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T L Bush

Publications and source records attributed to T L Bush.

At least 73 records · Page 4Linked to original sources
PubMed1991

Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-L-methionine.

We reported recently that administration of ([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811), an enzyme-activated irreversible inhibitor of S-adenosyl-L-methionine decarboxylase (AdoMetDC; EC 4.1.1.50), a key enzyme in the synthesis of spermidine, cures African trypanosome infections in mice. The precise mechanism of action of MDL 73811 was not clear because a rapid disappearance of trypanosomes from the bloodstream of treated rats occurred before significant depletion of spermidine. Administration of MDL 73811 to Trypanosoma brucei brucei-infected rats resulted in a 70% decrease in parasitaemia within 1 h and a complete disappearance of parasites by 5 h. The reduction in parasitaemia was accompanied by complete inhibition of AdoMetDC activity by 10 min after injection of MDL 73811; inhibition was sustained for at least 4 h. Polyamine levels in trypanosomes were unaffected during the first 1 h in which the marked decrease in parasitaemia was observed, but parasite AdoMet levels increased 20-fold within this time. In contrast, exposure of cultured mammalian cells to MDL 73811 resulted in only a 1.5-2-fold increase in AdoMet levels over a 6 h time course. Experiments with inhibitors of ornithine decarboxylase (ODC) also suggested that the increased AdoMet levels might be an important factor for antitrypanosomal efficacy. Trypanosomes taken from rats treated for 36 h with eflornithine, an inhibitor of ODC, were depleted of putrescine and had markedly decreased spermidine levels. These organisms also had less than 10% of control AdoMetDC activity, and had elevated decarboxy AdoMet (greater than 4000-fold) and AdoMet (up to 50-fold) levels. The methyl ester of alpha-monofluromethyl-3,4-dehydro-ornithine (delta-MFMO-CH3), which cures murine T. b. brucei infections, and the ethyl ester analogue of this compound (delta-MFMO-C2H5), which does not cure this infection, become ODC inhibitors upon hydrolysis and thus were tested for their effects on trypanosomal polyamines, AdoMet and decarboxy AdoMet levels. Although both esters of delta-MFMO depleted trypanosomal polyamines, AdoMet and decarboxy AdoMet levels were elevated in T. b. brucei from infected mice treated with delta-MFMO-CH3 but not in parasites from mice treated with the delta-MFMO-C2H5. These data suggest that inhibition of AdoMetDC, either directly with MDL 73811 or indirectly with inhibitors of ODC, apparently leads to a trypanosome-specific elevation of AdoMet. It is possible that major changes in AdoMet, rather than changes in polyamines, may be responsible for the antitrypanosomal effects of these drugs.

Adenosylmethionine Decarboxylase↗
PubMed1991

Extraskeletal effects of estrogen and the prevention of atherosclerosis.

A cumulative effect has been calculated by Henderson et al. concerning the estimated changes in mortality with estrogen therapy. Even assuming a twofold increase in the risk of breast cancer, the benefits derived from reduction of osteoporotic fractures and the decreased risk of heart disease, demonstrate a 41% decrease in mortality in women who receive estrogen therapy. Since cardiovascular disease is the major cause of morbidity and mortality in postmenopausal women, and since the beneficial effects of estrogen outweigh the documented and perceived risk of estrogen use, estrogen ought to be considered as prophylactic therapy, particularly in women at risk of heart disease.

Arteriosclerosis↗
PubMed1991

Prediagnostic serum levels of carotenoids and vitamin E as related to subsequent cancer in Washington County, Maryland.

In 1974 and 1975, serum specimens were collected from 25,802 volunteers in Washington County, Maryland. The serum was kept frozen at -73 degrees C until the time of assay. Prediagnostic samples from 436 cancer cases and 765 matched control subjects have been assayed. Nine sites have been studied: colon, rectum, pancreas, lung, melanoma, basal cell of skin, breast, prostate, and bladder. Serum beta-carotene levels showed a strong protective association with lung cancer, suggestive protective associations with melanoma and bladder cancer, and a suggestive but nonprotective association with rectal cancer. Serum vitamin E levels had a protective association with lung cancer; none of the other sites showed impressive associations. Low levels of serum lycopene were strongly associated with pancreatic cancer and less strongly associated with cancer of the bladder and rectum.

