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M Daly

Publications and source records attributed to M Daly.

At least 37 records · Page 2Linked to original sources
PubMed2001

A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers.

RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers. We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations. We discovered two single nucleotide polymorphisms (SNPs) at positions 135 g-->c and 172 g-->t of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 g-->c, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 g-->c with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4-40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 g-->c SNP. Analysis of the RAD51:135 g-->c SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele. We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown.

Adult↗
PubMed2000

Two loci on chromosomes 2 and X for premature coronary heart disease identified in early- and late-settlement populations of Finland.

Coronary heart disease (CHD) is a complex disorder constituting a major health problem in Western societies. To assess the genetic background of CHD, we performed a genomewide linkage scan in two study samples from the genetically isolated population of Finland. An initial study sample consisted of family material from the northeastern part of Finland, settled by a small number of founders approximately 300 years ago. A second study sample originated from the southwestern region of Finland, settled approximately 2,000 years ago. Families were ascertained through probands exhibiting premature CHD, defined as >50% stenosis of at least two coronary arteries at a young age, as verified by coronary angiography. Both study samples and the pooled data set provided evidence for linkage in two chromosomal regions. A region on chromosome 2q21.1-22 yielded two-point LOD scores of 3.2, 1.9, and 3.7, in the affected sib-pair (ASP) analyses of the northeastern, southwestern, and pooled study samples. The corresponding multipoint maximum-likelihood scores (MLSs) for these three study samples were 2.4, 1.3, and 3.0. In addition, a region on chromosome Xq23-26 resulted in two-point LOD scores of 1.9, 3.5, and 2.9 and in multipoint MLSs of 3.4, 3.1, and 2.5, respectively. In conclusion, this study identifies two loci likely to contribute to premature CHD: one on chromosome 2q21.1-22 and another on chromosome Xq23-26.

Age of Onset↗
PubMed2000

Identification and characterization of SKAT-2, a novel Th2-specific zinc finger gene.

We have identified a novel Kruppel-type zinc finger (ZF) gene, SKAT-2, which is selectively expressed by murine Th2 cells. The protein encoded by this gene has 14 C2H2-type ZF tandemly arrayed at its C terminus and N-terminal SCAN box and KRAB domains. SKAT-2 is tissue restricted in expression at the RNA level, detectable only in brain and at low levels in kidney and spleen and few hematopoietic cell lines. By in situ hybridization, SKAT-2 expression was found to peak in antigen-stimulated CD4(+) T cells after 2-3 days of culture under Th2 but not Th1 biasing conditions. This pattern of expression closely mirrored that of GATA-3 in the same cells. In transient transfection experiments in phorbol 12-myristate 13-acetate/ionomycin-stimulated EL4 cells, SKAT-2 was found to up-regulate the activity of the IL-4 but not the IL-5 promoter, contrasting with the ability of GATA-3 to activate both promoters. This result was confirmed using clones of EL4 cells stably expressing an inducible form of SKAT-2, thus SKAT-2 is a novel Th2-specific gene that may play a role in selective regulation of cytokine genes in T cells.

Amino Acid Sequence↗
PubMed2000

Forewarned is forearmed--benefits of preparatory information on video cassette for patients receiving chemotherapy or radiotherapy--a randomised controlled trial.

A series of UK and European audits have revealed that a high proportion of patients remain dissatisfied with the information they received following a diagnosis of cancer. Additional educational aids are often required to facilitate the consent process, and our previous work showed a high level of acceptability for video-directed information for this purpose. In this study a multidisciplinary team of health professionals worked with patients, a documentary film company and experienced television personalities to produce an information film. The aim of this study was to assess the benefits of receiving a cassette to take home following the first consultation and this was evaluated in a randomised multicentre controlled study among 220 patients receiving chemotherapy or radiotherapy over a 6-month period. There was a significant correlation between satisfaction and reduced treatment-related anxiety overall. In the video group, the mean Hospital Anxiety and Depression (HAD) anxiety score was significantly lower during treatment compared with the non-video group (4.6+/-3.7 (range: 0-18) versus 7.4+/-5.2 (range: 0-20), Chi square test P=0.001). Likewise, the mean HAD depression scores were also significantly lower in the patients prepared for the side-effects of treatment with the video (2.9+/-2.9 (range: 0-13) versus 5.3+/-4.7 (range: 0-21) Chi square test P=0.001). 81% felt the video was helpful, only 5% of patients felt this extra information was worrying. Well designed video cassettes should be regarded as a useful additional information strategy, within routine oncology practice.

