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Biomedical subjects

T L Bush

Publications and source records attributed to T L Bush.

At least 55 records · Page 3Linked to original sources
PubMed1994

Regression of human breast tumor xenografts in response to (E)-2'-deoxy-2'-(fluoromethylene)cytidine, an inhibitor of ribonucleoside diphosphate reductase.

(E)-2'-Deoxy-2'-(fluoromethylene)cytidine (MDL 101,731) is a mechanism-based inhibitor of ribonucleoside diphosphate reductase (J. Stubbe, personal communication), an enzyme involved in DNA synthesis and therefore a potential target for cancer chemotherapy. In the present report, we show that MDL 101,731 inhibits the proliferation of several human breast cancer cell lines, including the estrogen-dependent cell line, MCF-7, and the estrogen-independent cell lines MDA-MB-231, MDA-MB-468, and MDA-MB-435 in vitro at nanomolar concentrations (50% inhibitory concentration, 15-26 nM). Administration of MDL 101,731 caused marked regression of tumors which formed after s.c. inoculation of all four of the cell lines in athymic (nude) mice. MDA-MB-231 tumors were found to be most sensitive to MDL 101,731 with a 90-100% cure rate at doses of MDL 101,731 between 2 and 20 mg/kg, given as once daily i.p. injections, 5 days/week for as little as 3 weeks. Almost complete cessation of MDA-MB-231 tumor growth was obtained with a dose of 0.5 mg/kg MDL 101,731 following the same dosing regimen. MDA-MB-468, MDA-MB-435, and MCF-7 tumors were not as sensitive as MDA-MB-231, but tumor regression of 50, 65, and 80%, respectively, was obtained after 5-6 weeks of treatment. The effects of MDL 101,731 on spontaneous metastasis of MDA-MB-435 cells from the mammary fat pad to the lung was also examined, and it was found that the number of lung metastases was significantly decreased if mice received MDL 101,731 while the primary tumors were growing and after primary tumors were surgically excised. Additionally, preliminary evidence raises the possibility that MDL 101,731 may induce apoptosis in MDA-MB-231 tumors. Our data suggest that the use of MDL 101,731 for the treatment of breast cancer and possibly other solid tumors should be pursued.

Animals↗
PubMed1994

Correlates of bone mineral density in the postmenopausal estrogen/progestin interventions trial.

We assessed the cross-sectional relationship of age, menopausal years, body mass, previous estrogen use, and ethnic background to bone mineral status in a sample of 875 healthy postmenopausal women at the time they were recruited from the community to participate in a multicenter clinical trial. The women were 1-10 years postmenopause, 45-64 years of age, and had not received estrogen replacement therapy within 3 months of enrollment. Of the participants, 89% were white, 69% had a spontaneous menopause, and 53% had a history of previous estrogen replacement therapy. Bone mineral density (BMD) of the lumbar spine (L2-4) and proximal femur was measured by dual-energy x-ray absorptiometry. Results were consistent with a significant negative linear regression of BMD on age or years from menopause. Body mass index (BMI) correlated significantly with BMD at all sites (L 2-4 r = 0.28; femoral neck r = 0.34, p < 0.0001). BMD adjusted for age and BMI were higher at both sites in women who had taken estrogen versus those who had not (L2-4 0.976 +/- 0.009 versus 0.932 +/- 0.01; femoral neck 0.740 +/- 0.006 versus 0.708 +/- 0.008, p < 0.05). Adjusted BMD also increased with duration of ERT. Parity was negatively associated with L2-4 BMD (p = 0.03) but did not correlate significantly with BMD at the femoral neck. Black women had the highest L2-4 BMD, and Hispanic women had the highest femoral neck BMD, even when results were adjusted for age and BMI. When data were corrected for differences in bone size, these interethnic differences were no longer significant. We conclude that increased body mass is positively correlated with BMD, and this may confer a degree of skeletal protection to heavier postmenopausal women. Exposure for 5 years to exogenous estrogen is associated with significantly increased age- and BMI-adjusted BMD.

Absorptiometry, Photon↗
PubMed1994

A prospective study of endogenous hormones and breast cancer.