Adult↗
PubMed1991

Screening for total cholesterol. Do the National Cholesterol Education Program's recommendations detect individuals at high risk of coronary heart disease?

BACKGROUND: The National Cholesterol Education Program (NCEP) has provided guidelines for identification of persons at high risk of coronary heart disease (CHD) because of lipid abnormalities. These recommendations are based on total cholesterol as the initial screening tool and have become the stimulus for clinic- and community-based screening programs nationwide. However, the use of the guidelines may be problematic because individuals may have total cholesterol levels in the desirable range but low density lipoprotein (LDL) or high density lipoprotein (HDL) levels considered at high risk. This study evaluates the ability of the NCEP screening recommendations to identify correctly persons at high risk of CHD because of lipid abnormalities. METHODS AND RESULTS: Using the NCEP guidelines, we simulated a population-based screening program with data from visits 1 and 2 of the Lipid Research Clinics Program Prevalence Study. Individuals were considered to be at high risk of CHD if they had LDL levels greater than 160 mg/dl or HDL levels less than 35 mg/dl. Following the NCEP process, 21% of those with high LDL concentrations and 66% of those with low HDL concentrations would not be routinely referred for immediate treatment. Overall, 41% of those at high risk of CHD would not be promptly evaluated. The sensitivity of the guidelines for promptly identifying individuals with lipoprotein abnormalities is 59%. CONCLUSIONS: This relatively low sensitivity of total cholesterol as a screening tool should be the impetus for rethinking the screening guidelines. Specifically, the cost-benefit ratio of routine screening for lipoproteins, particularly HDL cholesterol, needs to be carefully considered.

Adult↗
PubMed1991

Estrogen therapy and cardiovascular risk in women.

Estrogen therapy in women has traditionally been used for the relief of menopausal symptoms and protection from osteoporosis. Recently, there has been a growing body of evidence suggesting that estrogen therapy protects against cardiovascular disease in women. An epidemiologic review of the literature demonstrates an approximately 50% reduction in cardiovascular risk in women using estrogen. A brief review of indications, complications, and routes of estrogen administration is presented. Current areas of controversy include the effects of parenteral estrogen administration and progestin administration on the cardioprotective aspects of estrogen therapy and the risk of breast cancer in estrogen users. Further study in these areas is needed.

Coronary Disease↗
PubMed1990

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

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids that are produced in the adrenal cortex. A number of studies have suggested that circulating levels of these hormones are related in some way to the risk of developing breast cancer. We measured serum levels of these steroids in 30 postmenopausal women who donated blood in 1974 for a community-based serum bank and who subsequently, at least 9 years later, developed breast cancer and in 59 matched controls from the same group of volunteers. Significantly elevated serum levels of dehydroepiandrosterone were found among cases prior to diagnosis compared to controls; serum levels of dehydroepiandrosterone sulfate were slightly increased among cases. In controls, current cigarette use was associated with increased serum levels of these steroids, and levels of both steroids decreased with age.

Aged↗
PubMed1990

Bis(benzyl)polyamine analogs as novel substrates for polyamine oxidase.

N,N'-Bis(benzyl)polyamine analogs were found to be substrates for highly purified polyamine oxidase. Metabolism of these analogs was apparently dependent on molecular O2 and resulted in the formation of benzaldehyde, H2O2, and a polyamine analog with free terminal amines. The debenzylation reaction was optimal between pH 9 and 10, identical to the pH optimum for polyamine oxidase activity when N1-acetylspermine was used as the substrate. On a molecular sieve column the debenzylating activity co-eluted with N1-acetylspermine oxidizing activity, at an apparent molecular mass of approximately 65 kDa. The purified enzyme also appeared to have a molecular mass of approximately 65 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Debenzylation of the bis(benzyl)polyamines was competitively inhibited by N1-acetylspermine and N1-acetylspermidine. The specific irreversible inhibitor of polyamine oxidase, N1,N4-bis(buta-2,3-dienyl)butanediamine also inhibited the debenzylation, whereas inhibitors of diamine and monoamine oxidases did not. The evolution of benzaldehyde from bis(benzyl)polyamine analogs by polyamine oxidase allowed the development of a simple rapid spectrophotometric assay for use in the measurement of polyamine oxidase activity in partially purified tissue or cell extracts. Further, metabolism of a bis(benzyl)polyamine analog by polyamine oxidase was found to be an important element in the growth inhibitory properties of the compound in a mouse model of malaria.

