed1992

Cardiac adaptation to obesity and hypertension after heart transplantation.

Obesity and hypertension frequently develop after heart transplantation. The cardiac adaptation to obesity and hypertension was studied by determining hemodynamic and echocardiographic indexes in 10 obese hypertensive patients (body mass index greater than or equal to 27.8 kg/m2 in men or greater than or equal to 27.3 kg/m2 in women) matched by mean arterial pressure, age and gender with 10 nonobese hypertensive patients 1 year after cardiac transplantation. Cardiac output was 30% greater (p less than 0.02) and systemic vascular resistance 25% lower (p less than 0.01) in the obese than in the nonobese patients. Right ventricular systolic and pulmonary artery systolic, diastolic and mean pressures were also significantly higher (p less than 0.05) in the obese patients. Left ventricular end-diastolic diameter was 25% greater (p less than 0.05), left ventricular mass 28% greater (p less than 0.02) and left ventricular end-diastolic volume 20% higher (p less than 0.01) in the obese subjects. Left ventricular ejection fraction was significantly lower in the obese than in the nonobese subjects (34% vs. 51%, p less than 0.05). These results indicate that the cardiac adaptation to obesity and hypertension after heart transplantation consists of left ventricular dilation and an increase in left ventricular mass associated with an increased cardiac output and lower peripheral vascular resistance. These adaptive changes that occur in obese hypertensive patients after heart transplantation might increase the long-term risk of graft failure, as suggested by their lower left ventricular ejection fraction 1 year after transplantation.

Adaptation, Physiological↗
PubMed1992

Successful treatment of heart transplant rejection with photopheresis.

Photopheresis is a potential therapy for rejection in which reinfusion of mononuclear cells exposed to ultraviolet-A light ex vivo, after treatment with 8-methoxypsoralen in vivo, initiates host immune responses that specifically inhibit the cytotoxicity of the photomodulated mononuclear cells. Between May 1990 and January 1991, 7 heart transplant (HT) patients (age 42.2 +/- 16.7 [mean +/- SD] years) on triple immunosuppression (cyclosporine, corticosteroids, and azathioprine) had 9 episodes of non-hemodynamically compromising moderate rejection that were treated with photopheresis. These episodes of rejection occurred at an average of 114.4 +/- 180.5 (range 8-575) days after HT. After oral administration the mean serum level of 8-methoxypsoralen achieved was 129.0 +/- 72.4 ng/ml. An average of 10.4 +/- 9.6 x 10(9) mononuclear cells were treated with each photopheresis procedure. Photopheresis was performed twice when less than 5 x 10(9) mononuclear cells had been treated with the first procedure. Of 9 rejection episodes treated with photopheresis, 5 required 1 procedure and 4 required 2 procedures. Photopheresis was used to treat a single episode of rejection in 5 pts. and 2 separate rejection episodes in 2 additional pts. Eight of 9 episodes of rejection were successfully reversed by photopheresis as assessed by endomyocardial biopsy (EMB) performed 7 days after treatment. Immunohistochemical analysis of EMB samples revealed that postphotopheresis cell counts for T cells, B cells, and macrophages were reduced compared to pretreatment values and correlated with the histopathologic resolution of rejection. Hemodynamics were normal prephotopheresis and remained unchanged at the time when the postphotopheresis EMB showed no evidence rejection No adverse effects have been observed with photopheresis. Over a follow-up period of 5.3 +/- 4.0 months, rejection and infection rates/pt./follow-up months were 0.3 +/- 0.4 and 0.04 +/- 0.07, respectively. The preliminary, short term results of this pilot study indicate that photopheresis may be efficacious in the treatment of moderate rejection in hemodynamically stable HT patients and thus may be an alternative to corticosteroid pulses.

Adult↗
PubMed1992

The evaluation of patients with a suspected pituitary microadenoma: computer tomography compared to magnetic resonance imaging.

OBJECTIVES: To perform a prospective study to compare the ability of magnetic resonance imaging (MRI) and computer assisted tomography (CT) to predict the position of a tumour within the pituitary fossa and to assess the clarity of the image generated by the two modalities in patients with suspected pituitary microadenomas. DESIGN: Nineteen patients were investigated with CT and MRI scans and underwent trans-sphenoidal exploration of the pituitary fossa. Both scans were assessed blind and independently by three neuroradiologists, A, B, and C; A and B examined the CT scans and B and C the MRI scans. The predicted site was then compared to the size and position of the tumour at surgery. PATIENTS: Twenty-five patients were recruited and had both CT and MRI scans, 19 subsequently underwent trans-sphenoidal exploration of the pituitary fossa and formed the study population. RESULTS: The joint opinions of A and B of the CT scans were correct in 10/19, and those of B and C of the MRI scans were correct in 17/19 cases, P = 0.008. Observer agreement was used to assess the clarity of the image. A and B agreed about the site of the tumour on the CT scan in 14 of 19 cases (Kappa statistic 0.556); B and C agreed on the MRI scans in 19/19 cases (Kappa statistic 1), P = 0.025. After the exclusion of five cases found to be macroadenomas at surgery, the joint opinions of A and B of the CT scans were correct in 8/14, and those of B and C of the MRI scans were correct in 12/14 cases, P = 0.133. A and B agreed about the site of the tumour on the CT scan in 12/14 cases (Kappa statistic 0.653), B and C agreed on the MRI scans in 14/14 cases (Kappa statistic 1, no significant difference). CONCLUSIONS: In the assessment of suspected pituitary microadenomas MRI is the imaging technique of choice in view both of its greater diagnostic accuracy and the avoidance of radiation exposure.

Adenoma↗
PubMed1992

Ca(2+)-dependent release from rat brain of cannabinoid receptor binding activity.

As a result of the identification, pharmacological characterization, and localization of the cannabinoid receptor in the CNS, the existence of an endogenous ligand for this receptor can be hypothesized. Following the premise that such a substance could have the properties of a neuromodulator being stored in intracellular vesicles, we tested the ability of increased intracellular Ca2+ levels to stimulate release. We demonstrate here that the Ca2+ ionophore A23187 can induce release of cannabinoid-like binding activity in the presence but not in the absence of Ca2+. The effect of A23187 was maximal at 1.2 microM, consistent with vesicular release. It was necessary to increase the concentration of extracellular free Ca2+ to greater than 60 nM to evoke release. The released cannabinoid-like binding activity displaced [3H]CP-55940 binding to cannabinoid receptors in rat synaptosomal membranes in a concentration-dependent manner. This is the first report of a substance present endogenously in brain that can be released in a Ca(2+)-dependent manner and that binds to the cannabinoid receptor.

Animals↗