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Biomedical subjects

J M Connor

Publications and source records attributed to J M Connor.

At least 19 recordsLinked to original sources
PubMed1995

Expression and loss of heterozygosity of c-met proto-oncogene in primary breast cancer.

The c-met proto-oncogene encodes the receptor to hepatocyte growth factor-scatter factor (HGF-SF), a mesenchyme-derived cytokine with cell-dissociating, invasion, and angiogenic properties. The expression of c-met in breast cancer is the subject of controversy; 111 primary breast cancers were examined for LOH of c-met by Southern blot electrophoresis. c-met expression was measured in a further 40 patients with breast cancer and in 8 patients with benign breast disease by flow cytometry. LOH of c-met was detected in only 4% of informative breast cancers. Expression of c-met was significantly greater in patients with breast cancer than in those with benign breast disease (P < 0.01, Mann-Whitney). There was no correlation however between increased c-met expression and clinicopathological prognostic variables. These results do not support the role of c-met as a tumour suppressor gene in breast cancer but suggest increased receptor expression in malignant breast disease. The significance of this increased expression in breast cancer is the subject of further investigation.

Blotting, Southern↗
PubMed1995

Analysis of maternal serum alpha-fetoprotein and free beta human chorionic gonadotrophin in the first trimester: implications for Down's syndrome screening.

The aim of this study was to determine the maternal population, pregnancy, serum alpha-fetoprotein (AFP) and free beta subunit of human chorionic gonadotrophin (F beta hCG) parameters in a large series of women attending prenatal clinics before 15 weeks' gestation and to assess the practical problems of population screening for Down's syndrome in the first trimester using these markers. Serum samples were collected from 8600 women attending prenatal clinic booking visits. Maternal serum AFP and F beta hCG medians were calculated for each day of gestation (49-104 days), using both dates and ultrasound estimates of gestation. The effects of maternal weight, twin pregnancies, and threatened abortion on AFP and F beta hCG levels were analysed. The median age of the population was 27.1 years and the median weight 62.1 kg. Twenty-six per cent of samples were collected before 70 days and 50 per cent before 78 days' gestation. Eighty-nine per cent of all samples had gestational estimates by dates, 60 per cent by ultrasound and 52 per cent by both dates and ultrasound. The AFP median was 5 kU/l at 49 days, 5.9 kU/l at 70 days, and 17.9 kU/l at 100 days. The peak median F beta hCG level was 66.4 ng/ml at 64 days, falling to 20.6 ng/ml at 100 days' gestation. Both AFP and F beta hCG levels showed log Gaussian distributions but the standard deviation for AFP was 20 per cent greater than that found in the second trimester. AFP and F beta hCG levels showed an inverse relationship with maternal weight and were increased in twin pregnancies (1.68 and 1.97 multiples of the median, respectively). AFP and F beta hCG can be readily measured in a large screening population in the first trimester. Down's syndrome screening protocols based on these markers could be refined by the use of gestations in individual days but AFP is likely to be a less effective marker and detection rates are likely to be lower than in the second trimester. To realize the potential of first-trimester screening, more women should be encouraged to attend the prenatal clinic in early pregnancy and ultrasound dating should be carried out for all pregnancies at this stage.

Abortion, Threatened↗
PubMed1995

Detection of mutations in ectopic factor VIII transcripts from nine haemophilia A patients and the correlation with phenotype.

Haemophilia A is a common X-linked recessive disorder of bleeding caused by deleterious mutations in the gene for clotting factor VIII. The large size of the factor VIII gene, the high frequency of de novo mutations and its tissue-specific expression complicate the detection of mutations. We have used a combination of reverse transcription/polymerase chain reaction (RT-PCR) of ectopic factor VIII transcripts and PCR of genomic DNA to amplify the entire essential sequence of the factor VIII gene. Chemical mismatch cleavage analysis and direct sequencing have then be employed in order to facilitate a comprehensive search for mutations. In this report, we describe the characterisation of nine potentially pathogenic mutations, six of which are novel. The mutations include six single base substitutions (five missense, viz. D56E, V162M, G701D, A1834T and R1869I, and one nonsense, viz. R-5X), a single base deletion (5697delC), a gross deletion of exon 16 and one mRNA abnormality characteristic of the common intron-22-embedded F8A-mediated DNA inversion. In each case, a correlation of the genotype with the observed phenotype is presented. In order to evaluate the pathogenicity of the five missense mutations, we have analysed them for evolutionary sequence conservation and for their involvement with sequence motifs catalogued in the PROSITE database of protein sites and patterns. Analysis of the sequences in the immediate vicinity of the mutations has revealed sequence features that may have had a possible role in mutagenesis.

Amino Acid Sequence↗
PubMed1995

Thrombocytopenia with absent radii (TAR) syndrome: a new increased cellular radiosensitivity syndrome.

