We compared systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP) in predicting the risk of cardiovascular disease (CVD), stratifying ...results at age 60 years, when DBP decreases while SBP continues to increase. We prospectively followed 11 150 male physicians with no history of CVD or antihypertensive treatment through the 2-year questionnaire, after which follow-up began. Reported blood pressure was averaged from both the baseline and 2-year questionnaires. During a median follow-up of 10.8 years, there were 905 cases of incident CVD. For men aged <60 years (n=8743), those in the highest versus lowest quartiles of average SBP (≥130 versus <116 mm Hg), DBP (≥81 versus <73 mm Hg), and MAP (≥97 versus <88 mm Hg) had relative risks (RRs) of CVD of 2.16, 2.23, and 2.52, respectively. Models with average MAP and PP did not add information compared with models with MAP alone (P >0.05). For men aged ≥60 years (n=2407), those in the highest versus lowest quartiles of average SBP (≥135 versus <120 mm Hg), PP (≥55 versus <44 mm Hg), and MAP (≥99 versus <91 mm Hg) had RRs of CVD of 1.69, 1.83, and 1.43, respectively. The addition of other blood pressure measures did not add information compared with average SBP or PP alone (all P >0.05). These data suggest that average SBP, DBP, and MAP strongly predict CVD among younger men, whereas either average SBP or PP predicts CVD among older men. More research should distinguish whether MAP, highly correlated with SBP and DBP, better predicts CVD.
More than 30 epidemiologic studies have found that postmenopausal women who use estrogen are at lower risk for coronary disease than those who do not use estrogen
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; however, most data are for ...estrogen alone.
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Progestins added to estrogen reduce or eliminate the excess risk of endometrial cancer due to the unopposed effect of estrogen.
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The use of progestins combined with estrogen is now common, but information about the risk of cardiovascular disease associated with combined therapy is sparse.
Experimental data suggest that the addition of progestin may diminish the apparent cardioprotective effect of hormone therapy. Progestins alone tend to . . .
Abstract Objective: To examine the association between birth weight and non-fatal adult cardiovascular disease while controlling for potential confounders such as socioeconomic group and adult ...lifestyle. Design: Retrospective self report of birth weight in an ongoing longitudinal cohort of nurses followed up by postal questionnaire every two years. Setting: Nurses' health study, a cohort of 121 700 women followed up since 1976. Main outcome measures: Non-fatal cardiovascular disease, including myocardial infarction, coronary revascularisation, and stroke. Results: Among the 70 297 women free of cardiovascular disease at baseline who reported birth weight in the 1992 questionnaire there were 1309 first cases of non-fatal cardiovascular disease. Increasing birth weight was associated with decreasing risk of non-fatal cardiovascular disease. There were 1216 first cases of non-fatal cardiovascular disease among women who were singletons and had been born full term; their relative risks adjusted for several cardiovascular risk factors were 1.49 (95% confidence interval 1.05 to 2.10) for birth weight <2268 g (<5 lb 0 oz); 1.25 (0.98 to 1.61) for birth weight 2268-2495 g (5 lb 0 oz to 5 lb 8 oz); 1.12 (0.98 to 1.27) for birth weight >2495-3175 g (>5 lb 8 oz to 7 lb 0 oz); 1.00 (referent) for birth weight >3175-3856 g (>7 lb 0 oz to 8 lb 8 oz); 0.96 (0.80 to 1.15) for birth weight >3856-4536 g (>8 lb 8 oz to 10 lb 0 oz); and 0.68 (0.46 to 1.00) for birth weight >4536 g (>10 lb 0 oz) (P value for trend=0.0004). The inverse trend was apparent for both coronary heart disease and stroke. Conclusions: These data provide strong evidence of an association between birth weight and adult coronary heart disease and stroke. Key messages Birth weight and mortality from cardiovascular disease are inversely associated in adult women This study found that birth weight and the risk of non-fatal cardiovascular disease is also inversely associated in adult women for both coronary heart disease and stroke This association is driven by the 13% of women born at the extremes of birth weight It seems to be largely independent of established cardiovascular risk factors also associated with birth weight: adult body weight, hypertension, and diabetes It is not weakened by controlling for childhood socioeconomic group or adjusting for adult lifestyle