To examine the association prospectively between endogenous hormones and breast cancer, a population-based, nested case-control study was conducted using serum collected in 1974. Serum hormone levels among 51 women, who subsequently developed breast cancer, were compared with controls matched on age and time since last menstrual period. The levels of estrogens, progesterone, sex-hormone binding globulin, and androstenedione were compared between cases and controls. No statistically significant differences in endogenous hormones levels were observed between women who subsequently developed breast cancer and controls. Despite the fact that risk factors for breast cancer implicated endogenous hormones, especially estrogen, in the etiology of this disease, our study failed to demonstrate a statistically significant association between endogenous hormones and the risk of breast cancer. If there is an association between endogenous hormones and breast cancer, the magnitude of the effect is weak.

Adult↗
PubMed1993

Plasma lipoprotein levels as predictors of cardiovascular death in women.

BACKGROUND: The association of lipoprotein levels with cardiovascular disease (CVD) is less well understood in women than in men. To better characterize any relationships, associations between CVD death and total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and triglyceride levels in women were explored using data from female participants in the Lipid Research Clinics' Follow-up Study. METHODS: Using a sample of 1405 women aged 50 to 69 years from the Lipid Research Clinics' Follow-up Study, age-adjusted CVD death rates and summary relative risk (RR) estimates by categories of lipid and lipoprotein levels were calculated. Multivariate analysis was performed to provide RR estimates adjusted for other CVD risk factors. RESULTS: Average follow-up was 14 years. High-density lipoprotein and triglyceride levels were strong predictors of CVD death in age-adjusted and multivariate analyses. Low-density lipoprotein and total cholesterol levels were poorer predictors of CVD mortality. After adjustment for other CVD risk factors, HDL levels less than 1.30 mmol/L (50 mg/dL) were strongly associated with cardiovascular mortality (RR = 1.74; 95% confidence interval [CI], 1.10 to 2.75). Triglyceride levels were associated with increased CVD mortality at levels of 2.25 to 4.49 mmol/L (200 to 399 mg/dL) (RR = 1.65; 95% CI, 0.99 to 2.77) and 4.50 mmol/L (400 mg/dL) or greater (RR = 3.44; 95% CI, 1.65 to 7.20). At total cholesterol levels of 5.20 mmol/L (200 mg/dL) or greater and at all levels of LDL and triglycerides, women with HDL levels of less than 1.30 mmol/L (< 50 mg/dL) had CVD death rates that were higher than those of women with HDL levels of 1.30 mmol/L (50 mg/dL) or greater. CONCLUSIONS: High-density lipoprotein and triglyceride levels are independent lipid predictors of CVD death in women. Cholesterol screening guidelines should be re-evaluated to reflect the importance of HDL and triglyceride levels in determining CVD risk in women.

Age Factors↗
PubMed1993

Prospective study of serum CA-125 levels as markers of ovarian cancer.

OBJECTIVE: To evaluate prospectively the sensitivity and specificity of serum CA-125 levels for the detection of ovarian cancer. DESIGN: Case-control study nested within a cohort of women who donated blood to a community-based serum bank established in 1974. SETTING: Washington County, Maryland. POPULATION: Cases consisted of 37 women who developed ovarian cancer from 1975 through 1989. Controls consisted of 73 women, matched on age and time since last menstrual period, and free of cancer until the cases' diagnoses. STUDY VARIABLE: Serum CA-125 levels. OUTCOME MEASURE: Histologically confirmed ovarian cancer. RESULTS: Levels of serum CA-125 among cases were higher than among controls for each 3-year interval up to 12 years prior to the time of the cases' diagnoses. The median level for cases diagnosed within the first 3 years of follow-up was 35.4 U/mL compared with 9.0 U/mL for controls (P = .002). The sensitivity of a serum CA-125 level greater than 35 U/mL within the first 3 years was 57% (95% confidence interval, 20% to 88%) and the specificity was 100% (95% confidence interval lower limit, 73%). Sensitivity and specificity decreased with increasing time to diagnosis. CONCLUSIONS: Measurement of serum CA-125 levels, particularly at a reference value of 35 U/mL, is not sufficiently sensitive to be used alone as a screening test for the detection of ovarian cancer. Lower CA-125 reference values could identify women at higher risk of developing ovarian cancer, but CA-125 measurement cannot be recommended for this purpose because of the high proportion of women who would be falsely classified as being at high risk for developing ovarian cancer.

Adolescent↗
PubMed1993

Decreased risk of stroke among postmenopausal hormone users. Results from a national cohort.