A 70-year-old woman with congenital absence of both radii but preservation of the thumb developed a marked pancytopenia after two i.v. injections of 1 g of 5-fluorouracil (5-FU) 1 week apart. She developed bloody diarrhoea after nine fractions of 2 Gy to parallel opposed 16 x 15 cm abdominal fields. This unusual response prompted an investigation of the radiosensitivity of the patient's cells by the sensitive G2 assay of transformed lymphocytes. The radiosensitivity of the patient's lymphoblastoid line appeared to be intermediate between that of normal individuals and an ataxia telangiectasia line. The clinical response and in vitro radiosensitivity testing suggest that the thrombocytopenia with absent radii (TAR) syndrome appears to be one of the inherited impaired DNA repair syndromes and is a very newly described radiation sensitivity syndrome. The development of three separate primary cancers in this patient (small bowel, ovary and bladder) suggests there is an increased risk of neoplasia in this condition.

Aged↗
PubMed1995

The SA gene: predisposition to hypertension and renal function in man.

1. The SA gene is expressed in the kidneys and is associated with hypertension in man and experimental animal models. Predisposition to hypertension is associated with renal haemodynamic abnormalities and increased renal SA gene expression. 2. We studied the distribution of the SA gene alleles (A1, A2), defined by the PstI polymorphism, in young adults with contrasting predisposition to hypertension to determine whether genetic variation at the SA gene locus is associated with variations in renal haemodynamics, electrolyte metabolism and the renin-angiotensin system. 3. The frequency of the A2 allele was not significantly different between subjects with high personal and parental blood pressures and subjects with low personal and parental blood pressures. We detected no overall relationship between blood pressures and SA genotype, even after taking sodium intake into account. 4. Glomerular filtration rate, renal blood flow, renal vascular resistance, plasma volume, exchangeable sodium and total body water did not differ according to SA genotypes. Moreover, we detected no significant effect of SA genotype on circulating components of the renin-angiotensin system or atrial natriuretic peptide. 5. In our population, genetic variation at the SA gene locus defined by PstI polymorphism does not influence the renal characteristics that contribute to the development of hypertension.

Adult↗
PubMed1994

Diagnosis in Prader-Willi syndrome.

Thirty one patients with the putative diagnosis of Prader-Willi syndrome were reassessed clinically and by DNA analysis. Eleven patients were judged not to have Prader-Willi syndrome and 20 to have the condition. This was confirmed by DNA analysis in all but one case. The diagnosis of Prader-Willi syndrome, especially in early infancy, should be made with caution unless confirmed by molecular genetic studies.

Adolescent↗
PubMed1994

Possible role of imprinting in the Turner phenotype.

We have attempted to investigate the role of imprinting in the phenotype of Turner's syndrome. Sixty-three patients were investigated for parental origin of the retained normal X chromosome; 43 were found to retain the maternal X (XM) and 20 the paternal (XP). The relationship between a child's pretreatment height centile and parental height centiles was examined in 36 patients. No significant correlation was found between child and parental height centiles for XP or child and paternal height centiles for XM (p > 0.05) but a strong correlation was found between child's height centile and maternal height centile (p < 0.01) for XM. Using pooled data from this and other studies there was no significant correlation with renal anomalies but a strong correlation between cardiovascular abnormalities and XM (0.01 > p > 0.001) and neck webbing and XM (p < 0.05). We conclude that imprinting may play a part in the Turner's syndrome phenotype, especially with respect to pretreatment height, cardiovascular anomalies, and neck webbing.

Female↗
PubMed1994

First trimester biochemical screening for trisomy 21: the role of free beta hCG, alpha fetoprotein and pregnancy associated plasma protein A.

The potential efficacy of screening for trisomy 21 in the first trimester, using maternal serum markers alpha fetoprotein, free beta human chorionic gonadotropin, unconjugated oestriol and pregnancy associated plasma protein A, was studied in an unselected population of women between the seventh and fourteenth week of gestation. Using a combination of alpha fetoprotein and free beta human chorionic gonadotropin, 53% of affected pregnancies could be identified at a false positive rate of 5%. Unconjugated oestriol and pregnancy associated plasma protein A levels were lower in cases of trisomy 21, but their inclusion with other markers did not significantly improve detection rate. Monitoring the same pregnancies also in the second trimester showed that screening in the first trimester identified the same cases as in the second. We conclude that first trimester screening using free beta human chorionic gonadotropin and alpha fetoprotein, is a viable possibility and will lead to detection rates in excess of 50%. Prospective studies are needed to confirm these observations.

Adolescent↗
PubMed1993

Second-trimester unconjugated oestriol levels in maternal serum from chromosomally abnormal pregnancies using an optimized assay.

