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Biomedical subjects

D J Brock

Publications and source records attributed to D J Brock.

At least 19 recordsLinked to original sources
PubMed1992

Prenatal screening for cystic fibrosis.

Screening for carriers of CF (cystic fibrosis) is now possible but the best way of delivering such a service is unknown. In one model 4348 women attending antenatal clinics in an Edinburgh maternity hospital were invited to participate in a trial of prenatal screening. Mouthwash samples were tested for six CF alleles (85% of mutant genes) and when a woman was found to be a CF carrier her partner was also tested. Heterozygous couples were offered prenatal diagnosis. 609 (14%) women declined to enter the trial and another 574 (13%) were not screened, usually because of late booking. Among the remaining 3165 women there were 111 carriers of a CF gene (1 in 29). 4 of these 111 had carrier partners and these couples opted for prenatal diagnosis, the 1 pregnancy with an affected fetus being terminated. The psychological impact of screening was assessed by the general health questionnaire. There was a significant increase in stress at the time of the test result among women identified as carriers. However, this disappeared when their male partners tested normal and did not reappear later in the pregnancy. By providing time for couples to discuss the possibility of screening and by offering the test at a point (the antenatal booking clinic) at which most pregnant women are seen, this approach has advantages, provided that counselling is readily available.

Alleles↗
PubMed1992

Detection of Pseudomonas aeruginosa in sputum from cystic fibrosis patients by the polymerase chain reaction.

A DNA amplification procedure using heat stable Taq polymerase and the polymerase chain reaction is described for the detection of Pseudomonas aeruginosa in specimens from cystic fibrosis patients. A set of primers was selected on the basis of the nucleotide sequence of the algD gene encoding GDP mannose dehydrogenase, a major enzyme in the biosynthesis of alginate by P. aeruginosa. Using this set of primers in conjunction with the polymerase chain reaction, P. aeruginosa could be specifically detected, with a sensitivity approximating 10 bacteria, in sputum harbouring large numbers of other respiratory pathogens, including Staphylococcus aureus and Haemophilus influenzae. These results suggest that amplification of specific sequences within the algD gene by the polymerase chain reaction may provide a highly sensitive and specific tool for the detection of P. aeruginosa in the early stages of pulmonary colonization.

Base Sequence↗
PubMed1992

Mutation in codon 713 of the beta amyloid precursor protein gene presenting with schizophrenia.

Following reports of mutations of codon 717 in exon 17 of the amyloid precursor protein (APP) gene in early-onset familial Alzheimer's disease, we screened exon 17 for new mutations in presenile dementia. The majority of the 105 patients screened had definite or probable Alzheimer's disease, but we also included atypical cases and some chronic schizophrenics. We identified a single abnormal case--a chronic schizophrenic with cognitive defects. Sequencing revealed a C to T nucleotide substitution which produces an alanine to valine change at codon 713. We were unable to detect the mutation in the remaining members of the original cohort nor in a further 100 chronic schizophrenics and 100 non-demented controls. Nonetheless, the position of the mutation in a critical portion of the APP gene suggests that it may well prove to be pathogenic.

Amino Acid Sequence↗
PubMed1992

Increased energy expenditure in cystic fibrosis is associated with specific mutations.

1. Measurements of resting metabolic rate were made by open-circuit indirect calorimetry in 78 unrelated cystic fibrosis patients and 30 healthy control subjects. The aims of this study were: (i) to determine the range of variability in resting metabolic rate in cystic fibrosis, (ii) to relate this to pulmonary function and body size, and (iii) to investigate the hypothesis that, in cystic fibrosis, genotype exerts a significant influence on energy requirements. 2. There was no significant difference in age or body weight between patients with cystic fibrosis and control subjects. Resting metabolic rates for control subjects fell within +/- 10% of predicted values. Fifty-nine per cent of patients with cystic fibrosis had elevated resting metabolic rates (i.e. greater than 111% of predicted). Genotype analysis divided the patients with cystic fibrosis into three groups: delta F508 homozygotes, delta F508 heterozygotes and others. Patients homozygous for the delta F508 allele had a significantly higher resting metabolic rate (121% of predicted, 95% confidence interval 116-126%), compared with other genotypes (P less than 0.005). 3. There were significant differences in pulmonary function between the groups (P less than 0.005). However, after adjustment of individual resting metabolic rates for differences in pulmonary function by using analysis of covariance, resting metabolic rates remained significantly higher for delta F508 homozygotes than for other genotypes (P less than 0.05). 4. We conclude that there is a significant contribution to resting metabolic rate in cystic fibrosis associated with specific mutations that is not explained by declining pulmonary function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation.