OBJECTIVE: To assess the impact of postmenopausal hormone use on the risk of stroke incidence and stroke mortality. DESIGN: Longitudinal study consisting of three data collection waves. The average follow up for cohort members was 11.9 years (maximum, 16.3 years). Cox proportional hazards regression models were used to estimate the relative risk of stroke for postmenopausal hormone ever-users compared with never-users. PARTICIPANTS: A national sample of 1910 (of 2371 eligible) white postmenopausal women who were 55 to 74 years old when examined in 1971 through 1975 as part of the first National Health and Nutrition Examination Survey and who did not report a history of stroke at that time. MAIN OUTCOME MEASURE: The main outcome measure was incident stroke (fatal and nonfatal). Events were determined from discharge diagnosis information coded from hospital and nursing home records and cause of death information coded from death certificates collected during the follow-up period (1971 through 1987). RESULTS: There were 250 incident cases of stroke identified, including 64 deaths with stroke listed as the underlying cause. The age-adjusted incidence rate of stroke among postmenopausal hormone ever-users was 82 per 10,000 woman-years of follow-up compared with 124 per 10,000 among never-users. Postmenopausal hormone use remained a protective factor against stroke incidence (relative risk, 0.69; 95% confidence interval, 0.47 to 1.00) and stroke mortality (relative risk, 0.37; 95% confidence interval, 0.14 to 0.92) after adjusting for the baseline risk factors of age, systolic blood pressure, diabetes, body mass index, smoking, history of hypertension and heart attack, and socioeconomic status. CONCLUSIONS: The results suggest that postmenopausal hormone use is associated with a decrease in risk of stroke incidence and mortality in white postmenopausal women.

Aged↗
PubMed1993

Medical conditions associated with driving cessation in community-dwelling, ambulatory elders.

The decision to stop driving leads to severe contraction of independence, and most localities do not curtail driving privileges in impaired elders. In a population of community-based, ambulatory individuals 70-96 years old, annual medical screening showed that 276 of 1,656 (16.7 +/- 1.8%) who reported driving regularly in the past do not currently drive. The cessation of driving behavior was examined in terms of specific medical conditions occurring within the past 5 years. Retired drivers were disproportionately female, and driving cessation risk rose with age. Age-sex-adjusted logistic regression found that six conditions explained about 50 percent of the decisions to stop driving: macular degeneration; retinal hemorrhage; any deficit in Activities of Daily Living; Parkinson's disease; stroke-related residual paralysis or weakness; and syncope. Strikingly, only 1.8 percent of those who stopped driving had ever had a license revoked; 58.7 percent reported voluntarily stopping; 31.9 percent gave health or medical reasons. Clearly, the decision to cede driving privileges is complex and not dependent solely on medical problems.

Aged↗
PubMed1993

Tamoxifen for the primary prevention of breast cancer: a review and critique of the concept and trial.

This paper has reviewed the rationale for and design of the NSABP Breast Cancer Prevention Trial and has provided a brief critique of the philosophy of chemoprevention of breast cancer and of certain practical aspects of the trial design. If the assumptions and estimates from the trial protocol are correct, the net benefit of the trial will be moderately large and positive (50 to 77 events prevented). However, over 500 women per year will be treated with tamoxifen unnecessarily. Recalculation of the net-benefit table using another set of reasonable assumptions regarding risks and the trial assumptions regarding benefits shows a negative effect to a small positive effect overall (-17 to 8 events). If the probability of adverse ocular events is included in the net-benefit equations, it appears that more harm than good will result from the intervention. In the face of the uncertainty regarding the net benefit of the trial, ranges of these risks and benefits should be provided to both potential and enrolled participants. The lack of significant benefit to participants seen with the recalculations may raise the question of whether the trial should continue as designed. One option would be to limit trial participation to postmenopausal women only, since 1) breast cancer is more common in postmenopausal women, 2) tamoxifen is more effective in postmenopausal women, 3) cardiovascular disease is more common in postmenopausal women, and 4) reductions in cholesterol levels and preservation of bone mass have only been documented in postmenopausal women (11, 27). Even in this case, however, the fundamental philosophical question of whether large numbers of healthy women should be "treated" with a toxic drug for the primary prevention of a rare event remains.

Adult↗
PubMed1993

Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. The CHS Collaborative Research Group.