Second-trimester unconjugated oestriol (UE3) levels were measured retrospectively in maternal serum from 78 chromosomally abnormal pregnancies and 390 matched controls using a radioimmunoassay kit (Amersham AMERLEX-M) optimized for use in the second trimester. Reduced levels of UE3 were found in a group of 49 Down's syndrome pregnancies with a median UE3 level of 0.79 multiples of the median (MOM) of the controls. Four trisomy 18 pregnancies had UE3 levels less than 0.7 MOM. There was a highly significant level of correlation between alpha-fetoprotein (AFP) and UE3 levels in the controls (r = 0.25, p < 0.01), the Down's syndrome pregnancies (r = 0.44, p < 0.01), and the other chromosome abnormalities (r = 0.61, p < 0.01). When used as an additional marker to AFP and human chorionic gonadotrophin in screening for Down's syndrome, UE3 does not appear to add to the sensitivity of such screening.

Chromosome Aberrations↗
PubMed1992

Tightly linked polymorphic markers for fragile X syndrome and prenatal cytogenetic diagnostic experience.

Linkage analysis using the polymorphic loci DXS369, DXS296, DXS297 and DXS306 was carried out on a cohort of 17 families segregating for fragile X syndrome. The observed recombination fractions at: DXS369 (Zmax = 3.02; theta = 0.06), DXS297 (Zmax = 2.92; theta = 0.0), DXS296 (Zmax = 3.82; theta = 0.0), DXA306 (Zmax = 4.55; theta = 0.05) confirm that these loci are tightly linked to FRAXA. Our experience in the cytogenetic analysis of 58 at risk pregnancies by chorionic villus or fetal blood sample examination documents a false negative rate in obligate carrier male pregnancies for CVS of 11% and for FBS of 3%.

Cytogenetics↗
PubMed1992

Fibrinogen genotype and risk of peripheral atherosclerosis.

There is conflicting evidence about the influence of fibrinogen genotype on plasma fibrinogen concentrations, and the relation between genotype and atherosclerotic disease has not been studied. In a population-based case-control study we aimed to find out whether certain fibrinogen genotypes are associated with an increased risk of peripheral atherosclerosis. 121 subjects with peripheral arterial disease and 126 healthy controls matched for age and sex were selected from a random population sample aged 55-74 years in the Edinburgh Artery Study. Mean fibrinogen concentrations were higher in cases than in controls (3.12 [95% confidence interval 2.99-3.26] vs 2.75 [2.64-2.85], p less than 0.001). A greater proportion of cases than controls were homozygous or heterozygous for an allele at the beta fibrinogen locus (4.2 kb allele, Bcl I digestion); the allele frequency was 0.197 in cases and 0.097 in controls (p less than 0.005). Extended haplotypes for 4.2 kb heterozygotes were also associated with an increased risk of peripheral arterial disease. However, haplotype had only a small effect on the association of plasma fibrinogen concentration with disease, and the relation of haplotype with disease was independent of age, sex, social class, smoking status, plasma fibrinogen, alcohol consumption, body mass index, and diabetes mellitus. We conclude that variation at the beta fibrinogen locus is associated with an increased risk of peripheral atherosclerosis. The influence is not mediated simply by way of increased fibrinogen concentrations but could be due to a structurally variant fibrinogen or linkage disequilibrium with a neighbouring gene.

Aged↗
PubMed1992

The psychosocial sequelae of a second-trimester termination of pregnancy for fetal abnormality.

A retrospective study to investigate the psychosocial sequelae of a second-trimester termination of pregnancy (TOP) for fetal abnormality (FA) is described. After appropriate consent was obtained, 84 women and 68 spouses were visited 2 years after the event and asked to complete an extensive questionnaire. Most couples reported a state of emotional turmoil after the TOP. There were differences in the way couples coped with this confusion of feelings. After 2 years about 20 per cent of the women still complained of regular bouts of crying, sadness, and irritability. Husbands reported increased listlessness, loss of concentration, and irritability for up to 12 months after the TOP. In the same period, there was increased marital disharmony in which 12 per cent of the couples separated for a while and one couple obtained a divorce. These problems could be attributed to a lack of synchrony in the grieving process. Confusing and conflicting feelings led to social isolation and lack of communication. Difficulties in coming to terms with the fetal loss were not found to be linked to the type of fetal abnormality or religious beliefs but were related to parental immaturity, inability to communicate needs, a deep-rooted lack of self-esteem before the pregnancy, lack of supporting relationships, and secondary infertility. Suggestions for improved management are given.

Abortion, Therapeutic↗
PubMed1992

Variation in the levels of pregnancy-specific beta-1-glycoprotein in maternal serum from chromosomally abnormal pregnancies.

Human pregnancy-specific beta-1-glycoprotein (SP1) was assayed retrospectively in stored maternal serum (MS) samples from 82 chromosomally abnormal pregnancies and 377 matched controls. The median MSSP1 concentration in 48 Down's syndrome pregnancies was significantly elevated at 1.17 multiples of the control median (MOM), and significantly reduced (0.5 MOM) in a group of eight cases of unbalanced translocations. There was no significant difference in median SP1 concentrations in cases of trisomy 18, trisomy 13, balanced translocations, or sex chromosome abnormalities. A comparison with human chorionic gonadotrophin results in the same series of samples indicates that SP1 is a less sensitive predictor of Down's syndrome pregnancies.

Chorionic Gonadotropin↗