Working in a developing country. Returned volunteers can advise.
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Developing Countries↗
Biomedical subjects
M R Johnson
Publications and source records attributed to M R Johnson.
Insulin-related growth factor binding protein-1 levels in ovum donation pregnancies.
The finding that endometrial maturation may be delayed following hormone replacement therapy has suggested that a generalised endometrial dysfunction may exist in ovum recipients. In order to investigate this suggestion further, circulating levels of IGFBP-1 were measured in samples taken throughout pregnancies conceived either spontaneously or following ovum donation. When analysed at two-weekly intervals, the serum levels of IGFBP-1 in ovum donation pregnancies failed to show the expected peak towards the end of the first trimester and were significantly reduced at week ten (U = 364.5, p = 0.0002) and twelve (U = 138.0, p = 0.0047). For the remainder of pregnancy, circulating IGFBP-1 levels were similar in both groups. The birth weight of children born to the ovum donation group was not significantly different from a normal control group, suggesting that circulating levels of IGFBP-1 in early pregnancy do not reflect local function and that IGFBP-1 does not have an essential function (in relation to birth weight) in early pregnancy.
Birth Weight↗
Superovulation, IGFBP-1 and birth weight.
In this study, the effect of superovulation on the circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) has been investigated. IGFBP-1 levels were measured in singleton pregnancies achieved either naturally (n = 203) or following superovulation, in-vitro fertilisation and embryo transfer (IVF-ET) with either pituitary desensitisation with buserelin and superovulation with human menopausal gonadotrophin (b/hMG) followed by IVF-ET (n = 15) or with clomiphene citrate and hMG (CC/hMG) followed by IVF-ET (n = 15, 1st trimester only). The circulating levels of IGFBP-1 were similar in all three groups during the first trimester, and in both normal and b/hMG pregnancies in the second, but were significantly higher during the third trimester in b/hMG pregnancies than in normal pregnancies (P = 0.0002). The birth weights were significantly lower in the b/hMG group (P = 0.04), but not in the CC/hMG group compared with natural conceptions. Gestational age at delivery was similar in control and b/hMG pregnancies, but significantly reduced in CC/hMG pregnancies (P = 0.04). These data suggest that pregnancies achieved following superovulation with b/hMG are associated with elevated levels of IGFBP-1 during the third trimester of pregnancy and reduced birth weight.
Adult↗
Maternal relaxin: a determinant of fetal heart rate?
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Estradiol↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
A normal coronary artery: what size is it?
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Animals↗
Coronary angioplasty in cardiac transplant patients. Results of a multicenter study.
BACKGROUND: Accelerated allograft atherosclerosis is the main cause of death of cardiac transplant recipients after the first year after transplantation. Because no medical therapy is known to prevent or retard graft atherosclerosis and transplantation is associated with a shortened allograft survival, alternative, palliative therapy with percutaneous transluminal coronary angioplasty (PTCA) has been attempted. Because no single medical center has performed angioplasty in a large number of cardiac transplant recipients, representatives of 11 medical centers retrospectively analyzed their complete experience of coronary angioplasty in cardiac transplant patients to determine the safety, efficacy, limitations, and long-term outcome of angioplasty in allograft coronary vascular disease. METHODS AND RESULTS: Thirty-five patients underwent 51 angioplasty procedures for 95 lesions 46 +/- 5 months (mean +/- SEM) after transplantation. The primary indications for angioplasty included angiographic coronary disease in 22 cases (43%) and noninvasive evidence of ischemia in 18 procedures (35%). Angiographic success, defined as less than or equal to 50% post-PTCA stenosis, occurred in 88 of 95 lesions (93%). Mean pre-PTCA stenosis was 83 +/- 1.1%; mean post-PTCA stenosis was 29 +/- 2.1% (p less than 0.0001). Periprocedural complications included myocardial infarction and late in-hospital death in one patient and three groin hematomas. Twenty-three of the 35 patients (66%) had no major adverse outcome such as death, retransplantation, or myocardial infarction at 13 +/- 3 months after angioplasty. Four patients died less than 6 months after angioplasty, and four died more than 6 months after angioplasty (range, 6-23 months). Two patients had retransplantation 2 months after PTCA, and one patients had retransplantation 18 months after angioplasty. CONCLUSIONS: Coronary angioplasty may be applied in selected cardiac transplant recipients with comparable success and complication rates to routine angioplasty. Whether angioplasty prolongs allografts survival remains to be determined by a prospective, controlled trial.