BACKGROUND: Postmenopausal estrogen replacement therapy has been associated with favorable levels of cardiovascular disease risk factors, but these associations and the relations between estrogen use and subclinical disease have not been examined in large samples of older women. METHODS AND RESULTS: Present and past estrogen use was ascertained in 2955 women > or = 65 years old in the Cardiovascular Health Study, a study of risk factors for coronary heart disease and stroke in the elderly. Present estrogen use was reported by 12% of these women and past use by an additional 26.5%. Estrogen use (past or present) was strongly associated with lower low-density lipoprotein cholesterol, fibrinogen, glucose, insulin, obesity, and age and higher high-density lipoprotein cholesterol and socioeconomic status (all P < .0001). Estrogen users also had lower levels of subclinical disease as measured by carotid intimal-medial thickness, carotid stenosis grade, ECG left ventricular mass, and Doppler mitral peak flow velocities (each P < .02). Relations were similar in younger and older women (65 to 74 versus > or = 75 years) and smokers and nonsmokers and were unchanged after women with poor medication compliance were excluded. After adjustment for other factors, estrogen use was associated with decreased carotid wall thickness, although this association was of borderline significance after further adjustment for lipids. CONCLUSIONS: Postmenopausal estrogen use in this sample of older women was associated with favorable cardiovascular disease risk factor profiles and with lower measures of subclinical disease. These findings suggest that postmenopausal estrogen use may be associated with lower risk of cardiovascular disease in women well into the eighth decade of life.

Aged↗
PubMed1992

Aging and total cholesterol levels: cohort, period, and survivorship effects.

This analysis describes the association of age with the serum total cholesterol level in 5,010 participants in a geriatric health screening program. Cholesterol levels were measured annually in participants monitored for up to 12 years. The association of age with cholesterol level is described via three approaches: cross-sectional analysis, descriptive longitudinal analysis, and longitudinal analysis using statistical modeling. The results were compared to examine the influence of cohort, period, and survivorship effects on the association between age and cholesterol. In cross-sectional analysis, the cholesterol level was fairly constant for the ages of 65 to 75 years, but decreased by 21% over the age range from 75 to 95 years. Descriptive longitudinal analysis suggested that both cohort and period effects were influencing the cross-sectional findings. In longitudinal analysis adjusting for both cohort and period effects, the findings were similar to those from cross-sectional analysis for the ages of 65 to 75 years, but from the ages of 75 to 95 years, cholesterol decreased by only 9%--half as great a decline as that estimated from cross-sectional analysis. When longitudinal data were limited to those with complete follow-up, the predicted decline for the age range from 75 to 95 years was only 6%. Although this flattening of the age trend was suggestive, there was no conclusive evidence that it reflected an association between baseline cholesterol and loss to follow-up.

Age Factors↗
PubMed1992

Serum retinol, beta-carotene, vitamin E, and selenium as related to subsequent cancer of specific sites.

Case-control differences in prediagnostic serum levels of retinol, beta-carotene, vitamin E, and selenium are compared for 10 cancer sites in 10 study populations. For all four nutrients, the majority of results showed lower levels among persons who subsequently became cases than among controls. Low levels of beta-carotene were most likely to be associated with subsequent cancer, but there were marked differences by cancer site. The results indicate that it is unlikely that any of these serum micronutrients are associated with protection against carcinogenesis at all sites. A plea is made for greater emphasis on replication of results, for reporting findings for all sites no matter how small the number of cases may be, and for keeping constantly in mind the fact that observational associations are not necessarily causal in nature.

Antioxidants↗
PubMed1992

Relationship of prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing premenopausal breast cancer.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are steroids which may be associated with the development of breast cancer. To examine the association between serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate and the risk of developing premenopausal breast cancer, we measured hormone levels in 15 women who donated blood to a community-based serum bank in 1974 and who subsequently developed premenopausal breast cancer and in 29 matched controls from the same group of volunteers. The mean serum level of dehydroepiandrosterone among cases was 10% lower than among controls. The risk of developing breast cancer for women in the highest tertile compared with the lowest tertile of serum dehydroepiandrosterone was 0.40 with a suggestion of a dose-response trend with increasing levels. No consistent association between dehydroepiandrosterone sulfate and the risk of premenopausal breast cancer was evident. In contrast to postmenopausal breast cancer, a protective effect of dehydroepiandrosterone against premenopausal breast cancer is suggested, but because of the small sample size, the results of this study need to be replicated by others.

