http://www.hirsla.lsh.is/lsh Hirsla captures, stores, indexes, preserves, and distributes digital research material. Search the Channel search http://www.hirsla.lsh.is/lsh/simple-search http://hdl.handle.net/2336/108530 Titill: BRCA2 and p53 mutations in primary breast cancer in relation to genetic instability<br/><br/>Höfundar: Gretarsdottir, S; Thorlacius, S; Valgardsdottir, R; Gudlaugsdottir, S; Sigurdsson, S; Steinarsdottir, M; Jonasson, J G; Anamthawat-Jonsson, K; Eyfjord, J E<br/><br/>Útdráttur: The products of the BRCA breast cancer susceptibility genes have been implicated in cell cycle control and DNA repair. It has been suggested that mutations in the p53 gene are a necessary step in tumorigenesis in BRCA tumors. We tested samples from 402 breast cancer patients for germ-line BRCA2 and p53 mutations in tumors. p53 mutations are more frequent in BRCA2 mutation carriers than they are in controls. Tumors with mutations in either gene had multiple chromosomal abnormalities, as shown by cytogenetic analysis.<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Sat, 28 Feb 1998 22:58:59 GMT http://hdl.handle.net/2336/108521 Titill: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.<br/><br/>Höfundar: Ford, D; Easton, D F; Stratton, M; Narod, S; Goldgar, D; Devilee, P; Bishop, D T; Weber, B; Lenoir, G; Chang-Claude, J; Sobol, H; Teare, M D; Struewing, J; Arason, A; Scherneck, S; Peto, J; Rebbeck, T R; Tonin, P; Neuhausen, S; Barkardottir, R; Eyfjord, J; Lynch, H; Ponder, B A; Gayther, S A; Zelada-Hedman, M<br/><br/>Útdráttur: The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Sat, 28 Feb 1998 22:58:59 GMT http://hdl.handle.net/2336/108520 Titill: Consortium study on 1280 breast carcinomas: allelic loss on chromosome 17 targets subregions associated with family history and clinical parameters.<br/><br/>Höfundar: Phelan, C M; Borg, A; Cuny, M; Crichton, D N; Baldersson, T; Andersen, T I; Caligo, M A; Lidereau, R; Lindblom, A; Seitz, S; Kelsell, D; Hamann, U; Rio, P; Thorlacius, S; Papp, J; Olah, E; Ponder, B; Bignon, Y J; Scherneck, S; Barkardottir, R; Borresen-Dale, A L; Eyfjord, J; Theillet, C; Thompson, A M; Larsson, C<br/><br/>Útdráttur: The pattern of loss of heterozygosity (LOH) on chromosome 17 in human breast cancer is complicated and shows many different regions of loss. In an attempt to narrow down the relevant regions of LOH on chromosome 17, we have studied the deletion pattern and its association with clinical parameters in 1280 breast carcinoma-venous blood lymphocyte pairs. In total, 42 different chromosome 17 loci were investigated, and between 25 and 625 cases were analyzed at each locus. The frequency of LOH observed on the p arm was much higher than that observed on the q arm. The opposite effect was observed in 52 ovarian cancer cases investigated, with less LOH on 17p than on 17q. Patterns of loss consistent with interstitial and terminal deletions, as well as loss of either the p or q arm or monosomy 17 were observed. To determine whether loss at particular loci may be associated with biological features of breast tumors, clinical data including age of onset, family history of breast cancer, tumor histopathology, tumor size, estrogen receptor (ER) status, and occurrence of lymph node or distant metastases were collected for each case. Overall, large-sized, ER-negative, lymph node-positive ductal tumors showed the highest frequencies of LOH, with ER-negative and ductal tumors showing LOH for markers along the majority of the chromosome. Eight regions of chromosome 17 appear to be associated with human breast cancer, two on 17p and six on 17q. These regions were not necessarily in the areas exhibiting the highest frequencies of LOH but were defined by interstitial and terminal deletions in multiple independent cases. Seven of these regions showed statistically significant differences in LOH associated with clinical parameters. These data strongly suggest that loci on chromosome 17 may determine aspects of tumor presentation and disease behavior in human breast cancer and pinpoint candidate tumor suppressor gene loci.