Diagnosis and management of fetal cardiac tumors.
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Fetal Diseases↗
Biomedical subjects
L Allan
Publications and source records attributed to L Allan.
Pulmonary venous flow reversal.
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Humans↗
Ascertainment of familial ovarian cancer in the Aberdeen Genetic Clinic.
Ovarian cancer is the fifth most common malignancy in women in the UK. Patients with a family history including ovarian cancer make up nearly 15% of family cancer referrals to the Genetic Clinic in Aberdeen. To date, only one pedigree has been suitable for linkage studies, which has enabled us to target screening more accurately at those people at highest risk. Following discovery of a strong candidate for the BRCA1 gene, direct mutation testing may soon be possible. People who seek testing will require further counselling. Therefore we anticipate an increased demand on both clinical and laboratory resources, but more accurate ascertainment of high risk subjects should lead to more appropriate targeting of screening services.
Adult↗
Encapsulation of mitomycin C in albumin microspheres markedly alters pharmacokinetics, drug quinone reduction in tumour tissue and antitumour activity. Implications for the drugs' in vivo mechanism of action.
Pharmacokinetics and metabolism of mitomycin C (MMC) have been studied in NMRI mice bearing MAC 16 colon adenocarcinoma after direct intratumoural injection of either 500 micrograms free MMC or the same dose incorporated in albumin microspheres. Microspheres produced a tumour pharmacokinetic profile of steady state drug levels, avoiding the much higher early peak (20.5 micrograms/tumour vs 98.9 micrograms/tumour) and lower trough of free MMC, and reducing significantly the levels of drug reaching the systemic circulation (AUC 1.8 micrograms/mL x hr for microspheres vs 6.8 micrograms/mL x hr for free drug). 2,7-Diaminomitosene (2,7-DM), a key intermediate in MMC quinone bioreduction, was used as an indicator of drug metabolic activation in tumour tissue. Peak levels were 10-fold higher (11.2 micrograms/tumour vs 1.1 micrograms/tumour) and area under the curve 5-fold higher after free drug. Even taking into account differences in tumour pharmacokinetic profiles of the parent drug, microspheres actively inhibited 2,7-DM formation 3-fold. However, the microspheres generated a completely different pattern of drug metabolism where four previously uncharacterized mitosane metabolites and elevated levels of cis and trans 1-hydroxy 2,7-diaminomitosene were detected. Despite similar parent drug exposure in tumours, free drug was significantly more active (P < 0.05, Student's t-test) against MAC 16. These results suggest that formation of 2,7-DM correlates more closely with antitumour activity than sustained parent drug levels or appearance of other key metabolites. Potentially, they provide the first direct evidence for an in vivo mechanism of action dependent on bioreductive activation and formation of 2,7-DM.
Adenocarcinoma↗
Ebstein's anomaly: presentation and outcome from fetus to adult.
OBJECTIVES: This study was conducted to investigate the presentation and outcome of patients with Ebstein's anomaly of the tricuspid valve. BACKGROUND: Ebstin's anomaly may present at any age and has a highly variable clinical course. Previous natural history studies have been based on clinical and angiographic diagnosis and have included mainly older children and adults. Echocardiography, however, has facilitated fetal and neonatal diagnosis so that the natural history needs to be redefined. METHODS: We reviewed 220 cases of Ebstein's anomaly presenting from fetal to adult life between 1958 and 1991, with 1 to 34 years of follow-up. RESULTS: The most common presentation in each age group was abnormal routine prenatal scan for fetuses (86%), cyanosis for neonates (74%), heart failure for infants (43%), incidental murmur for children (63%) and arrhythmia for adolescents and adults (42%). Early presentation was frequently associated with other cardiac lesions, usually pulmonary stenosis or atresia. Surgery was undertaken at some stage in 86 (39%) of the 220 patients. Actuarial survival for all liveborn patients was 67% at 1 year and 59% at 10 years. There were 58 deaths, including 26 from heart failure, 19 perioperative and 8 sudden. Predictors of death included echocardiographic grade of severity at presentation (relative risk 2.7 for each increase in grade, 95% confidence limits 1.6 to 4.6), fetal presentation (6.9, confidence limits 1.6 to 16.5) and right ventricular outflow tract obstruction (2.1, confidence limits 1.1 to 4.4). Morbidity was mainly related to arrhythmias and late hemodynamic deterioration. Of 155 survivors, 129 (83%) were in functional class 1 and 104 (67%) were receiving no medical therapy. CONCLUSIONS: In Ebstein's anomaly, fetal and neonatal presentation is associated with a poor outcome and can be predicted by the echocardiographic appearance and presence of associated lesions. In older children and adults, incidental findings and arrhythmia are common and the long-term outcome is superior.