Adolescent↗
PubMed1992

Lipoprotein lipids in older people. Results from the Cardiovascular Health Study. The CHS Collaborative Research Group.

BACKGROUND: Cardiovascular disease is the leading cause of death and disability in older people. There is little information about the distributions of risk factors in older populations. This article describes the distribution and correlates of lipoprotein lipids in people greater than or equal to 65 years old. METHODS AND RESULTS: Lipoprotein lipid concentrations were measured in 2,106 men (M) and 2,732 women (F) who were participants in the Cardiovascular Health Study, a population-based epidemiological study. Distributions of lipids by age and sex and bivariate and multivariate relations among lipids and other variables were determined in cross-sectional analyses. Mean concentrations of lipids were cholesterol: M, 5.20 +/- 0.93 mmol/l (201 +/- 36 mg/dl) and F, 5.81 +/- 0.98 mmol/l (225 +/- 38 mg/dl); triglyceride (TG): M, 1.58 +/- 0.85 mmol/l (140 +/- 75 mg/dl) and F, 1.57 +/- 0.78 mmol/l (139 +/- 69 mg/dl); high density lipoprotein cholesterol (HDL-C): M, 1.23 +/- 0.33 mmol/l (48 +/- 16 mg/dl), and F, 1.53 +/- 0.41 mmol/l (59 +/- 16 mg/dl); low density lipoprotein cholesterol (LDL-C): M, 3.27 +/- 0.85 mmol/l (127 +/- 33 mg/dl) and F, 3.57 +/- 0.93 mmol/l (138 +/- 36 mg/dl). The total cholesterol to HDL-C ratios were M, 4.49 +/- 1.29 and F, 4.05 +/- 1.22. TG, total cholesterol, and LDL-C concentrations were lower with increasing age, the last more evident in men than in women. TG concentration was positively associated with obesity (in women), central fat patterning, glucose intolerance, use of beta-blockers (in men), and use of estrogens (in women) and negatively associated with age, renal function, alcohol use, and socioeconomic status. In general, HDL-C had opposite relations with these variables, except that estrogen use was associated with higher HDL-C concentrations. LDL-C concentration was associated with far fewer variables than the other lipids but was negatively associated with age in men and women and positively correlated with obesity and central fat patterning and negatively correlated with renal function and estrogen use in women. There were no differences in total cholesterol and LDL-C concentrations among participants with and without prevalent coronary heart disease and stroke, but TG concentration was higher and HDL-C lower in men with both coronary heart disease and stroke and in women with coronary heart disease. CONCLUSIONS: Cholesterol and cholesterol/HDL-C ratio were lower and HDL-C higher than previously reported values in older people, suggesting that lipid risk profiles may be improving in older Americans. TG and HDL-C concentrations, and to a lesser extent LDL-C, were associated with potentially important modifiable factors such as obesity, glucose intolerance, renal function, and medication use.

Aged↗
PubMed1992

Prediagnostic serum levels of 1,25-dihydroxyvitamin D and malignant melanoma.

A prospective nested case-control study of the relationship between prediagnostic serum levels of 1,25-dihydroxyvitamin D and subsequent development of malignant melanoma was done to test the hypothesis that increased levels are protective. Serum from 23 cases of malignant melanoma that developed between 1975 and 1987 in donors to the Washington County, Maryland serum bank was assayed along with that from 46 matched controls. There were no demonstrable differences among controls by sex, age, smoking or use of multivitamin supplements. The mean serum levels of 1,25-dihydroxyvitamin D were only 5% lower among cases than controls, a difference that could easily have occurred by chance.

Adolescent↗
PubMed1991

Estrogen and coronary heart disease in women.

We review herein the evidence that estrogen is protective against the development of cardiovascular disease in women. To our knowledge, no studies in women have looked at endogenous estrogen levels as predictors of cardiovascular disease. Studies of surrogate measures of endogenous estrogen such as parity, age at menarche, and age at menopause have provided inconsistent results. Current use of oral contraceptives increases risk in older women who smoke cigarettes, but most studies of past use show no increased risk. Most, but not all, studies of hormone replacement therapy in postmenopausal women show around a 50% reduction in risk of a coronary event in women using unopposed oral estrogen. These important observations need to be confirmed in a double-blind, randomized clinical trial, since the protection is biologically plausible and the magnitude of the benefit would be quite large if selection factors can be excluded.

Age Factors↗