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ABSTRACT: Sections of chorion laeve were perfused with a solution of medium E199 for five hours. Samples were collected every 20 minutes and the concentration of active and inactive renin in the perfusate was measured. The addition of prostaglandin E2 (PGE2)(10−6M to 10−4M) to the medium did not alter the concentration of active or inactive renin in the perfusate. Similarly, blockade of prostaglandin synthesis with indomethacin (10−4M to 10−3M) had no effect on the pattern of renin release. These results suggest that the E-series prostaglandins which are produced by the utero-placental unit do not stimulate the release of renin from human chorion
07/2009; b4(1):49-62.
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ABSTRACT: 26 patients with mild to moderate pregnancy induced hypertension (PIH), were treated for 5-7 days with labetalol 100mg three times a day or with a placebo. The labetalol group showed a statistically significant decrease in their mean arterial blood pressure (P<0.05) and forearm venous tone (P<0.05). Whereas the placebo group (bed rest only) had an insignificant fall in their mean arterial pressure and a statistically significant rise in their forearm venous tone. Labetalol is a suitable agent for reducing both the arterial and venous tone in patients with PIH. Possible mechanisms are discussed.
07/2009; b8(2):293-304.
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ABSTRACT: Angiotensin converting enzyme (ACE) levels have been determined in human fetal menbranes, placenta, amniotic fluid and cord venous serum. Mean levels of ACE in cord venous sera were not significantly different from those in normal non-pregnant individuals. Small quantities of ACE were detected in hanogenates of chorio-decidua, amnion and placenta and in amniotic fluid. Incubations of chorio-decidua and amnion in Krebs Ringer buffer at 0°C for 24 hours resulted in the release of. ACE. In all these samples the levels were significantly lower than in serum (p < 0.001). It is concluded that angiotensin conversion may occur locally in these tissues or in amniotic fluid but it would appar that the main conversion of angiotensin I takes place in the umbilical vessels, releasing angiotensin II close to its receptors.
07/2009; b3(1):51-60.
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ABSTRACT: To assess the safety and targeting ability of the engineered human antibody (hCTMO1) in women with ovarian carcinoma.
The monoclonal antibody labelled with Indium-111 was administered to women with suspected primary or recurrent ovarian carcinoma six days pre-operatively. The first group of women was given a dose of 0.1 mg per kg body weight of radiolabelled antibody. A second group of women received 1 mg per kg body weight and finally a third group was given 1 mg per kg body weight of unlabelled antibody followed one hour later by 0.1 mg per kg body weight of radiolabelled antibody. All the women were then imaged using a gamma camera one hour and up to 96 hours after injection.
Fourty-four women in whom there was a high suspicion of primary ovarian carcinoma on the basis of ultrasound or CT imaging and serum CA125 and those in whom there was a suspicion of recurrent ovarian carcinoma after being treated for histologically confirmed carcinoma.
The Queen's Medical Centre, Nottingham and University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
At the low dose of antibody the sensitivity for detection of ovarian carcinoma was 70%. After increasing the dose of antibody and also after pre-dosing with unlabelled antibody the sensitivity increased to 100%, but there was a large number of false positive results at the higher dose, and therefore the specificity was low. The liver and bone marrow were the organs with the highest activities.
The genetically engineered antibody hCTMO1 is safe for use in women. This antibody effectively targets ovarian carcinoma and has greater potential as a vector for therapeutic use than as a diagnostic agent.
British Journal of Obstetrics and Gynaecology 02/1999; 106(1):31-7.