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Etoposide is a substrate for P-glycoprotein, CYP3A4, CYP3A5, and UGT1A1. Glucocorticoids modulate CYP3A and P-glycoprotein in preclinical models, but their effect on clinical etoposide disposition is ...unknown. We studied the pharmacokinetics of etoposide and its catechol metabolite in children with acute lymphoblastic leukemia, along with polymorphisms in CYP3A4, CYP3A5, MDR1, GSTP1, UGT1A1, and VDR. Plasma pharmacokinetics were assessed at day 29, after 1 month of prednisone (n = 102), and at week 54, without prednisone (n = 44). On day 29, etoposide clearance was higher (47.4 versus 29.2 mL/min/m2, P < .0001) than at week 54. The day 29 etoposide or catechol area under the curve (AUC) was correlated with neutropenia (P = .027 and P = .0008, respectively). The relationship between genotype and etoposide disposition differed by race and by prednisone use. The MDR1 exon 26 CC genotype predicted higher day 29 etoposide clearance (P = .002) for all patients, and the CYP3A5 AA and GSTP1 AA genotypes predicted lower clearance in blacks (P = .02 and .03, respectively). The UGT1A1 6/6, VDR intron 8 GG, and VDR Fok 1 CC genotypes predicted higher week 54 clearance in blacks (P = .039, .036, and .052, respectively). The UGT1A1 6/6 genotype predicted lower catechol AUC. Prednisone strongly induces etoposide clearance, genetic polymorphisms may predict the constitutive and induced clearance of etoposide, and the relationship between genotype and phenotype differs by race.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
25.
Postmenopausal Hormone Therapy and Mortality Grodstein, Francine; Stampfer, Meir J; Colditz, Graham A ...
New England journal of medicine/The New England journal of medicine,
06/1997, Volume:
336, Issue:
25
Journal Article
Peer reviewed
Open access
Whether to take postmenopausal hormones is a difficult decision. Hormone use carries many benefits, including decreased risks of osteoporosis
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and cardiovascular disease,
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as well as hazards, ...especially an increase in the risks of breast and endometrial cancers.
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Observational studies have reported reduced mortality among women taking hormones,
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–
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but many of the studies have had methodologic flaws that limit firm conclusions. Specifically, women for whom estrogens are prescribed are often healthier initially, and those who continue to take hormones tend to be free of disease (for example, women in whom cancer is diagnosed often stop taking hormones).
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,
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,
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Thus, . . .
Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a ...physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.
Trans isomers of fatty acids, formed by the partial hydrogenation of vegetable oils to produce margarine and vegetable shortening, increase the ratio of plasma low-density-lipoprotein to ...high-density-lipoprotein cholesterol, so it is possible that they adversely influence risk of coronary heart disease (CHD). To investigate this possibility, we studied dietary data from participants in the Nurses' Health Study. We calculated intake of
trans fatty acids from dietary questionnaires completed by 85 095 women without diagnosed CHD, stroke, diabetes, or hypercholesterolaemia in 1980. During 8 years of follow-up, there were 431 cases of new CHD (non-fatal myocardial infarction or death from CHD). After adjustment for age and total energy intake, intake of
trans isomers was directly related to risk of CHD (relative risk for highest vs lowest quintile 1·50 95% Cl 1·12-2·00, p for trend = 0·001). Additional control for established CHD risk factors, multivitamin use, and intakes of saturated fat, monounsaturated fat, and linoleic acid, dietary cholesterol, vitamins E or C, carotene, or fibre did not change the relative risk substantially. The association was stronger for the 69 181 women whose margarine consumption over the previous 10 years had been stable (1·67 1·05-2·66, p for trend = 0·002). Intakes of foods that are major sources of
trans isomers (margarine, cookies biscuits, cake, and white bread) were each significantly associated with higher risks of CHD. These findings support the hypothesis that consumption of partially hydrogenated vegetable oils may contribute to occurrence of CHD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBJE, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
To assess the safety and efficacy of CT-guided brachytherapy alone or in combination with laser-induced thermotherapy (LITT) in patients with liver malignancies.