Adolescent↗
Assessment of changes in blood flow through the lungs and foramen ovale in the normal human fetus with gestational age: a prospective Doppler echocardiographic study.
OBJECTIVE: To measure lung blood flow and flow through the foramen ovale in the normal human fetus and to assess the changes in each with gestational age and the proportions of combined ventricular output that the respective flows represent. PATIENTS AND DESIGN: 38 normal fetuses (gestational age 18-37 weeks) were studied prospectively with Doppler echocardiography. METHODS: Echocardiographic images and Doppler velocity signals were obtained from the ascending aorta, main pulmonary artery, and ductus arteriosus from each fetus and digitised to obtain arterial diameters, heart rates, and velocity-time integrals. Blood flow in each artery was calculated as the product of heart rate, flow-velocity integral, and arterial cross sectional area. Blood flow through the lung was assessed as the difference between flow in the pulmonary artery and ductal flow; combined ventricular output as the sum of aortic and pulmonary artery flows; and flow through the foramen ovale as the difference between flows through the aorta and lungs. RESULTS: Blood flow through the lungs increased exponentially with gestational age (r = 0.89, p < 0.001), by almost four-fold over the period of gestation studied, and was a mean (SD) of 22% (7%) of combined ventricular output. Blood flow through the foramen ovale increased exponentially by threefold (r = 0.77, p < 0.001), representing between 17% and 31% of combined ventricular output. CONCLUSIONS: Blood flow through the lungs and across the foramen ovale can be calculated non-invasively in the normal human fetus. Both flows increase exponentially with age and comprise between one fifth and one quarter of the combined ventricular output, proportions that remain unchanged through the second and third trimesters of pregnancy.
Aorta↗
Chemico/biological investigation of contaminated sediment from the Hamilton Harbour area of western Lake Ontario.
Highly contaminated sediment from the Hamilton Harbour area of western Lake Ontario was examined using a bioassay-directed fractionation methodology. A sediment sample was extracted using a Soxhlet apparatus and the resulting extract was fractionated into compound classes using an alumina clean-up step and high performance liquid chromatographic techniques. The resulting fractions were subjected to bioassays using TA98- and TA100-like strains modified by the inclusion of genes for the activating enzymes nitroreductase and O-acetyl-transferase. The majority of the mutagenic activity displayed by the sample extract was found to be present in the fraction containing the polycyclic aromatic hydrocarbons (PAH). Extracts of the PAH-containing fraction displayed dramatically higher responses with the TA100 type strains with metabolic activation. Further separation of the PAH-containing fraction showed the majority of the biological activity coeluted with PAH having molecular masses of 276, 278, and 302 amu.
Dose-Response Relationship, Drug↗
Incorporation and release of chemically intact mitomycin C from albumin microspheres: a high performance liquid chromatography evaluation.
