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Biomedical subjects

F Douglas

Publications and source records attributed to F Douglas.

At least 19 recordsLinked to original sources
PubMed2004

A randomised comparison of UK genetic risk counselling services for familial cancer: psychosocial outcomes.

The aim of the study was to compare psychosocial outcomes for 50 new clinic attendees, referred for cancer genetic counselling to five UK centres. The centres represented England, Scotland and Wales, and were randomly selected from groups ranked by different levels of clinical activity in cancer genetics practice. Questionnaires assessed demographic data, risk perception, mental health and use of health services pre-consultation and at 1 and 12 months follow-up. Satisfaction was measured for attendees and referring doctors at follow-up. A total of 256 unaffected adults fulfilled the study criteria. The five centres varied widely with respect to service organisation and activity, but all had a greater proportion of unaffected attendees with a breast cancer risk (61-91%) than either a bowel cancer risk (0-33%) or ovarian cancer risk (3-25%). There were no significant differences in the psychosocial data between centres pre-counselling. No significant change over time occurred for any of the centres for risk perception or general psychological distress. There were significant differences between centres in reduction of cancer worry from baseline to 12 months and with the number of women who were recommended to have mammographic surveillance who had not received this. Overall, one-third of women for whom mammography had been recommended had not been screened within 1 year of follow-up. Subsequent attendance at the GP, but not at a hospital, was associated with risk level, but differences between centres could not be analysed. Satisfaction differed significantly between centres for 4 : 14 aspects of service provision and with 3 : 17 items concerning communication; satisfaction was high overall. Over 90% of referring doctors were moderately/very satisfied with the service, but 23% were dissatisfied with waiting times and 19% with access to preventive treatment. Results differed significantly between centres for doctor's satisfaction with the provision of referral criteria and prescribing information. In conclusion, there were relatively few significant differences in psychosocial outcomes between centres, considering the wide variation in service organisation and activity. These significant differences were not consistent across the centres, therefore, differences could not be linked to specific aspects of service provision.

Adult↗
PubMed2003

What motivates interest in attending a familial cancer genetics clinic?

The motivation of people who seek advice about a family history of cancer was explored in a cross sectional study of new cancer referrals to five regional cancer genetics centres in England: the PACT (patient and clinical team) psychosocial study. One hundred sixty-two people took part. Measures were source of referral, estimated and perceived cancer risk, level of cancer worry, and personal and family-centred reasons for wanting to be seen in clinic. General practitioners referred more people than hospital doctors, and referred a larger proportion of people at low genetic risk of developing cancer. More than half of the participants had been the first to raise the issue of their family history of cancer. Personal motivation for referral is clearly different for those who have had a diagnosis of cancer and for those with children, compared to unaffected and childless people, and is characterised by altruistic concern for other family members rather than a perception of increased personal risk. Men and people from ethnic minorities are very significantly under-represented. Understanding people's motivation may be useful in targeting genetic counselling for people with a family history of cancer.

Adult↗
PubMed2002

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS).

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS) is in progress. The study design, accrual to date, and related research projects are described. Revised accrual rates and expected recruitment are given. 15 cancers have been detected to date, from a total of 1236 screening measurements. This event rate and the tumour grades reported are compared with recent reports from other studies in women at high risk of breast cancer.

Adult↗
PubMed2001

A descriptive study of UK cancer genetics services: an emerging clinical response to the new genetics.

The objective was to describe NHS cancer genetic counselling services and compare UK regions. The study design was a cross-sectional study over 4 weeks and attendee survey. The setting was 22 of the 24 regional cancer genetics services in the UK NHS. Participants were individuals aged over 18 attending clinics at these services. Outcome measures were staff levels, referral rates, consultation rates, follow-up plans, waiting time. There were only 11 dedicated cancer geneticists across the 22 centres. Referrals were mainly concerned with breast (63%), bowel (18%) and ovarian (12%) cancers. Only 7% of referrals were for men and 3% were for individuals from ethnic minorities. Referral rates varied from 76 to 410 per million per annum across the regions. Median waiting time for an initial appointment was 19 weeks, ranging across regions from 4 to 53 weeks. Individuals at population-level genetic risk accounted for 27% of consultations (range 0%, 58%). Shortfalls in cancer genetics staff and in the provision of genetic testing and cancer surveillance have resulted in large regional variations in access to care. Initiatives to disseminate referral and management guidelines to cancer units and primary care should be adequately resourced so that clinical genetics teams can focus on the genetic testing and management of high-risk families.