Angioplasty, Balloon, Coronary↗
Effect of food deprivation and altered thyroid status on the hypothalamic-pituitary-thyroid axis in the rat.
Propylthiouracil (PTU) was administered to rats for different lengths of time with or without food deprivation on the last 2 days. Within 4 days of PTU treatment peripheral 3,5,3'-tri-iodothyronine (T3) fell to low levels and beta-subunit of thyroid-stimulating hormone (beta-TSH) mRNA increased significantly in the anterior pituitary. Pro-thyrotrophin-releasing hormone (pro-TRH) mRNA in the hypothalamic paraventricular nucleus (PVN) increased significantly in the control group of animals by 8 days and in the food-deprived group by day 12; the increment of pro-TRH mRNA in the food-deprived group on day 12 was significantly less than that in the control group. In a second study, animals were treated with intraperitoneal injections of T3 with or without the food deprivation. After 4 days of T3 treatment, peripheral T3 levels were markedly increased and pro-TRH mRNA in the PVN and beta-TSH mRNA in the anterior pituitary were significantly reduced. Food deprivation had no additional suppressive effect. These studies confirm that the predominant effect of food deprivation on the thyroid axis is at the hypothalamic or suprahypothalamic level and that it can, at least in part, overcome the increase in TRH mRNA due to diminished T3 feedback.
Animals↗
Distribution of relaxin between human maternal and fetal circulations and amniotic fluid.
Relaxin was measured in maternal blood and amniotic fluid samples at 9-40 weeks and in fetal blood samples at 19-41 weeks of pregnancy. In amniotic fluid, concentrations of relaxin rose from 58 ng/l (geometric mean) at 10 weeks to 142 ng/l at 14 weeks and declined subsequently to 55 ng/l at 22 weeks. In maternal blood, mean relaxin concentrations were ten times greater than in amniotic fluid, and concentrations decreased with gestation. Since there was no significant association between the relaxin concentrations in the two compartments, relaxin in the amniotic fluid may be derived from the decidualized endometrium rather than the maternal circulation, alternatively its metabolism may be different in the two compartments. The absence of detectable concentrations of relaxin in any of the fetal blood samples demonstrates that there is no significant placental transfer or fetal synthesis of this peptide.
Amniotic Fluid↗
Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents.
Opening of the pyran ring of delta 9-tetrahydrocannabinol (THC) produces cannabidiol, a bicyclic cannabinoid devoid of many pharmacological properties produced by delta 8-THC or delta 9-THC. Interestingly, the bicyclic compound CP-47,497 (VI) has been described as producing many of the pharmacological effects produced by delta 9-THC, and another related bicyclic analog CP-55,940 (XIV) has been used to successfully define a cannabinoid binding site. A series of 16 bicyclic analogs of VI and XIV were evaluated and compared with the pharmacological profile of cannabidiol, delta 8-THC and delta 9-THC. The goals of the studies described herein were to determine whether these bicyclic analogs possess similar pharmacological properties of delta 9-THC, to compare pharmacological activity after s.c. and i.v. administration, and to evaluate the structure-activity relationship of this series of analogs for further insight into cannabinoid mechanism of action. Each analog was evaluated for its ability to produce hypoactivity, hypothermia, antinociception and catalepsy in mice. The ED50 values generated from these assays were averaged to provide an index of activity. The ED50 values for delta 9-THC varied from 1.0 to 1.5 mg/kg, giving an overall index of activity of 1.3. The index for delta 8-THC was 6.0, making this isomer 4-fold less potent. Although several bicyclic analogs (V, VI, VII, VIII, XI, XII, XIV and XVI) proved to be truly cannabimimetic, three (IV, IX and X) were sufficiently unique to be classified as noncannabimimetic. The index of activity of cannabimimetic bicyclic analogs varied from 0.2 to 2.2, although some minor differences between the bicyclics and delta 9-THC exist.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenylyl Cyclases↗