We have used the chemical cleavage mismatch technique to screen for mutations in the cystic fibrosis gene. Analysis of exons 10 and 11 in the first nucleotide binding fold led to the detection of several described mutations and two novel mutations, V520F and C524X. V520F results from a G-->T nucleotide substitution changing a valine to a phenylalanine residue, while C524X (a nonsense mutation), results from a C-->A transversion. A third novel mutation, Q1291H (G-->C), at the last nucleotide of exon 20, would substitute a histidine residue for glutamine. Further study, involving RNA based PCR, revealed that Q1291H was also a splice mutation. Both correctly and aberrantly spliced mRNAs are produced from the Q1291H allele. The incorrectly spliced product results from the use of a nearby cryptic splice site 29 bases into the adjacent intron.

Adult↗
PubMed1992

Molecular screening of partners of cystic fibrosis heterozygotes.

We have screened 100 partners of known or suspected CF heterozygotes for ten CF mutations which account for 88% of the CF mutations seen by us on CF chromosomes. We have identified six CF heterozygotes amongst the 100 low-risk people screened. As two of the six people at high-risk of being CF carriers were subsequently shown not to be CF carriers this gave rise to four couples with a one in four risk of CF in a pregnancy and so far to two PND's. The risk of CF in the remaining 94 couples was reduced to less than one in 800. We have concentrated on the screening of partners for the commoner CF mutations rather than haplotyping them for the CF linked markers XV-2c/TaqI and KM19/PstI which are in linkage disequilibrium with CF. For individuals shown not to carry these ten mutations, a five fold difference in risk of being a CF carrier remains between those who have the XV-2c/KM19 genotypes associated with the highest risk(BB), as compared to those with the lowest risk(CC). Nevertheless we feel that effort is better expended in mutation screening rather than haplotyping.

Chorionic Villi Sampling↗
PubMed1992

Cystic fibrosis patients bearing both the common missense mutation Gly----Asp at codon 551 and the delta F508 mutation are clinically indistinguishable from delta F508 homozygotes, except for decreased risk of meconium ileus.

The glycine-to-aspartic acid missense mutation at codon 551 (G551D), which is within the first nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator (CFTR), is the third most common cystic fibrosis (CF) mutation, with a worldwide frequency of 3.1% among CF chromosomes. Regions with a high frequency correspond to areas with large populations of Celtic descent. To determine whether G551D confers a different phenotype than does delta F508, the most common CF mutation, we studied 79 compound heterozygotes for G551D/delta F508, from nine centers in Europe and North America. Each subject was matched, by age and sex, with a delta F508 homozygote from the same center. A retrospective cohort analysis was performed on the following outcome parameters: age at diagnosis, sweat chloride, meconium ileus at birth, height, weight, weight for height, FVC, FEV1, chest X-ray score, pseudomonas colonization, pancreatic sufficiency, and Shwachman clinical score. There was less meconium ileus among the G551D/delta F508 compound heterozygotes (relative risk 0.33; 95% confidence interval .13-.86), as well as a trend toward later age at diagnosis of pancreatic insufficiency. No statistically significant difference was found between the groups for any other parameter. These results suggest that the CF genotype can be a predictor of pancreatic and intestinal phenotype. Prenatal counseling for the two genotype groups should differ only with respect to probability of meconium ileus. Clinical outcome (after survival of meconium ileus) for G551D/delta F508 compound heterozygotes and delta F508 homozygotes is indistinguishable; therefore, prognostic counseling should not differ.

