Biomedical subjects

D Ford

Publications and source records attributed to D Ford.

At least 55 records · Page 3Linked to original sources

PubMed1996

Requirements for induction of vitamin D-mediated gene regulation in normal human B lymphocytes.

Mature human lymphocytes are unique targets of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) in that vitamin D receptors (VDR) are not constitutively expressed, and specific cellular activation signals are required for both the up-regulation of VDR and establishment of reactivity to the lipophilic ligand. Treatment of B lymphocytes with the cytokine IL-4 (IL-4), in the absence of prior activation, induces a weak up-regulation of VDR expression but fails to generate vitamin D-responsive element (VDRE)-reactive nuclear protein complexes or to initiate the genomic transcription of 25-hydroxyvitamin D3 24-hydroxylase. Stimulation of B lymphocytes by either ligation of CD40 Ag or cross-linking the Ig receptor is also insufficient to render B lymphocytes responsive to 1 alpha,25(OH)2D3. However, this apparent lack of response to the secosterol can be overcome by stimulation of B lymphocytes with a combination of these cellular activation signals, which are sufficient to lead to G1 cell cycle progression. In the presence of 1 alpha,25(OH)2D3, cellular activation associated with stimulation of such a progression appears to be sufficient for the up-regulation of VDR message and protein and necessary for the establishment of VDRE binding complexes and the induction of 24-hydroxylase message. Furthermore, biologic functions are modulated, in that the hormone inhibits proliferation in a subset of the activated B cells. These observations suggest that reactivity to 1 alpha,25(OH)2D3 is tightly regulated in B lymphocytes, requiring specific signals for its initiation.

B-Lymphocytes↗

PubMed1996

Cancer mortality in relatives of women with breast cancer: the OPCS Study. Office of Population Censuses and Surveys.

Mortality from cancer and other causes in male and female first-degree relatives of women with breast cancer diagnosed before age 60 has been examined in a large population-based cohort study, providing estimates of familial risks free from ascertainment or recall bias. Relatives of 3,295 patients with breast cancer diagnosed in the UK between 1954 and 1981 were identified through a register of households established in 1939. The 11,678 first-degree relatives thus identified were followed up through national records until the end of 1992. Over this period 5,421 deaths (including 1,527 cancer deaths) occurred in these relatives. Mortality from breast cancer was significantly raised in first-degree relatives (SMR 187, 248 deaths), and there was also significant excess mortality from cancers of the larynx (SMR 177, 17 deaths), endometrium (SMR 166, 29 deaths) and unspecified neoplasms (SMR 153, 70 deaths). The SMR for ovarian cancer was 130, based on 58 deaths (p = 0.06). There was no marked excess for other sites or for non-neoplastic causes of death, but there was a significant deficit in mortality from cervical cancer (SMR 63, 18 deaths). The SMR for breast cancer increased significantly with decreasing age of the relative. After allowing for age, sisters of cases had a slightly (though non-significantly) higher risk than mothers (ratio of SMRs 1.22). These results, together with penetrance estimates from linked families, suggest that approximately one woman in 800 carries BRCAI, the susceptibility gene on chromosome 17q, and that this gene causes about 1% of all breast cancers.

Adult↗

PubMed1996

Cancer mortality in relatives of women with ovarian cancer: the OPCS Study. Office of Population Censuses and Surveys.