Animals↗
PubMed1990

Diabetes mellitus and other cardiovascular risk factors in an elderly population.

The purpose of this study was to describe the prevalence of diabetes in a community-dwelling elderly population, and to assess whether other cardiovascular disease risk factors were more frequent in older diabetics than in non-diabetics. Results suggest that, with the exception of hypertension, other cardiovascular disease risk factors are not more prevalent in older diabetics and do not aggregate in older diabetics. However, there was a very high prevalence of hypertension among older diabetics. Of particular concern is the observation that 40% of diabetic individuals under treatment for hypertension still have unacceptably high blood-pressure levels. These results indicate a need for follow-up of high-blood-pressure treatment in older diabetic people.

Aged↗
PubMed1990

Cancer mortality and lipid and lipoprotein levels. Lipid Research Clinics Program Mortality Follow-up Study.

The associations of serum lipid and lipoprotein levels with the risk of cancer mortality were assessed in 2,753 men and 2,476 women aged 40-79 years at baseline (1972-1976) who participated in the Lipid Research Clinics Program Mortality Follow-up Study through 1984. Seventy-nine cancer deaths occurred in men and 65 occurred in women during an average follow-up time of 8.4 years. Total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly inversely associated with overall cancer mortality in men, but no relation was observed in women. Neither high-density lipoprotein (HDL) cholesterol nor triglycerides were significantly related to total cancer mortality in either sex, although in women. HDL cholesterol was positively associated with risk of death from gynecologic cancers. Compared with men with higher cholesterol levels, the relative risk of death from colon cancer, adjusted for age, body mass, cigarette smoking, and alcohol consumption, was 5.20 (95 percent confidence interval (Cl) 1.61-16.8) in men with total cholesterol levels less than or equal to 187 mg/dl and 4.79 (95 percent CI 1.37-16.8) in those with LDL cholesterol levels less than or equal to 119 mg/dl. Death from smoking-related cancers was inversely related to baseline total cholesterol but not to LDL cholesterol. The absence of an association with HDL cholesterol, which has been shown to be lower in persons with clinically manifest malignancy, and evidence from survival curves suggest that the inverse relation in men is not due to preexisting disease.

Adult↗
PubMed1990

The epidemiology of cardiovascular disease in postmenopausal women.

This manuscript has described the principal modifiable risk factors for the major killer of postmenopausal women. Clearly women who smoke should be convinced to quit, and those who have hypertension and hypercholesterolemia should be encouraged initially to adopt hygienic interventions (that is weight reduction and moderate exercise) to lower their blood pressures and cholesterol levels. Further, given the magnitude of the risk reduction in CVD seen in estrogen users, estrogen use ought to be considered as a preventive therapy for postmenopausal women, but particularly for those who are at high risk of cardiovascular disease.

Blood Pressure↗
PubMed1990

Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase.

A structural analog, 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxy adenosine (MDL 73811), of decarboxy S-adenosyl-L-methionine, the product of the reaction catalyzed by S-adenosyl-L-methionine (AdoMet) decarboxylase (DC), was found to inhibit Trypanosoma brucei brucei AdoMet DC. The inhibition was time dependent (tau 50, 0.3 min), exhibited pseudo-first-order kinetics (Ki, 1.5 microM), and was apparently irreversible. The natural substrate of the reaction, AdoMet, protected the enzyme from inactivation, suggesting that MDL 73811 was directed at the enzyme active site and was probably catalytically activated. Administration of MDL 73811 to T. b. brucei-infected rats resulted in rapid inhibition of AdoMet DC activity, a decrease in spermidine, and an increase in putrescine in the trypanosomes isolated from treated rats. Treatment of T. b. brucei-infected mice with MDL 73811 (20 mg/kg of body weight intraperitoneally twice daily for 4 days) resulted in cures of the trypanosome infections. Additionally, drug-resistant T. brucei rhodesiense infections in mice were cured by either a combination of MDL 73811 (50 mg/kg intraperitoneally three times per day for 5 days) and relatively low oral doses of alpha-difluoromethylornithine or MDL 73811 (50 mg/kg per day for 7 days) administered alone in implanted miniosmotic pumps. These data suggest that MDL 73811 and, perhaps, other inhibitors of AdoMet DC have potential for therapeutic use in various forms of African trypanosomiasis.