Adolescent↗
PubMed2000

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Child↗
PubMed2000

The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.

Genetic association studies are viewed as problematic and plagued by irreproducibility. Many associations have been reported for type 2 diabetes, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(PPARgamma) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARgamma. An initial study found a threefold effect, but four of five subsequent publications failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARgamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.

Adult↗
PubMed2000

Full-genome scan for linkage in 50 families segregating the bipolar affective disease phenotype.

A genome scan of approximately 12-cM initial resolution was done on 50 of a set of 51 carefully ascertained unilineal multiplex families segregating the bipolar affective disorder phenotype. In addition to standard multipoint linkage analysis methods, a simultaneous-search algorithm was applied in an attempt to surmount the problem of genetic heterogeneity. The results revealed no linkage across the genome. The results exclude monogenic models and make it unlikely that two genes account for the disease in this sample. These results support the conclusion that at least several hundred kindreds will be required in order to establish linkage of susceptibility loci to bipolar disorder in heterogeneous populations.

Bipolar Disorder↗
PubMed2000

The concept of social care and the analysis of contemporary welfare states.

Care is now a widely-used concept in welfare state research, firmly established in the literature by feminist analysis. We believe that the concept as it has been used and developed to date has limitations that have hampered its development as a general category of welfare state analysis. In essence we argue that the political economy aspects of the concept have remained underdeveloped. The main purpose of this article is to elaborate a care-centered concept--which we name social care--that countenances and develops care as an activity and set of relations lying at the intersection of state, market and family (and voluntary sector) relations. We are especially concerned to examine what the concept of social care can tell us about welfare state variation and welfare state change and development. The article works systematically through these themes, beginning with a brief historical sketch of the concept of care and then moving on to elaborate the analytic potential of the concept of social care. In the latter regard we make the case that it can lead to a more encompassing analysis, helping to overcome especially the fragmentation in existing scholarship between the cash and service dimensions of the welfare state and the relative neglect of the latter. The concept of social care serves to shift the centre of analysis from specific policy domains so that instead of focusing on cash benefits or services in isolation it becomes possible to consider them as part of a broader set of inter-relating elements. In this and other regards, the concept has the potential to say something new about welfare states.

Adult↗
PubMed2000

Characterization and chromosomal mapping of antimicrobial resistance genes in Salmonella enterica serotype typhimurium.

Two hundred and twenty-six Salmonella enterica serotype Typhimurium isolates were examined for the presence of integron-associated gene cassettes. All but two of the non-DT104 isolates, together with DT104 isolates, contained gene cassettes. Amplicons of 1.5 kbp each were found in two non-DT104 isolates, encoding a dhfrI gene (trimethoprim resistance) linked to an aadA gene (streptomycin and spectinomycin resistance), by site-specific recombination. DT104 isolates of resistance (R) type ACSSuT possessed the recently described 1.0- and 1.2-kbp gene cassettes. Macrorestriction analysis with XbaI and DNA probing mapped ant(3")-1a, bla(PSE-1), and dhfrI genes to large multiresistant gene clusters in a DT170a isolate and a DT193 isolate. In contrast, all DT104 isolates (R-type ACSSuT) possessed a conserved 10-kbp Xba1 DNA fragment. Our study highlights the occurrence of integrons (and antimicrobial resistance determinants) among serotype Typhimurium isolates other than DT104. Larger and previously unrecognized multiresistance gene clusters were identified in these isolates by DNA probing.

Animals↗
PubMed2000

Molecular characterization of Irish Salmonella enterica serotype typhimurium: detection of class I integrons and assessment of genetic relationships by DNA amplification fingerprinting.