Mortality from cancer and other causes in first-degree relatives of women with ovarian cancer diagnosed before age 60 has been examined in a large population-based cohort study in England and Wales. Relatives of 1,188 ovarian-cancer cases diagnosed between 1954 and 1981 were identified through a register of households established in 1939. Some 4,111 first-degree relatives living in the same household and having the same surname as the index case were followed up through national records until the end of 1992. Over this period, 1,950 deaths (including 574 cancer deaths) occurred in the relatives. Mortality rates within the cohort were compared with age-, sex- and period-adjusted mortality rates for England and Wales. Mortality from ovarian cancer in first-degree relatives was significantly raised (SMR 223, 95% CI 155-310) although the excess was smaller than that found in case-control studies. The SMR increased with decreasing age of the relative, though not with decreasing age of the index case. After allowing for age, sisters of cases had higher ovarian-cancer mortality than mothers (sister:mother SMR ratio 1.89, p = 0.06). The SMR was greater in individuals having 2 first-degree relatives with ovarian cancer (4 deaths versus 0.17 expected, SMR 242). Relatives of ovarian cancer cases also had significantly increased mortality from cancers of the stomach (SMR 146, 69 deaths) and rectum (SMR 150, 33 deaths), and increased mortality from colon cancer, breast cancer and pancreatic cancer which failed to reach statistical significance. Individuals having a relative with colorectal cancer and a relative with ovarian cancer showed a high mortality from both cancers (11 colorectal-cancer deaths versus 1.23 expected, 4 ovarian-cancer deaths versus 0.66 expected.

Adult↗

PubMed1996

HIV-1 survival kinetics in peritoneal dialysis effluent.

Viable and potentially infectious HIV-1 has been recovered from the peritoneal dialysis effluent (PDE) of patients with end-stage renal disease (ESRD) who are infected with the human immunodeficiency virus (HIV). No information had previously been available as to how long HIV-1 could survive in this environment, and no data were available as to how long HIV-1 could survive on peritoneal dialysis exchange tubing (PDET). Therefore, this study was designed to answer these questions. HIV-1 Mn was added to PDE and allowed to incubate at room temperature for 0 to 14 days. Following centrifugation, the cellular component of the PDE mixture was placed in co-culture with peripheral blood mononuclear cells (PBMC) from HIV negative donors. Aliquots from the co-cultures were removed after 14 days and assayed for the HIV-1-P24 antigen. High levels of HIV P24 antigen were recovered up to and including seven days of room temperature incubation. HIV could not be recovered from PDE that had been incubated at room temperature for 10 to 14 days. Ten milliters of HIV-PDE mixture was placed within PDET and incubated at room temperature for 10 minutes. The solution was then removed by gravity drainage. After drying times of 0 to 168 hours, the tubing was flushed with HIV culture medium and placed in co-culture with PBMCs from HIV negative donors. The culture supernatant was assayed for the HIV-1 P24 antigen as a marker of viral replication. High levels of HIV-1 P24 antigen were recovered from the PDET wash for up to and including 48 hours of drying time. No viable virus could be detected for drying times of between 72 and 168 hours. To determine if common disinfectants found in the dialysis unit could inactivate HIV, dilutions of Amukin 50% and household bleach were prepared at final concentrations ranging from 1:32 to 1:2048. These disinfectant solutions were incubated with PDE containing HIV for 10 minutes. The cellular fraction of the PDE was isolated by centrifugation, washed, and placed in co-cultures with peripheral blood mononuclear cells. HIV P24 antigen levels were assayed every three days for 28 days. Amukin 50% and a 10% household bleach solution were effective in killing HIV in PDE at dilutions up to and including 1:512. These results indicate that HIV can survive in PDE at room temperature for up to seven days. HIV can survive on peritoneal dialysis exchange tubing for up to 48 hours. Final dilutions of 1:512 Amukin 50% and 10% household bleach, after 10 minutes of exposure, are effective viricidal agents in disinfecting PDE.

Culture Media↗

PubMed1996

Genetics of coeliac disease.

Coeliac disease is one of the most common gastrointestinal disorders. The clinical features of the disease are protean, possibly due to heterogeneity. A familial basis for coeliac disease is well recognized, and although a strong HLA association is seen, this cannot entirely account for the increased risk seen in relatives of affected cases. A gene (or genes) at an HLA-unlinked locus also participates in causing coeliac disease and is likely to be a stronger determinant of disease susceptibility than the HLA locus. Such a gene (or genes) could theoretically act either additively or multiplicatively in conjunction with HLA. However, the familial risks seen in siblings and monozygotic twins are most parsimonious with a multiplicative model. Without evidence for a particular HLA-unlinked gene, and because no genetic model can be reliably ascribed to the non-HLA-linked locus, identifying causative non-linked HLA genes is likely to be through a genome-wide linkage search using non-parametric methods.