Adenosylmethionine Decarboxylase↗
PubMed1990

Body mass definitions of obesity: sensitivity and specificity using self-reported weight and height.

A high correlation between continuous measures of self-reported and measured weight and height has led investigators to infer that self-report of these variables is appropriate in epidemiologic studies. We evaluated the sensitivity and specificity of categorical definitions of body mass defined using self-reported height and weight on 7,455 adult participants of the Lipid Research Clinics Family Study (1975-1978) on whom both self-reported and measured height and weight were available. The categorical definition of obesity used here was a body mass index of at least 30 kg/m2. Overall, the sensitivity of the obese category when defined with self-reported weight and height was 74% (95% CI = 72%-76%), and the specificity was 99%. The sensitivities of the categories defined using self-reported measures varied considerably by sex, age, and educational level. Overall, the sensitivities were higher for women compared with men, as men were less accurate in reporting height. The sensitivity of the categorical definitions of obesity decreased with increasing age and education in both men and women. The sensitivity for elderly obese men was below 50%. These results suggest that substantial misclassification can occur when self-reported information is used to define body mass categories.

Adult↗
PubMed1989

Regulation of polyamine biosynthesis in rat hepatoma (HTC) cells by a bisbenzyl polyamine analogue.

A bisbenzyl polyamine analogue, MDL 27695, rapidly repressed ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase (AdoMet DC) activity and depleted polyamines in rat hepatoma (HTC) cells. The suppression of ODC and AdoMet DC activity was temporally related to metabolism of MDL 27695 by intracellular polyamine oxidase to a free-amine analogue, MDL 26752, which, when added directly to HTC cells, suppressed ODC activity and polyamine biosynthesis more rapidly and to a greater extent than did the bisbenzyl analogue. The ODC suppression caused by MDL 27695 was completely blocked by the addition of a polyamine oxidase inhibitor to the HTC-cell cultures along with MDL 27695. These data suggested that MDL 27695 acted as a prodrug, with metabolism to an active analogue being necessary for ODC repression to occur. MDL 27695 and MDL 26752 completely abolished division of HTC cells when added to cultures at 1 microM. This established them as being among the most potent antiproliferative polyamine analogues yet described. MDL 27695 has also been shown to possess significant antimalarial effects both in vitro and in vivo, and it is possible that the marked suppression of polyamine biosynthesis described herein may contribute to its anti-malarial effects as well as its antiproliferative effects in mammalian cells.

Adenosylmethionine Decarboxylase↗
PubMed1989

Blood pressure changes with aging: evidence for a cohort effect.

Data from cross-sectional surveys show an increase in systolic blood pressure with increasing age. However, cross-sectional data can be misleading. Our purpose in this study is to prospectively describe changes in systolic and diastolic blood pressure levels over time in community-dwelling elderly persons. The participants were 1,917 men and women aged 65 to 98 yr who had participated at least seven years in the Florida Geriatric Research Program, a community-based, multi-phasic health screening program located in Dunedin, Florida (USA). Our results show that contrary to the cross-sectional data, systolic and diastolic blood pressure levels tend to decrease with increasing age. Mean systolic blood pressure in women at the baseline visit (Visit 2) was 143 mmHg and three years later (Visit 5) it had dropped to 140 mmHg. This downward trend was consistent at all ages and for both men and women. Stratification by use of antihypertensive medication, weight change, and survivorship did not alter this association. Further follow-up of this cohort to Visit 7 revealed a U-shaped trend of blood pressure with aging. There was also clear evidence of a cohort effect, as the age-specific mean systolic blood pressure was consistently lower in each younger 5 yr birth cohort. Our results suggest that in a healthy elderly population, systolic and/or diastolic blood pressure levels do not increase with aging; this finding may have implications for the diagnosis and treatment of hypertension in the elderly.

Aged↗