Preparation of mitomycin C-loaded human serum albumin (HSA) microspheres using a new technique that avoids the use of heat denaturation, which is known chemically to degrade incorporated drug, is described. This method is based on cross-linking of protein by glutaraldehyde (2.2%) during emulsification (W/O) at room temperature. The resultant particles have a mean (s.d.) diameter of 16.9 (0.34) microns (50% weight average), contain mean (s.d.) 1.15 (0.05%) mitomycin C (MMC) (w/w, n = 17) and maintain sustained release of drug over 20 h. High performance liquid chromatography (HPLC) with diode array detection was used to study the chemical integrity of the drug. Two classes of decomposition products were evaluated: chemical degradation products and drug/nucleophile covalent adducts. The HPLC separation was validated by a number of standards of proposed degradation products. To examine incorporated drug, a complete microsphere system was solubilized with 0.4% trypsin for 24 h, while to examine released drug, microspheres were immobilized on a flow-through glass wool column and fractions were collected. No evidence of significant chemical degradation or covalent coupling to protein was detected in microsphere digests. Two candidate decomposition products, representing approximately 10% of drug released from microspheres (assuming similar molar extinction coefficients to MMC), were identified in column fractions. One of these products appeared to be a covalent adduct, the other possibly an isomeric form of intact MMC. Thus, MMC is predominantly incorporated into and released (90%) chemically intact from HSA microspheres prepared by the technique described.
Chromatography, High Pressure Liquid↗
A large, dominant pedigree of atrioventricular septal defect (AVSD): exclusion from the Down syndrome critical region on chromosome 21.
We describe a large pedigree of individuals with autosomal dominant atrioventricular septal defect (AVSD). The pedigree includes affected individuals and individuals who have transmitted the defect but are not clinically affected. AVSDs are a rare congenital heart malformation that occurs as only 2.8% of isolated cardiac lesions. They are the predominant heart defect in children with Down syndrome, making chromosome 21 a candidate for genes involved in atrioventricular septal development. We have carried out a linkage study in the pedigree by using 10 simple-sequence polymorphisms from chromosome 21. Multipoint linkage analysis gives lod scores of less than -2 for the region of trisomy 21 associated with heart defects, which excludes a locus within this region as the cause of the defect in this family.
Adult↗
The enzymology of doxorubicin quinone reduction in tumour tissue.
We have reported previously that enzymes present in the Sp 107 rat mammary carcinoma catalyse doxorubicin quinone reduction (QR) to 7-deoxyaglycone metabolites in vivo [Willmott and Cummings, Biochem Pharmacol 36: 521-526, 1987]. In order to provide insights into the role of QR in the antitumour mechanism of action of doxorubicin, we have attempted in this work to identify the enzyme(s) responsible. NAD(P)H: (quinone acceptor) oxidoreductase (DT-diaphorase) was the major quinone reductase in the tumour accounting for approximately 70% of all the activity measured in microsomes and cytosols (microsomal activity, 28.4 +/- 4.6 nmol/min/mg; cytosolic activity, 94.3 +/- 11.9 nmol/min/mg). Its presence was confirmed by western blot analysis. Low levels of NADH cytochrome b5 reductase (15.6 +/- 6.3 nmol/min/mg) and NADPH cytochrome P450 reductase (14.5 +/- 4.0 nmol/min/mg) were detectable in microsomes. The presence of the latter was confirmed by western blot analysis. Pretreatment of tumours with doxorubicin (48 hr) at a therapeutic dose decreased the level of activity of all the reductases studied by at least 2-fold (P < 0.01, Student's t-test). Doxorubicin was shown not to be a substrate for purified rat Walker 256 tumour DT-diaphorase with either NADH or NADPH as co-factor and utilizing up to 20,000 units of enzyme/incubation but was confirmed to be a substrate for purified rat liver cytochrome P450 reductase. 7-Deoxyaglycone metabolite formation by purified cytochrome P450 reductase had an absolute requirement for NADPH as co-factor, was inhibited by molecular oxygen and dicoumarol (IC50 approx. 50 microM), and modulated by specific reductase antiserum. Reductive deglycoslation of doxorubicin to 7-deoxyaglycones was localized to the microsomal fraction of the Sp 107 tumour, with negligible activity being found in cytosols (NADH, NADPH and hypoxanthine as co-factors) and mitochondria (NADH and NADPH). The tumour microsomal enzyme had an absolute co-factor requirement for NADPH, was inhibited by oxygen and dicoumarol, and modulated by cytochrome P450 reductase antiserum. These data indicate strongly that NADPH cytochrome P450 reductase is the principal enzyme responsible for catalysing doxorubicin QR in the Sp 107 tumour.