Genetic Counseling↗
PubMed2001

Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.

The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.

Amino Acid Sequence↗
PubMed2001

Germline SDHD mutation in familial phaeochromocytoma.

The genetic basis for familial phaeochromocytoma is unknown in many cases. Since the disorder has been reported in some cases of familial head and neck paraganglioma, which is caused by a mutation in the gene encoding succinate dehydrogenase complex subunit D (SDHD), we investigated this gene in kindreds with familial phaeochromocytoma. A germline SDHD frameshift mutation was identified in a two-generation family consisting of four children with phaeochromocytoma, but somatic mutations were not detected in 24 sporadic phaeochromocytoma tumours. Germline SDHD mutation analysis should be done in individuals with familial, multiple, or early-onset phaeochromocytomas even if a personal or family history of head and neck paraganglioma is absent.

Adolescent↗
PubMed1998

Neurofibromatosis pseudogene amplification underlies euchromatic cytogenetic duplications and triplications of proximal 15q.

Cytogenetically visible interstitial duplications of proximal 15q, which lack the Prader-Willi Angelman critical region (PWACR) frequently segregate in families without phenotypic effect, but the nature of the extra euchromatin has remained unclear. We used comparative genome hybridisation to confirm that the extra material in a cytogenetic triplication originated from proximal 15q. A PAC clone containing sequences specific for the type-1 neurofibromatosis (NF-1) pseudogenes, which map to 15q11.2, hybridised along the length of the enlarged region between the PWACR and the centromere. Computerised measurement of the fluorescent signal from the enlarged and normal chromosomes gave an average ratio of 9.85:1, consistent with amplification. In a second family, an amplified P1-4 signal co-segregated with a cytogenetic duplication and the average ratio between amplified and normal signals in the proband was 8.22:1. Ratios in noncarrier family members and control individuals were close to unity in most cases, but significantly greater than one in at least one instance. Our results provide a novel explanation for cytogenetic variation in 15q11.2. They also suggest that NF-1 pseudogene copy number may be polymorphic in the normal population, and that high copy numbers can produce G bands which do not reflect those of the normal constitutional karyotype.

Adolescent↗
PubMed1998

Autosomal dominant juvenile recurrent parotitis.

Juvenile recurrent parotitis is a common cause of inflammatory salivary gland swelling in children. A variety of aetiological factors has been proposed for the condition. Here we present a family where four members had juvenile recurrent parotitis and where two other family members may have had an atypical form of the condition. The segregation pattern in the family is consistent with autosomal dominant inheritance with incomplete penetrance and this suggests that, at least in some cases, genetic factors may be implicated in juvenile recurrent parotitis.

Child↗
PubMed1994

Topoisomerase I and II activity in human breast, cervix, lung and colon cancer.

The identification of human DNA topoisomerases as cellular targets for active anti-cancer drugs has stimulated further interest in topoisomerase function in tumour biology. Topoisomerase I and II catalytic activity is detectable in many normal and malignant tissues. However, little is known about the expression of topoisomerases in most human solid tumours. The present study evaluated topoisomerase I and II activity in biopsy samples from 86 patients with breast, lung, cervix or colon cancers. Significant intra- and inter-tumour variation in topoisomerase expression was observed. Topoisomerase I activity was relatively high in cervix and colon tumours in comparison to lung and breast cancers. Topoisomerase II activity was high in cervix, colon and lung cancers relative to breast cancer. Topoisomerase I and II activity co-segregated in individual colon tumour samples, but no correlation was observed in cervix, lung or breast tumours. The large heterogeneity in both topoisomerase I and II activity within a tumour type suggests a mechanism for variable response to topoisomerase-directed therapy. The differences in activity between tumour groups suggest that the potential efficacy of inhibitors of topoisomerase I in colon and cervical tumours may be greater than in lung and breast tumours. Future in vivo evaluation is required to establish the clinical relevance of the observed heterogeneity in topoisomerase activity.

Breast Neoplasms↗
PubMed1993

Co-amplification of erbB2, topoisomerase II alpha and retinoic acid receptor alpha genes in breast cancer and allelic loss at topoisomerase I on chromosome 20.