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H M Prinssen,
C F Molthoff,
R H Verheijen,
T J Broadhead,
P Kenemans,
J C Roos,
Q Davies,
A C van Hof,
M Frier,
W den Hollander,
A J Wilhelm,
T S Baker,
M Sopwith, E M Symonds,
A C Perkins
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ABSTRACT: mAb hCTM01 binds a carcinoma-associated antigen, the MUC1 gene product. The antigen is also present in the circulation, and administration of 111In-labelled hCTM01 results in the formation of immune complexes with enhanced accumulation in the liver. To avoid the unwanted effect of circulating radioactive immune complexes, a strategy to remove the circulating antigen was investigated using a split-dosage schedule. Eleven patients suspected of having ovarian carcinoma were injected with 1 mg/kg unlabelled hCTM01, 1 h before receiving 0.1 mg/kg 111In-labelled hCTM01 (100 M Bq). The amount of radioactivity was determined in resected tumour tissue, various normal tissues and blood samples obtained at laparotomy 6 days postinjection (p.i.). In all patients, the circulating antigen decreased to its nadir after the unlabelled antibody infusion and immune complex formation was demonstrated. Uptake in tumour deposits 6 days p.i. was 11.1 times higher than in normal tissues (P < 0.0001) and 5.9 times higher than in blood (P < 0.0001). 111In activity in liver tissue was comparable to 111In uptake in tumour tissue, and considerably lower than previously reported in patients not pretreated with unlabelled antibody. The split-dosing strategy would appear to be advantageous for use of hCTM01 as a specific carrier for the delivery of cytotoxic agents to patients with ovarian cancer.
Cancer Immunology and Immunotherapy 10/1998; 47(1):39-46. · 3.70 Impact Factor
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ABSTRACT: Our purpose was to investigate a possible role for apoptosis in the pathophysiologic mechanisms of intrauterine growth restriction.
Placental samples were obtained from 43 uncomplicated third-trimester pregnancies and from 26 pregnancies complicated by intrauterine growth restriction. The definition used to identify cases of intrauterine growth restriction depended on three criteria: clinical evidence of suboptimal growth, ultrasonographic evidence of deviation from an appropriate growth percentile, and individualized birth weight ratios <10th percentile. Light microscopy was used to quantify the incidence of apoptosis. Electron microscopy and TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) staining were used to confirm the occurrence of apoptosis.
Quantification of apoptosis (medians and interquartile ranges) resulted in the following values: normal third trimester (n = 43) 0.14% of cells (0.08% to 0.20%) and intrauterine growth restriction third trimester (n = 26) 0.24% of cells (0.16% to 0.29%). The incidence of apoptosis was significantly higher in placentas from pregnancies with intrauterine growth restriction compared with normal third-trimester placentas (p < 0.01, Mann Whitney U test).
These results suggest that apoptosis may play a role in the pathophysiologic mechanisms of intrauterine growth restriction.
American Journal of Obstetrics and Gynecology 12/1997; 177(6):1395-401. · 3.47 Impact Factor
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ABSTRACT: The study aims were to conclusively demonstrate apoptosis in the human placenta and to quantify its incidence at different stages of pregnancy.
Placental samples were obtained from 28 first-trimester pregnancies and 38 uncomplicated third-trimester pregnancies. Light microscopy, electron microscopy, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate marker nick end-labeling staining were used to identify apoptosis. Light microscopy was used to quantify its incidence.
Apoptosis has been conclusively demonstrated within placental tissue. Quantification of apoptosis (medians and interquartile ranges) was as follows: first trimester (n = 28), 0.07% of cells (0.05% to 0.14%); third trimester (n = 39), 0.14% of cells (0.09% to 0.20%). The incidence of apoptosis was significantly higher in the third trimester than in the first trimester (p < 0.01, Mann-Whitney U test).
Placental apoptosis increases significantly as pregnancy progresses, suggesting that it may play a role in the normal development and aging of the placenta.
American Journal of Obstetrics and Gynecology 07/1997; 177(1):57-65. · 3.47 Impact Factor
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ABSTRACT: Clinical studies are currently underway to assess the biodistribution and therapeutic potential of the genetically engineered human antibody hCTM01 directed against polymorphic epithelial mucin (PEM) in patients with ovarian carcinoma. The present study was undertaken to assess the effect of circulating PEM antigen on the biodistribution of the anti-PEM antibody in mice bearing MUC-1 transfected adenocarcinoma cell lines. Tumour xenografts were established from three cell lines: 413-BCR, which expressed antigen on the cell surface and also shed antigen into the circulation, E3P23, which expressed the antigen but did not shed into the circulation, and a negative control (410.4 MUCI). Groups of five mice were injected with 1.0 mg/kg antibody, imaged after 72 h and then sacrificed, followed by assay of tissue uptake. The results showed a clear difference in the tumour and liver uptake, with the non-secreting cell line showing almost twice the tumour uptake and approximately 20% of the liver uptake of the secreting cell line.