Celiac Disease↗

PubMed1996

A method for determining familial cancer risks in clinical practice.

There is interest in estimating familial cancer risks in clinical practice for counselling and determining patients' screening requirements. Empiric methods can be used to estimate an individual's risk, however, every family history is unique making such methods relatively non-specific. In contrast if an underlying genetic model can be assumed the risk of disease can be calculated for any individual using his or her family history. A method of estimating familial cancer risks based on segregation models and linkage data is presented and its implementation discussed.

Genetic Linkage↗

PubMed1996

Physician leadership. How do physician executives view themselves?

Most physician executives today have acquired substantial management training and experience, and many have worked with and relied on the expertise of mentors for their career guidance and development. Physician executives are actually becoming executives who happen to be physicians. They view themselves first as leaders, then as physicians, and finally as managers. That is a remarkable transformation in perception. To chronicle this process, Witt/Kieffer, Ford, Hadelman & Lloyd conducted a national survey this spring among senior physician executives in both payer and provider organizations. The data provide a "snapshot" of their role, and may also suggest some future scenarios for the industry. The primary reasons for choosing to pursue a management role noted by most participants include a desire to be part of the health care solution and an interest in management and leadership challenges.

Altruism↗

PubMed1996

Analysis of the contribution of HLA genes to genetic predisposition in inflammatory bowel disease.

Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology. First-degree relatives of IBD patients have a 10-fold increase in risk of developing the same disease, and distinct associations between specific HLA types and both CD and UC have been reported. We have evaluated the contribution of genes at the HLA locus to susceptibility in IBD by linkage analysis of highly informative microsatellite polymorphisms in 43 families with multiple affected cases. No evidence for linkage of HLA to IBD was obtained under any of the four models tested. Analysis of HLA haplotype sharing in affected relatives indicated that the relative risk to a sibling conferred by the HLA locus was 1.11 in UC and 0.75 in CD, with upper (95%) confidence limits of 2.41 and 1.37, respectively. This suggests that other genetic or environmental factors are responsible for most of the familial aggregation in IBD.

Colitis, Ulcerative↗

PubMed1996

Changing fertility patterns, 1974 to 1994.

From 1974 to 1994, the number of children Canadian women are likely to have during their lifetime decreased. This downturn in fertility meant that the annual number of live births rose only slightly during this period, even though it marked the prime childbearing years for the baby-boom generation. As they pursued higher education and employment in the paid workforce, women have postponed childbearing. Consequently, the average age of women giving birth has risen. More than a quarter of women over age 30 who have a baby are first-time mothers. And by starting families later in life, women tend to have fewer children. In addition, largely because of the growing number of common-law relationships, over a quarter of all births are to unmarried women. Using data provided by the provincial and territorial Vital Statistics Registries, this article examines national and provincial/territorial trends in births and fertility from 1974 to 1994.

Adolescent↗

PubMed1995

Risk of cutaneous melanoma associated with pigmentation characteristics and freckling: systematic overview of 10 case-control studies. The International Melanoma Analysis Group (IMAGE).

Using individual subject data from 10 case-control studies, comprising over 3000 cases and almost 4000 controls, we have estimated the relative risk of melanoma associated with aspects of complexion, namely, hair, eye and skin colour and freckling in adulthood, and have examined the relationships between these factors and naevus count in terms of melanoma risk. Compared with individuals with black or dark brown hair, the relative risks for developing melanoma in those with light brown, blonde and red hair were 1.49 (95% CI 1.31, 1.70), 1.84 (95% CI 1.54, 2.21) and 2.38 (95% CI 1.90, 2.97), respectively. Individuals with blue eyes had a risk 1.55 (95% CI 1.35, 1.78) times that for those with brown eyes, or 1.15 (95% CI 0.94, 1.40) after adjusting for hair colour and freckling in adulthood. The relative risks associated with hair and eye colour were independent of those for naevus count and skin colour. Light skin colour and high freckle density were also highly significant risk factors, independent of each other and of naevus count and hair and eye colour. The risks associated with these factors, while individually modest, are largely independent, and thus pigmentation characteristics and freckling tendency should be useful in identifying high risk groups to be targeted for prevention.