Animals↗
The role of transvaginal sonography in the early detection of congenital heart disease.
The antenatal diagnosis of congenital heart disease by fetal echocardiography is rarely achieved before 18-20 weeks' gestation. Transvaginal sonography allows examination of fetal anatomy at earlier gestations than the transabdominal approach. In a screening study of 270 low-risk women between 8 and 14 weeks' gestation using a 5 MHz vaginal transducer, it was possible to obtain adequate four-chamber views in over 70% from 12 weeks. In a second study of 32 women at high risk of congenital heart disease scanned between 14 and 15 weeks' gestation, satisfactory views were obtained transvaginally in 21 women. Seven of the remainder had normal cardiac anatomy confirmed by transabdominal scanning. In three of the four where normal cardiac anatomy could not be demonstrated by either transvaginal or transabdominal scanning, severe congenital heart disease was diagnosed and later confirmed. It is unlikely that transvaginal sonography will replace abdominal scanning for the screening of low-risk pregnancies, but it is a valuable addition to the early examination of those women identified as being at high risk of congenital heart disease.
Journal Article↗
Disposition of the atrioventricular conduction tissues in the heart with isomerism of the atrial appendages: its relation to congenital complete heart block.
OBJECTIVES: Our goal was to compare histologically the mechanisms producing congenital complete heart block in normally structured hearts and in hearts with isomerism of the atrial appendages. BACKGROUND: It is known that several different histologic patterns can underscore the existence of congenital complete heart block in the normally structured heart, and that block is particularly frequent in the setting of isomerism of the atrial appendages. The histologic findings in the latter setting were compared and contrasted with those found in the normally structured heart. METHODS: Serial section techniques were used to study 14 hearts with isomerism of the atrial appendage (12 with left isomerism and 2 with right isomerism) and 7 normally structured hearts. RESULTS: Discontinuity between the atrioventricular (AV) node and the ventricular conduction tissues was found in 10 of the 12 hearts with left isomerism; the other 2 hearts had a normally formed conduction axis and heart block was not present in these cases. In both hearts with right isomerism, "slings" of ventricular conduction tissue connected dual AV nodes; congenital complete heart block was not present in either case. In six of the seven cases with a normally structured heart, anti-Ro antibodies had been found in the maternal serum. All six of these hearts had discontinuity between the atrial tissues and the ventricular conduction axis. Intraventricular discontinuity was found in the seventh case, in which anti-Ro antibodies were not found in the mother. CONCLUSIONS: The pattern of congenital complete heart block in cases with left isomerism is discontinuity between the AV node and the conduction axis, in contrast to the pattern of atrial-axis discontinuity produced in the normally structured heart when anti-Ro antibodies are found in the maternal serum.
Abnormalities, Multiple↗
Pathologic spectrum of malformations of the tricuspid valve in prenatal and neonatal life.