European Journal of Nuclear Medicine 03/1997; 24(2):206-9.
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A C van Hof,
C F Molthoff,
Q Davies,
A C Perkins,
R H Verheijen,
P Kenemans,
W den Hollander,
A J Wilhelm,
T S Baker,
M Sopwith,
M Frier, E M Symonds,
J C Roos
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ABSTRACT: Thirty-one patients suspected of having ovarian cancer received a single i.v. injection of radiolabeled (100 MBq (111)In) engineered human CTMO1 (hCTMO1) to investigate its potential as an internalizing drug carrier. hCTMO1 is a complementary-determining region-grafted human IgG4 monoclonal antibody recognizing an ovarian carcinoma-associated antigen, the MUC-1-gene product. The amount of radioactivity was determined in tumor tissue, various normal tissues, including liver biopsies, and blood samples obtained at laparotomy, 6 days after injection of either 0.1 or 1.0 mg hCTMO1/kg of body weight. Circulating antigen-15-3 was measurable in all patients before injection, and immune complex formation was already present at the end of infusion. In the 0.1 mg/kg group, most of the radioactivity was bound to immune complexes, whereas in the 1.0 mg/kg group, most was bound to IgG monomers. Increasing the hCTMO1 dose 10-fold did not influence the overall disappearance of (111)In from the blood, but the elimination half-life of (111)indium bound to immune complexes was increased 2-fold. Uptake in tumor tissue 6 days postinjection at the 0.1 mg/kg dose was 7.6 times higher (P = 0.0009) than in normal tissue and 2.5 times higher (P = 0.03) than in blood. At the 1.0 mg/kg dose, the uptake in tumor tissue was 14.0 times higher (P = 0.0003) than in normal tissue and 8.1 times higher (P = 0.0007) than in blood. Liver activity was substantial (23.7 +/- 10.5 and 18.3 +/- 6.7% of the injected dose/kg for the 0.1 and 1.0 mg/kg dose group, respectively). These results are superior to those found with other clinically tested anti-MUC-1 gene product antibodies. hCTMO1 seems to be a suitable carrier for cytotoxic agents in ovarian carcinoma patients; the better uptake results and tumor-to-blood ratios are obtained at the higher dose of 1.0 mg hCTMO1/kg body weight.
Cancer Research 12/1996; 56(22):5179-85. · 7.86 Impact Factor
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ABSTRACT: A retrospective study was performed at the Queens Medical Centre, Nottingham, UK to evaluate the potential value of PR interval analysis of the FECG compared to conventional intrapartum assessment with fetal heart rate monitoring. Two-hundred sixty-five labours were selected for monitoring. Outcome was assessed by the number of fetal scalp blood samples (FBS) performed and the associated incidence of acidosis in the first stage of labour, the mode of delivery and whether or not this was expedited for fetal heart abnormality or an abnormal scalp pH. The condition of the fetus at delivery was assessed by arterial and venous blood acid-base status, Apgar score and the need for admission to the neonatal intensive care unit. Conventional electronic fetal heart rate monitoring (EFM) was used in all labours. The addition of PR interval assessment would potentially reduce the numbers of normal FBSs being carried out from 85.5% to 26.8% and the proportion of cases of missed acidosis at delivery from 8.5% to 4.5%. These results highlight the potential benefit of PR interval analysis in improving interpretation of the intrapartum cardiotocograph and need to be tested by prospective randomised controlled study.
European Journal of Obstetrics & Gynecology and Reproductive Biology 10/1996; 68(1-2):87-92. · 1.97 Impact Factor
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ABSTRACT: The evaluation of the changes in the relationship of the PR interval and fetal heart rate during prolonged fetal compromise in sheep at levels of acidosis comparable to those seen during human fetal compromise and to see whether these changes are potentially of use in the detection of fetal distress.
A retrospective analysis of continuous fetal electrocardiogram recordings during graded fetal hypoxemia in 20 chronically cannulated fetal sheep was performed. Baseline recordings during normoxemia were compared with recordings during hypoxemia by use of Fisher's exact test and the Student t test.