Salmonella enterica is among the principal etiological agents of food-borne illness in humans. Increasing antimicrobial resistance in S. enterica is a cause for worldwide concern. There is concern at present in relation to the increasing incidence of human infection with antimicrobial agent-resistant strains of S. enterica serotype Typhimurium, in particular of phage type DT104. Integrons appear to play an important role in the dissemination of antimicrobial resistance genes in many Enterobacteriaceae including S. enterica. In this study the antimicrobial susceptibilities and phage types of 74 randomly collected strains of S. enterica serotype Typhimurium from the Cork region of southern Ireland, obtained from human, animal (clinical), and food sources, were determined. Each strain was examined for integrons and typed by DNA amplification fingerprinting (DAF). Phage type DT104 predominated (n = 48). Phage types DT104b (n = 3), -193 (n = 9), -195 (n = 6), -208 (n = 3), -204a (n = 2), PT U302 (n = 1), and two nontypeable strains accounted for the remainder. All S. enterica serotype Typhimurium DT104 strains were resistant to ampicillin, chloramphenicol, streptomycin, Sulfonamide Duplex, and tetracycline, and one strain was additionally resistant to trimethoprim. All DT104 strains but one were of a uniform DAF type (designated DAF-I) and showed a uniform pattern of integrons (designated IP-I). The DT104b and PT U302 strains also exhibited the same resistance phenotype, and both had the DAF-I and IP-I patterns. The DAF-I pattern was also observed in a single DT193 strain in which no integrons were detectable. Greater diversity of antibiograms and DAF and IP patterns among non-DT104 phage types was observed. These data indicate a remarkable degree of homogeneity at a molecular level among contemporary isolates of S. enterica serotype Typhimurium DT104 from animal, human, and food sources in this region.

Animals↗
PubMed2000

Assembly of multimeric von Willebrand factor directs sorting of P-selectin.

We designed a model system to study the role of von Willebrand factor (vWF) in the sorting of P-selectin and the biogenesis of Weibel-Palade body (WPB)-like organelles. For that purpose, a human epithelial cell line (T24) that synthesizes P-selectin mRNA, but which is devoid of vWF mRNA synthesis and storage organelles, was transfected with full-length vWF cDNA or a deletion mutant thereof. Stable transfectants of T24 with full-length vWF cDNA revealed the generation of WPB-like organelles as demonstrated by colocalization of vWF and P-selectin with double-labeling immunofluorescence. In contrast, T24 cells transfected with vWF delD'D3 cDNA, encoding a mutant that is unable to form vWF multimers, displayed only perinuclear vWF staining, whereas no indication was found for the presence of WPB-like organelles. The contents of the organelles in full-length vWF cDNA-transfected T24 cells were released on activation of the protein kinase C pathway, similar to the situation with genuine endothelial cells. The expression of vWF did not affect the biosynthesis of P-selectin, as deduced from the observation that untransfected and vWF cDNA-transfected T24 cells contained the same amount of P-selectin mRNA. We propose that the biosynthesis of multimeric vWF directs the generation of WPB-like organelles, as evidenced by the sequestering and anchoring of P-selectin into these storage granules.

Biological Transport↗
PubMed2000

Exceptional familial clustering for extreme longevity in humans.

Four families highly clustered for extreme longevity are described here, representing the first report of clustering for this phenotype. Families such as these may prove to be helpful in the further understanding of the genetic contribution to achieving exceptional longevity.

Aged↗
PubMed1999

Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2.

BACKGROUND: Early age at first full-term pregnancy and increasing parity are associated with a reduced risk of breast cancer. However, whether pregnancy decreases the risk of early-onset hereditary breast cancer is unknown. There is concern that pregnancy may increase breast-cancer risk in carriers of BRCA1 and BRCA2 germline mutations. We aimed to establish whether pregnancy is a risk factor for hereditary breast cancer. METHODS: We did a matched case-control study of breast cancer in women who carry deleterious BRCA1 or BRCA2 mutations. Cases were carriers who developed breast cancer by age 40 years, and controls were carriers of the same age without breast cancer, or who were diagnosed with breast cancer after age 40 years. Women who had undergone preventive mastectomy, hysterectomy, or oophorectomy, or who were diagnosed with ovarian cancer before the age at which breast cancer was diagnosed in the matched case were excluded. Information about pregnancies and pregnancy outcome was derived from a questionnaire completed by women in the course of genetic counselling. FINDINGS: A higher proportion of cases than controls had had a full term pregnancy (173/236 vs 146/236; odds ratio 1.71 [95% CI 1.13-2.62], p=0.01). The mean number of births was also greater for cases than for controls (1.62 vs 1.38, p=0.04). The risk increased with the number of births and did not diminish with time since last pregnancy. There were no significant differences in age at first birth or age at last birth between cases and controls. INTERPRETATION: Carriers of the BRCA1 and BRCA2 mutations who have children are significantly more likely to develop breast cancer by age 40 than carriers who are nulliparous. Each pregnancy is associated with an increased cancer risk. An early first pregnancy does not confer protection for carriers of BRCA1 or BRCA2 mutations.

Adult↗