<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Sat, 28 Feb 1998 22:58:59 GMT http://hdl.handle.net/2336/108553 Titill: Rheumatoid factor isotypes, disease activity and the outcome of rheumatoid arthritis: comparative effects of different antigens<br/><br/>Höfundar: Houssien, D A; Jonsson, T; Davies, E; Scott, D L<br/><br/>Útdráttur: The value of rheumatoid factor (RF) isotypes for assessing rheumatoid arthritis (RA) remains debatable. We investigated whether using different antigens to measure RF alters the relationships between RF isotypes and clinical variables. The association between IgA and IgM RF, disease activity, and cumulative anatomical joint damage in RA was studied in 140 patients. The RF isotypes were measured using both rabbit IgG and horse IgG as antigens. Cumulative anatomical damage was assessed radiologically using Larsen's score and disease activity was determined by C-reactive protein (CRP), the health assessment questionnaire (HAQ), and a combined disease activity score (DAS). Patients positive for IgA RF and IgM RF against rabbit IgG had significantly higher disease activity and more radiological damage than negative patients. With horse IgG as antigen these differences were smaller or absent. Patients positive for only IgM RF had milder disease than patients positive for IgA RF with or without IgM RF. The clinical relationships of RF isotypes are related to the antigen used. Measuring IgA RF against rabbit IgG provides most information about disease activity, functional impairment and joint damage.<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Thu, 30 Apr 1998 22:58:59 GMT http://hdl.handle.net/2336/108546 Titill: Cyclodextrins: new drug delivery systems in dermatology<br/><br/>Höfundar: Loftsson, T; Olafsson, J H<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Tue, 31 Mar 1998 22:58:59 GMT http://hdl.handle.net/2336/108545 Titill: Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)<br/><br/>Höfundar: Pedersen, T R; Olsson, A G; Faergeman, O; Kjekshus, J; Wedel, H; Berg, K; Wilhelmsen, L; Haghfelt, T; Thorgeirsson, G; Pyörälä, K; Miettinen, T; Christophersen, B; Tobert, J A; Musliner, T A; Cook, T J<br/><br/>Útdráttur: BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides < or =2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed. METHODS AND RESULTS: The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P<.00001). CONCLUSIONS: These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Mon, 20 Apr 1998 22:58:59 GMT http://hdl.handle.net/2336/108543 Titill: Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.<br/><br/>Höfundar: Niimura, H; Bachinski, L L; Sangwatanaroj, S; Watkins, H; Chudley, A E; McKenna, W; Kristinsson, A; Roberts, R; Sole, M; Maron, B J; Seidman, J G; Seidman, C E<br/><br/>Útdráttur: BACKGROUND: Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown. METHODS: DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed. RESULTS: Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly. CONCLUSIONS: The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy.<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Wed, 29 Apr 1998 22:58:59 GMT http://hdl.handle.net/2336/108541 Titill: Possible association of a cholecystokinin promotor polymorphism (CCK-36CT) with panic disorder<br/><br/>Höfundar: Wang, Z; Valdes, J; Noyes, R; Zoega, T; Crowe, R R<br/><br/>Útdráttur: We searched for mutations in the CCK gene in panic disorder with single-strand conformational polymorphism (SSCP) analysis of the three exons and promotor region of the gene. We found a C-->T transition at position -36 (CCK(-36C-->T)) in a GC box, a binding site for transcription factor Sp1, in the promotor region. The allele frequency was 0.168 (95% CI, 0.116-0.221) in 98 persons with panic disorder and 0.083 (95% CI, 0.059-0.107) in 247 geographically matched, unscreened controls. A transmission disequilibrium test based on panic disorder as the affected phenotype was nonsignificant (chi2 = 0.93), but when panic disorder or attacks were considered as affected, statistically significant transmission disequilibrium was detected (chi2 = 4.00, P < 0.05). Linkage analysis was uninformative. In exploratory analyses to search for clinical correlations, the "T" allele was found in 59% of 22 persons with panic attacks but not panic disorder, compared with 31% of those who met the criteria for panic disorder. An association between the CCK polymorphism and panic disorder cannot be considered established due to the inconsistencies in the results noted above, but if the provisional association can be replicated, the findings are consistent with CCK(-36C-->T) being a disease-susceptibility allele that alone is neither necessary nor sufficient to cause panic disorder but that increases vulnerability by acting epistatically.