Sixteen of the 20 cases could be used for final analysis. Twelve showed a statistically significant change from a predominantly negative relationship between the PR interval and the fetal heart rate during normoxemia to a predominantly positive relationship during hypoxemia. Two cases showed an obvious trend in the same direction, which was statistically not significant. In two other cases no change in the relationship was observed.
A changing relation between the PR interval and the fetal heart rate is of potential use in the detection of fetal compromise.
American Journal of Obstetrics and Gynecology 10/1996; 175(3 Pt 1):548-54. · 3.47 Impact Factor
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ABSTRACT: Advances in microprocessing technology have made fetal ECG analysis a feasible adjunct to fetal surveillance. Time interval and morphology changes of the FECG occur during fetal hypoxia. The use of these changes to detect a fetus at risk of intrapartum asphyxia awaits validation in terms of both future and ongoing clinical trials. Recognition of FECG changes during decelerations may improve the sensitivity of EFM. Antepartum FECG analysis has potential for the detection of a number of pathological fetal conditions, including intrauterine growth retardation, but remains hampered by low signal-to-noise ratios, rendering successful signal acquisition unreliable.
Baillière s Clinical Obstetrics and Gynaecology 07/1996; 10(2):273-94.
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E M Symonds
Archives of Disease in Childhood - Fetal and Neonatal Edition 04/1995; 72(2):F139-44. · 3.05 Impact Factor
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E M Symonds
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ABSTRACT: Seventy per cent of all claims concerning intrapartum care in relation to fetal brain damage are based on abnormalities of the cardiotocograms and electronic fetal monitoring. Claims arise because of failure to take action in the presence of an abnormal cardiotocogram, or because of delayed response to an abnormal tracing. Difficulties in court arise from variations in the interpretation of the significance of recordings. The importance of taking appropriate action in the presence of an abnormal cardiotocogram, and in keeping accurate time-sensitive records is emphasized.
Current Opinion in Obstetrics and Gynecology 11/1994; 6(5):430-3. · 2.38 Impact Factor
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American Journal of Obstetrics and Gynecology 10/1994; 171(3):867-8. · 3.47 Impact Factor
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ABSTRACT: A prospective study investigated platelet cytosolic calcium in non-pregnant volunteers (n = 30) and samples from the umbilical veins of babies from both normotensive (n = 18) and hypertensive (n = 15) primigravidae, and their mothers. There was no significant difference between the neonatal umbilical venous platelet cytosolic calcium concentration (p[Ca2+]i) in babies born to normotensive primigravidae or to those whose pregnancies were complicated by gestational hypertension (88 x 9 (SE) 2 x 5) in normotensive primagravidae, 80 x 6 (2 x 8) in pregnancy induced hypertension without proteinuria, and 89 x 3 (3 x 2) nmol/l in pre-eclampsia. There was also no significant difference in the p[Ca2+]i from the umbilical veins of the pregnancies studied and those of non-pregnant female volunteers in the follicular phase of their menstrual cycle. This was despite a gradual and significant rise in p[Ca2+]i with increasing severity of disease in the mothers of the babies studied (119 x 9 (4 x 1) in normotensive primagravidae, 130 x 8 (7 x 3) in pregnancy induced hypertension without proteinuria, and 148 x 2 (4 x 5 ) nmol/l in pre-eclampsia). The mean maternal p[Ca2+]i in the three samples returned to concentrations comparable with those in non-pregnant subjects by 12 weeks after birth. These data demonstrate no significant difference between the mean p[Ca2+]i in non-pregnant women and those obtained from the umbilical venous blood of normotensive or hypertensive primigravidae. They suggest that the functional hypoactivity of neonatal platelets is probably not secondary to a decrease in basal p[Ca2+]i. They also suggest that the progressively raised p[Ca2+]i in normal and hypertensive pregnancies might be due to a pregnancy specific factor that does not cross the placenta,
Archives of Disease in Childhood - Fetal and Neonatal Edition 08/1994; 71(1):F6-10. · 3.05 Impact Factor
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ABSTRACT: Previous studies have shown that the relationship between P-R interval of the fetal electrocardiogram (FECG) and the fetal heart rate (FHR) varies according to the acid-base status of the fetus. In the normal fetus there is a negative correlation between these two parameters. However, as acidosis develops, the relationship becomes positive. In order to express this relationship in a quantitative form, an index known as the ratio index (RI) has been derived. This index provides a cumulative time based description of the relationship between the P-R interval and FHR for the whole labour. The aim of this study was to evaluate this derived index and compare it with fetal hypoxia. The FECG was recorded from 132 fetuses during labour using a fetal scalp electrode, and analysed using the Nottingham FECG system. Changes in the nature of this relationship between the P-R interval and heart rate were compared against biochemical markers of asphyxia, namely umbilical artery pH, lactate and umbilical venous norepinephrine and hypoxanthine. Significant correlations were demonstrated between the RI and umbilical arterial pH (r = -0.38, P < 0.01), lactate (r = 0.36, P < 0.01), log10norepinephrine (r = 0.37, P < 0.01), and hypoxanthine (r = 0.28, P < 0.01). The measurement of the ratio index during labour may be a useful method of determining fetal hypoxia during labour.