Thirty-seven patients presented with ...36 liver metastases and two primary liver carcinomas. Twenty-one patients were treated with CT-guided high-dose-rate brachytherapy alone using a
192Ir source. Sixteen patients received brachytherapy directly after MRI-guided LITT. The indications for brachytherapy alone were a tumor size >5 cm, adjacent central bile duct or adjacent major vessels causing unfavorable cooling effects for thermal ablation, and technical failures of LITT. The dosimetry for brachytherapy was performed using three-dimensional CT data acquired after percutaneous applicator positioning. On average, a minimal dose of 17 Gy inside the tumor margin was applied (range, 10–20 Gy).
The mean tumor size was 4.6 cm (range, 2.5–11 cm). The mean liver volume receiving ≥5 Gy was 16% (range, 2–40%) of the total liver. Severe complications were recorded in 2 patients (5%). One patient developed acute liver failure possibly related to accidental continuation of oral capecitabine treatment. Another patient demonstrated obstructive jaundice owing to tumor edema after irradiation of a metastasis adjacent to the bile duct bifurcation. A commonly encountered moderate increase of liver enzymes was greatest in patients with combined treatment. The local control rate after 6 months was 73% and 87% for combined treatment and brachytherapy alone, respectively.
CT-guided brachytherapy using three-dimensional CT data for dosimetry is safe and effective alone or in combination with LITT. Brachytherapy as a stand-alone treatment displayed genuine advantages over thermal tumor ablation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
29.
Vitamin E consumption and the risk of coronary disease in women Stampfer, M.J. (Channing Laboratory, Boston, MA); Hennekens, C.H; Manson, J.E ...
New England journal of medicine/The New England journal of medicine,
05/1993, Volume:
328, Issue:
20
Journal Article
Peer reviewed
Open access
Background. Interest in the antioxidant vitamin E as a possible protective nutrient against coronary disease has intensified with the recognition that oxidized low-density lipoprotein may be involved ...in atherogenesis. Methods. In 1980, 87,245 female nurses 34 to 59 years of age who were free of diagnosed cardiovascular disease and cancer completed dietary questionnaires that assessed their consumption of a wide range of nutrients, including vitamin E. During follow-up of up to eight years (679,485 person-years) that was 97 percent complete, we documented 552 cases of major coronary disease (437 nonfatal myocardial infarctions and 115 deaths due to coronary disease). Results. As compared with women in the lowest fifth of the cohort with respect to vitamin E intake, those in the top fifth had a relative risk of major coronary disease of 0.66 (95 percent confidence interval, 0.50 to 0.87) after adjustment for age and smoking. Further adjustment for a variety of other coronary risk factors and nutrients, including other antioxidants, had little effect on the results. Most of the variability in intake and reduction in risk was attributable to vitamin E consumed as supplements. Women who took vitamin E supplements for short periods had little apparent benefit, but those who took them for more than two years had a relative risk of major coronary disease of 0.59 (95 percent confidence interval, 0.38 to 0.91) after adjustment for age, smoking status, risk factors for coronary disease, and use of other antioxidant nutrients (including multivitamins). Conclusions. Although these prospective data do not prove a cause-and-effect relation, they suggest that among middle-aged women the use of vitamin E supplements is associated with a reduced risk of coronary heart disease. Randomized trials of vitamin E in the primary and secondary prevention of coronary disease are being conducted; public policy recommendations about the widespread use of vitamin E should await the results of this trials
Background. Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic ...research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation. Methods. In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days) we enrolled 22,071 male physicians, 40 to 84 years of age in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene. Results. Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group) the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points. Conclusions. In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.
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