<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Thu, 07 May 1998 22:58:59 GMT http://hdl.handle.net/2336/108535 Titill: Survival and prognostic factors of endometrial cancer patients in Iceland 1964-1985: can attendance at population-based Pap-smear screening affect survival?<br/><br/>Höfundar: Sigurdsson, K; Sigurdardottir, B; Steinsson, S; Benediktsdottir, K; Sigurvinsson, T; Sigvaldason, H<br/><br/>Útdráttur: After histological review of all cases registered during the period 1964-1985 at the Cancer Registry, 260 cases with endometrial carcinoma were eligible for analyses of survival rates and prognostic factors, as well as the association of Pap-smear screening attendance with these factors and survival. The total age-adjusted 5- and 10-year relative survival rates were 76% and 75%, respectively. The prognostic factors were tested by univariate analysis and simultaneously by a multivariate analysis using the Cox proportional hazards model. Factors that independently gave a less favorable prognosis were non-attendance at screening, older age at diagnosis, deep myometrial invasion, advancing stages and tumor grading, radiotherapy only, extra-genital symptoms and histology types of serous, clear cell and undifferentiated tumors (histologic type 3). Tested simultaneously with the Cox proportional hazards model, parameters that maintained a less favourable prognosis were grade 3, stage III-IV, deep myometrial invasion, older age, radiotherapy only and extra-genital symptoms. In addition, screening attendance showed significant interaction with age. In stages III and IV only grade 3 maintained a significantly less favorable prognosis. We conclude that our results indicate that attendance at Pap-smear screening (taking Pap smears and screening for genital symptoms) has a favorable prognostic value, especially among women under the age of 62.<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Thu, 16 Apr 1998 22:58:59 GMT http://hdl.handle.net/2336/108533 Titill: Isotypes and opsonophagocytosis of pneumococcus type 6B antibodies elicited in infants and adults by an experimental pneumococcus type 6B-tetanus toxoid vaccine<br/><br/>Höfundar: Vidarsson, G; Sigurdardottir, S T; Gudnason, T; Kjartansson, S; Kristinsson, K G; Ingolfsdottir, G; Jonsson, S; Valdimarsson, H; Schiffman, G; Schneerson, R; Jonsdottir, I<br/><br/>Útdráttur: Streptococcus pneumoniae is a major respiratory pathogen of infants, children, and the elderly. Polysaccharide vaccines have been useful in adult populations but do not elicit protective immunity in infants and young children. To enhance their immunogenicity, vaccines of pneumococcal polysaccharides conjugated to proteins are being developed. In this study antibody levels and opsonic activities were compared in sera of infants and adults injected with pneumococcal polysaccharide type 6B (Pn6B) conjugated to tetanus toxoid (TT) (Pn6B-TT). Healthy infants were injected with Pn6B-TT; group A was injected at 3, 4, and 6 months of age, and group B was injected at 7 and 9 months of age. A booster injection was given at 18 months. Adults were injected once. Antibodies were measured by enzyme-linked immunosorbent assay and radioimmunoassay, and their functional activities were measured by opsonophagocytosis of radiolabelled pneumococci. In adults, increases in immunoglobulin M (IgM), IgG, IgA, IgG1, and IgG2 to Pn6B were observed. Infants reached adult levels of IgG1 anti-Pn6B after the primary injections. After the booster injection the infant groups had total IgG- and IgM-Pn6B antibody levels similar to those of adults. After the booster injection, IgG1 was the dominant infant anti-Pn6B isotype and at a level higher than in vaccinated adults, but IgA and IgG2 antibodies remained at very low levels. Opsonic activity increased significantly after Pn6B-TT injections; the highest infant sera showed opsonic activity comparable to that of vaccinated adults. Overall, opsonic activity correlated best with total and IgG anti-Pn6B antibodies (r = 0.741, r = 0.653, respectively; n = 35) and was highest in sera with high levels of all Pn6B antibody isotypes. The results indicate the protective potential of a pneumococcal 6B polysaccharide protein conjugate vaccine for young infants.<br/><br/>Lýsing: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Fri, 29 May 1998 22:58:59 GMT