European Journal of Obstetrics & Gynecology and Reproductive Biology 05/1994; 55(1):63-70. · 1.97 Impact Factor
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ABSTRACT: Concern has been expressed about possible neonatal side effects after the use of maternal anti-platelet agents in pregnancy, particularly low dose aspirin treatment. We have studied neonatal platelet behaviour using whole blood techniques, and assessed the neonatal effect of the maternal ingestion of 60 mg aspirin daily.
Cross sectional and randomised, double-blind, placebo-controlled.
University hospital.
1. Eight normal women, studied before conception, and their infants. 2. Twenty-four infants whose mothers had been randomised to receive either 60 mg aspirin daily, or placebo, in double-blind fashion.
The Clay Adams Ultra Flo 100 whole blood single platelet counter was employed to measure platelet aggregation in response to various agonists. The platelet release reaction was also measured in whole blood, and serum thromboxane B2 (TxB2) production was measured by radio-immunoassay. Umbilical cord blood samples were obtained at delivery.
1. Neonatal platelet aggregation induced by adrenaline, ADP and platelet activating factor was reduced in comparison with their mothers (P < 0.01), whereas the neonatal platelet release reaction was reduced when stimulated by collagen and U46619 (a thromboxane mimetic) (P < 0.01). Serum TxB2 production was similar in mothers and babies. 2. Neonatal platelet aggregation, release reaction and serum TxB2 production were not significantly reduced in infants exposed to maternal aspirin in comparison with those neonates exposed to maternal placebo. This is in contrast to the effect on maternal platelets.
Although only a small number of patients were studied, we interpret this as a relative sparing of neonatal platelet reactivity due to the presystemic action of low dose aspirin.
British Journal of Obstetrics and Gynaecology 03/1994; 101(3):203-8.
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ABSTRACT: Five pregnant women whose pregnancies were complicated only by essential hypertension had significantly elevated platelet cytosolic calcium levels as compared with those of their normotensive counterparts. There seems to be an association between platelet cytosolic calcium level and arterial blood pressure that has previously been described in both nonpregnant and preeclamptic women.
American Journal of Obstetrics and Gynecology 08/1993; 169(1):141-3. · 3.47 Impact Factor
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ABSTRACT: An anti-polymorphic epithelial mucin (PEM) monoclonal antibody NCRC48 (IgG3) has been tested for its capacity to localize in tumours according to accepted guidelines for human administration. Following radiolabelling with 111In, 1 mg antibody was administered to 19 patients with a clinical suspicion of ovarian malignancy. Initial imaging and biodistribution studies confirm the safety of this conjugate although six out of 11 patients tested developed an antibody response to the monoclonal antibody. Immunoscintigraphy with this antibody was compared with magnetic resonance imaging and ultrasound in relation to the final tumour histology, the final accuracies being 79, 79 and 64% respectively. Positive localization of antibody was confirmed in malignant tissue with little evidence of uptake in benign tissue.
Nuclear Medicine Communications 08/1993; 14(7):578-86. · 1.40 Impact Factor