Case-Control Studies↗

PubMed1995

Risk of cutaneous melanoma associated with a family history of the disease. The International Melanoma Analysis Group (IMAGE).

In a combined analysis of 2952 melanoma patients and 3618 controls from 8 case-control studies in white populations the risk of cutaneous melanoma was 2.24-fold higher (95% CI, 1.76-2.86) in subjects who reported at least one affected first-degree relative than in subjects who did not. There was no evidence for heterogeneity in the relative risk between the studies, which were from a wide range of latitudes and hence degrees of sun exposure. The effect of family history on melanoma risk was independent of age, naevus count, hair and eye colour, and freckling. There was no evidence for a relationship between family history and primary site of melanoma but there was some suggestion that the familial patients were more likely to have superficial spreading melanoma or lentigo maligna melanoma than acral lentiginous melanoma or nodular melanoma.

Case-Control Studies↗

PubMed1995

Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13.

A small proportion of breast cancer is attributable to the inheritance of dominant, high penetrance susceptibility genes. One of these genes, BRCA2, has recently been localised by genetic linkage analysis to chromosome 13q12-13. This is a region known to exhibit loss of heterozygosity in 20-40% sporadic breast cancers. In this study, we have examined cancers from a family showing strong evidence of linkage to BRCA2. LOH was seen in seven out of eight informative cancers. In all cases the allele lost was the wild type allele that does not segregate with the disease in the family. The data suggest that both alleles of BRCA2 are inactivated in cancers, the pattern expected of a recessive oncogene or tumour suppressor gene.

Alleles↗

PubMed1995

Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer.

We searched for criteria that could indicate breast cancer families with a high prior probability of being caused by the breast/ovarian cancer susceptibility locus BRCA1 on chromosome 17. To this end, we performed a linkage study with 59 consecutively collected Dutch breast cancer families, including 16 with at least one case of ovarian cancer. We used an intake cut-off of at least three first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of the breast-ovarian cancer families were estimated to be linked to BRCA1, which could be due to a founder effect in the Dutch population. Given the expected logistical problems in clinical management now that BRCA1 has been identified, we propose an interim period in which only families with a strong positive family history for early onset breast and/or ovarian cancer will be offered BRCA1 mutation testing.

Adult↗

PubMed1995

Filters on the pathway to mental health care, I. Incident mental disorders.

This study investigates health and mental health services use by adults with and without newly incident mental disorders and uses prospectively gathered data from the Epidemiologic Catchment Area Program, a multi-site interview survey of adult household residents in the United States. Study subjects were 13,400 participants who completed interviews in the initial survey and also in a follow-up 1 year later, and who reported no contact with mental health services in either the specialized mental health sector or in the general medical sector in the 6 months prior to the initial survey. Case ascertainment was by means of a standardized interview method, the Diagnostic Interview Schedule. Separately, and before the mental health assessments were made, respondents were asked about their use of health and mental health services. 'Hierarchical' and 'filter' models of mental health services provide frameworks useful in understanding the possible effects of specific categories of psychiatric disturbances on use of health services. Only a minority of individuals with newly incident psychiatric disorder report discussion of mental health issues in a health care setting. Persons who developed a mental disorder during the follow-up interval were just as likely to consult a non-psychiatrist physician for their mental health problems as to consult a specialist in mental health, even accounting for other factors known to be associated with differential use of health care services. This large community study of incident psychiatric disorders strengthens prior evidence on the importance of the general medical sector in the care of individuals with psychiatric disturbances.

Adolescent↗

PubMed1995

Filters on the pathway to mental health care, II. Sociodemographic factors.