Adolescent↗
PubMed1992

An exclusion map for pre-eclampsia: assuming autosomal recessive inheritance.

Pre-eclampsia is a common complication of the second half of pregnancy that is associated with substantial fetal and maternal morbidity. Although the genetic basis of the disorder is unclear, epidemiological studies suggest that it occurs predominantly in the first pregnancies of women who are homozygous for a relatively common susceptibility gene. Using this epidemiological model, we have begun to construct an exclusion map by using both candidate genes and random DNA markers on a panel of two-generation families in which pre-eclampsia was rigorously defined. No evidence was found for linkage to the HLA region or to several genes implicated in the pathogenesis of hypertension.

Chromosomes, Human, Pair 1↗
PubMed1979

Significance of elevated mid-trimester maternal plasma-alpha-fetoprotein values.

In a prospective trial of 15,481 pregnancies, 667 women (4.3%) had two sequential mid-trimester plasma-alpha-fetoprotein (A.F.P.) values above 2 times the median. The outcome of these pregnancies was open neural-tube defect (12.4%), birthweight less than 2.5 kg (10.3%), twins (9.8%), fetal wastage (9.5%), perinatal death (2.6%), other (1.3%), and "normal" singleton (54.1%). At higher A.F.P. cutoffs the proportion of "normal" singleton pregnancies declined rapidly, being 19% at 3 times the median and 9% at 4 times the median. If it is assumed that ultrasonography and amniotic-fluid A.F.P. assay can detect twins and most cases of neural-tube defect, the outcome of the residual pregnancies is still strongly influenced by plasma-A.F.P. level. Thus at a cut-off of 4 times the median two-thirds of the pregnancies in this residual group will end in spontaneous abortion, stillbirth, or neonatal death. It is suggested that counselling of women taking part in A.F.P. screening programmes should be strongly influenced by maternal plasma-A.F.P. levels, even if ultrasonographic findings and amniotic-fluid levels are normal.

Birth Weight↗
PubMed1979

The relation between maternal plasma alpha-fetoprotein and birth weight in twin pregnancies.

In the course of routine screening for neural tube defects, maternal plasma alpha-fetoprotein (AFP) was measured between 15 and 23 weeks of gestation in 64 twin pregnancies. Women with AFP levels more than twice the median for singleton pregnancies gave birth to infants with significantly decreased birth weights. Women with AFP less than the median also tended to produce twins with decreased birth weights. The distribution of gestations at delivery suggested that in twin pregnancies low AFP values gave an early warning of growth retardation while high values signal possible premature delivery.

Birth Weight↗
PubMed1978

Amniotic fluid cell morphology in early antenatal prediction of abortion and low birth weight.

The morphology of rapidly adherent (RA) amniotic fluid cells was examined in 201 pregnant women referred for amniocentesis because of two sequential high serum alpha-fetoprotein (AFP) concentrations. Out of 43 amniotic fluid samples containing increased amounts of AFP, 42 had neural or peritoneal cells predominating among the RA cells, the outcome being an infant with a neural-tube defect or exomphalos. In the other case with a raised amniotic fluid AFP concentration but only anterior placental cells the infant was normal. In 25 amniotic fluid samples containing normal amounts of AFP distinctive new patterns of RA cells were observed, termed fetal distress cells. These pregnancies resulted in five spontaneous abortions and 20 infants with birth weights under 2500 g. Fetal distress cells were not detected in any of the remaining 133 samples. One pregnancy was terminated because of a chromosomal abnormality, and there were seven twin pairs not recognised on ultrasonography before amniocentesis. The remaining 125 pregnancies went to term, resulting in infants with birth weights exceeding 2500 g. The results suggest that RA-cell morphology will prove to be of value in the early antenatal prediction of spontaneous abortion and low birth weight.

Abortion, Spontaneous↗