The morphologic spectrum of malformations of the tricuspid valve in 14 fetal and 5 neonatal heart specimens is described. Echocardiography during fetal life had revealed the valvular malformations along with dilation of the right-sided chambers of the heart and atrioventricular (AV) valve incompetence. This functional impairment reflected either Ebstein's malformation (10 cases) or dysplasia of valve leaflets having a normal junctional attachment (9 cases). The right atrium and right ventricle were markedly enlarged, and heart weight was increased to 181% (median) and 179% (median) in the groups with Ebstein's malformation and valvular dysplasia, respectively. In contrast, lung weight was in the lower range of normal, showing a decrease of 67% (median) in patients with Ebstein's malformation and of 43% (median) in those with valvular dysplasia. One ventricular septal defect and six atrial septal defects were noted in each group. Severe obstruction at the level of the pulmonary valve was seen in 40% of the group with Ebstein's malformation and in 66% of those with valvular dysplasia. The most important factor in the particularly poor prognosis in these patients is the incompetence of the tricuspid valve, leading to right atrial enlargement and subsequent pulmonary hypoplasia. No significant difference was found between the pathologic features of fetal and neonatal hearts and no features that might have prompted the valve to become regurgitant during fetal life were identified.
Abnormalities, Multiple↗
Fetal blood sampling and pregnancy loss in relation to indication.
OBJECTIVE: To assess the relation between the indication for fetal blood sampling and pregnancy loss following the procedure. DESIGN: Retrospective study. SETTING: The tertiary referral Fetal Medicine Units at Guy's and University College Hospitals, London. SUBJECTS: Women undergoing diagnostic fetal blood sampling in four groups: (1) 94 having prenatal diagnosis with normal ultrasound findings; (2) 94 with a structural fetal abnormality; (3) 30 having fetal assessment and (4) 35 with non-immune hydrops. INTERVENTIONS: Freehand ultrasound guided fetal blood sampling from umbilical cord, intrahepatic vein or fetal heart. MAIN OUTCOME MEASURES: Pregnancy losses were divided into those within 2 weeks and those 2 weeks after the procedure, obstetric accidents and neonatal deaths. RESULTS: The 253 patients had fetal blood sampled on 268 occasions. Fifty-one pregnancies were terminated. Overall, 51 of the remaining 202 desired continuing pregnancies were lost, of which 19 (9%) were lost within 2 weeks of the procedure. After exclusion of the pregnancies that were terminated, the procedure-related losses within 2 weeks of sampling were 1 in 76 (1%), 5 in 76 (7%), 4 in 29 (14%) and 9 in 36 (25%) in groups 1, 2, 3 and 4 respectively. CONCLUSIONS: The risk of fetal blood sampling is increased in abnormal pregnancies, reflecting the underlying pathology and this must be taken into account when counselling patients before the procedure.
Abortion, Spontaneous↗
Balloon dilatation of the aortic valve in the fetus: a report of two cases.
Because they had irreversible damage to the left ventricular myocardium none of 12 patients with critical aortic stenosis diagnosed prenatally survived after postnatal treatment. This experience prompted three attempts at intrauterine balloon dilatation of the aortic valve in two fetuses with this condition. On each attempt the balloon catheter was successfully delivered to the left ventricle. In the first fetus the aortic valve was not crossed and the fetus died the next day. In the second fetus the balloon was correctly positioned across the aortic valve and inflated in the valve ring. After delivery, a further balloon angioplasty was performed; this relieved the stenosis but the patient died five weeks later from persisting left ventricular dysfunction related to endocardial fibroelastosis. Balloon angioplasty is feasible in fetal life but the prognosis depends on the ability of the relief of stenosis to limit, prevent, or allow regression of left ventricular damage before delivery.
Adult↗
The assessment of persistent bradycardia in prenatal life.
Twelve patients with persistent fetal bradycardia were referred for echocardiographic assessment; in 10 patients the fetus had complete heart block, six isolated and four with associated structural heart disease. In the remaining two patients an atrial arrhythmia was producing a fetal sinus bradycardia. Complete heart block with structural heart disease has a poor prognosis. Isolated complete heart block has a good prognosis if the pregnancy is carefully managed. A sinus bradycardia due to atrial ectopic beats is a benign arrhythmia. Echocardiographic assessment of the heart can give an accurate prognosis in fetal bradycardia and provide a basis for appropriate obstetric management.
Arrhythmias, Cardiac↗