This study uses the prospectively gathered data of the Epidemiologic Catchment Area Program, a multi-site interview survey of mental disturbances among adult household residents in the United States, to compare health services use by individuals with different sociodemographic characteristics, accounting for the first-time occurrence of psychiatric disorder, over the course of a 1-year follow-up interval. Case ascertainment was by means of a standardized interview method, the Diagnostic Interview Schedule. In the present investigation, 13,400 continuing participants in the household sample who reported no contact with mental health services in the 6 months prior to the initial interview were studied with regard to health services use and sociodemographic characteristics. Separately, and before the mental health assessments were made, respondents were asked about their use of health and mental health services. African-Americans were significantly less likely than whites to have consulted with a specialist in mental health (estimated relative odds, 0.22, 95% confidence interval 0.10 to 0.52), even accounting for coincident psychiatric disorder, gender, and other covariates known to be associated with differential use of health care services. Hispanics and other minorities were also less likely to have consulted a specialist in mental health (estimated relative odds, 0.37 and 0.26, respectively). This large community study extends previous work on mental health services and ethnicity.

Adult↗

PubMed1995

The genetics of breast and ovarian cancer.

A number of genes are known to be involved in inherited susceptibility to breast and/or ovarian cancer. In the context of high-risk families the most important genes are BRCA1 on chromosome 17q, which is associated with a high penetrance of both breast and ovarian cancer, and BRCA2 on chromosome 13q, which causes a high risk of breast cancer but a lower risk of ovarian cancer. Other high-risk cancer genes that confer increased risks of breast or ovarian cancer in addition to other cancers include the hereditary non-polyposis colorectal cancer genes and the TP53 gene, which causes breast cancer as part of the Li-Fraumeni syndrome. The predisposing mutations in these genes are relatively rare in the population. More common genes which are associated with an increased, but lower, risk of breast cancer are the ataxiatelangiectasia gene and the HRAS1 gene. This paper reviews recent progress in mapping and cloning of these susceptibility genes, and provides estimates of the cancer risks associated with each gene and the frequency of predisposing mutations.

Ataxia Telangiectasia↗

PubMed1995

Localisation of the Fanconi anaemia complementation group A gene to chromosome 16q24.3.

Fanconi anaemia (FA) is an autosomal recessive disorder associated with diverse developmental abnormalities, bone-marrow failure and predisposition to cancer. FA cells show increased chromosome breakage and hypersensitivity to DNA cross-linking agents such as diepoxybutane and mitomycin C. Somatic-cell hybridisation analysis of FA cell lines has demonstrated the existence of at least five complementation groups (FA-A to FA-E), the most common of which is FA-A. This genetic heterogeneity has been a major obstacle to the positional cloning of FA genes by classical linkage analysis. The FAC gene was cloned by functional complementation, and localised to chromosome 9q22.3 (ref. 2), but this approach has thus far failed to yield the genes for the other complementation groups. We have established a panel of families classified as FA-A by complementation analysis, and used them to search for the FAA gene by linkage analysis. We excluded the previous assignment by linkage of an FA gene to chromosome 20q, and obtained conclusive evidence for linkage of FAA to microsatellite markers on chromosome 16q24.3. Strong evidence of allelic association with the disease was detected with the marker D16S303 in the Afrikaner population of South Africa, indicating the presence of a founder effect.

Chromosome Mapping↗

PubMed1995

Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12-q13: evidence for its role as a tumour suppressor gene.

The human skin is a complex organ composed of the surface epidermis, the subjacent dermis (in which blood vessels, lymphatics and nerves are located) and the skin appendages. The latter include hair follicles, sebaceous glands (which secrete lipids that may serve as a permeability barrier, emollient or antimicrobial agent), apocrine glands (which secrete scents) and eccrine glands (which produce sweat for temperature control). Hereditary cylindromatosis (MIM 123850) is a rare autosomal dominant disease characterised by the development of multiple neoplasms originating from the skin appendages. These neoplasms have been termed cylindromas due to their characteristic microscopic architecture and are believed to exhibit apocrine or eccrine differentiation. We have carried out a genome search using two families with this disease, which has provided strong evidence for linkage of cylindromatosis to loci on chromosome 16q12-q13. Using markers close to the cylindromatosis gene, consistent loss of the wild-type allele was observed in 19 tumours from four individuals in the two families, indicating that the gene is likely to be a tumour suppressor gene.

Carcinoma, Adenoid Cystic↗