The DNA topoisomerase enzymes are targets for the cytotoxic effects of a number of anticancer agents termed topoisomerase inhibitors. We have analysed breast cancer biopsy specimens for genetic alterations at and around topoisomerase loci in order to obtain molecular insight into factors which may determine how tumours respond to chemotherapy. We show that of 50 tumours examined, the topoisomerase II alpha locus is co-amplified in 3 cases out of 6 with erbB2 amplification and that amplification can be accompanied by high expression of topoisomerase II alpha. In our attempts to distinguish amplification from aneuploidy and define the limits of amplification, we also observed co-amplification of the retinoic acid-alpha receptor with erbB2 and topoisomerase II alpha in the same three samples. At the topoisomerase I locus on chromosome 20, we observed allelic loss in two out of 17 samples. Genetics abberations at topoisomerase loci, therefore, appear to be relatively common in breast cancer.

Aged↗
PubMed1990

MRI evaluation of left ventricular hypertrophy in a canine model of aortic stenosis.

The progression of ventricular myocardial mass in nine puppies with experimental left ventricular hypertrophy and three controls was observed over a period of 7 months using magnetic resonance imaging (MRI). Left ventricular hypertrophy was created by surgically induced aortic stenosis when the puppies were 1 month old. Quantification of the progression of the left ventricular mass due to aortic stenosis as compared to the controls of similar age was then performed during the subsequent 7 months. Cardiac gated spin-echo technique was used for the imaging of the heart. Novel edge detection techniques were applied for automated identification of the border of the myocardium for measurement. Methods for correction of partial volume effect were applied in the analysis of the data. Clear-cut differences in myocardial mass (P less than .001) and in radius-to-wall thickness ratio (r/h, P less than .02) between puppies with aortic stenosis and controls were observed. The differences in end-diastolic volume between the two groups, however, were significant during the initial phase of hypertrophic compensation (P less than .001) and insignificant (P greater than .05) during the long-term phase of hypertrophic compensation. The results demonstrated that MRI is applicable in serial assessment of myocardial hypertrophy.

Animals↗
PubMed1989

Identification of a cysteine residue at the active site of Escherichia coli isocitrate lyase.

Escherichia coli isocitrate lyase was inactivated by iodacetate in a pseudo-first-order process. Complete inactivation was associated with the incorporation of only one carboxymethyl group per enzyme subunit. The substrate and products of the enzyme protected against inactivation, suggesting that the reactive group may be located at the active site. Isolation and sequencing of a carboxymethylated peptide showed that the modified residue was a cysteine, in the sequence Cys-Gly-His-Met-Gly-Gly-Lys. The reactivity of isocitrate lyase to iodoacetate declined with pH, following a titration curve for a group of pKa 7.1. The Km of the enzyme for isocritrate declined over the same pH range.

Amino Acid Sequence↗
PubMed1989

Inhibition of cholera-toxin-stimulated intestinal secretion by CGS 9343B in rats: a specific calmodulin inhibitor.

In this study, the effect of CGS 9343B on cholera-toxin-stimulated intestinal secretion in rats was determined using in vivo isolated loops. This recently developed compound is a potent and specific inhibitor of calmodulin, but not of protein kinase C. At a luminal dose of 15 mg/kg, CGS 9343B has little effect on basal intestinal absorption but completely inhibited the secretory effects of cholera toxin. The less specific calmodulin inhibitor, trifluoperazine, has a similar antisecretory effect, but unlike with CGS 9343B, severe toxicity was noted at luminal doses of 7.5 mg/kg. In animals where two intestinal loops were created, one with cholera toxin alone and the other with CGS 9343B and cholera toxin, significant inhibition of secretion was observed in both loops, consistent with a systemic effect of this compound. Finally, both CGS 9343B and trifluoperazine inhibited choleratoxin stimulated increases in mucosal cyclic AMP content, whereas basal levels were unaffected. We conclude that CGS 9343B significantly inhibits choleratoxin-stimulated intestinal secretions, possibly by inhibition of calmodulin-dependent adenylate cyclase activity. Its lack of major toxicity at therapeutic doses makes this compound potentially useful for the treatment of enterotoxigenic diarrheal diseases.

Animals↗