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[Serum cholesterol and cancer. Is there a causal relationship?].

Several studies have reported an inverse relationship between serum cholesterol levels and the risk of cancer, especially of the colon (Seven Countries, Framingham, Chicago studies, London Whitehall Study, Paris prospective study, New Zealand Maori, Honolulu Heart Study, Hypertension Detection and Follow-Up Program, ...). For example, in the Multiple Risk Factor Intervention Trial (361 662 men), the global mortality graph was J-shaped, higher at either side of the 4.6-5.1 mmol/l value of serum cholesterol. This increased mortality with lower serum cholesterol levels was due to increased numbers of death from cancer. However, when the relationship is studied with respect to the time elapsed between the cholesterol measurement and death from cancer, the relative risk of death in the lowest decile with respect to the average of the following deciles, decreases with the period between measurement of the serum cholesterol and time of death. The negative relationship between serum cholesterol and death by cancer, very significant for deaths occurring within the first 5 years, disappeared almost completely for deaths occurring after 5 years. Other trials designed mainly to examine cardiovascular risk, and concerning smaller numbers, have not demonstrated this inverse relationship between serum cholesterol and cancer. This negative relationship between serum cholesterol and cancer must be acknowledged. It is weak and concerns mainly colonic cancer, especially in men in the elderly age groups. Several explanations have been put forward: influence of the combination of factors, competition of risk of death by other causes, chance, alteration of normal biological function of the cell membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

[Is regression of atherosclerosis possible?].

Experimental studies have shown the regression of atherosclerosis in animals given a cholesterol-rich diet and then given a normal diet or hypolipidemic therapy. Despite favourable results of clinical trials of primary prevention modifying the lipid profile, the concept of atherosclerosis regression in man remains very controversial. The methodological approach is difficult: this is based on angiographic data and requires strict standardisation of angiographic views and reliable quantitative techniques of analysis which are available with image processing. Several methodologically acceptable clinical coronary studies have shown not only stabilisation but also regression of atherosclerotic lesions with reductions of about 25% in total cholesterol levels and of about 40% in LDL cholesterol levels. These reductions were obtained either by drugs as in CLAS (Cholesterol Lowering Atherosclerosis Study), FATS (Familial Atherosclerosis Treatment Study) and SCOR (Specialized Center of Research Intervention Trial), by profound modifications in dietary habits as in the Lifestyle Heart Trial, or by surgery (ileo-caecal bypass) as in POSCH (Program On the Surgical Control of the Hyperlipidemias). On the other hand, trials with non-lipid lowering drugs such as the calcium antagonists (INTACT, MHIS) have not shown significant regression of existing atherosclerotic lesions but only a decrease on the number of new lesions. The clinical benefits of these regression studies are difficult to demonstrate given the limited period of observation, relatively small population numbers and the fact that in some cases the subjects were asymptomatic. The decrease in the number of cardiovascular events therefore seems relatively modest and concerns essentially subjects who were symptomatic initially. The clinical repercussion of studies of prevention involving a single lipid factor is probably partially due to the reduction in progression and anatomical regression of the atherosclerotic plaque.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

[Optimal serum cholesterol and efficacy of methods for lowering cholesterolemia].

Analysis of epidemiological studies enables definition of the optimal serum cholesterol level between 2 and 2.2 g/l (5.2 and 5.7 mmol/l). Higher levels are associated with an exponential risk of coronary artery disease: lower levels should be interpreted with caution because of the J-shaped curve of global mortality reported in several trials. In primary prevention, therapeutic trials have clearly shown that a significant reduction in the number of coronary event may be obtained by lowering the serum cholesterol (15 for every 1,000 patients treated). In trials performed to date this benefit has not resulted in any gain in global mortality. In secondary prevention, the benefits of lowering serum cholesterol on the incidence of coronary disease seems identical in terms of relative risk to that observed in primary prevention. Nevertheless, the benefits in terms of absolute risk are much higher because of the high incidence of coronary mortality in a patient population with a previous coronary event. Thus, for 1,000 patients treated, there are 50 less cardiac events and this is reflected in a reduction of global mortality of about 20 for every 1,000 patients treated.

Cholesterol↗

[Should men aged 20 to 30 years with hypercholesterolemia be managed in the same way as older men?].

Serum cholesterol intervention studies have been mainly performed in middle-aged men. Is the extrapolation of these results to men aged 20 to 30 years justified? Atherosclerosis is a process which continues throughout life. It is clear that increased serum cholesterol levels are associated with a higher coronary risk. In addition, serum cholesterol levels increase with age up to 60 years old. Do young men obtain the same benefits from medical intervention as older men? Therapeutic trials have been performed in middle-aged men. The increase in life expectancy associated with a 6.7% lowering of the serum cholesterol by life-long dietary restrictions would only be 4 months in 20 year old subjects at high risk (hypertension, smokers, low HDL cholesterol). With a 20% reduction in serum cholesterol, the gain would be 12 months. There is no reason for not extrapolating acquired data in the over 30s to 20 to 30 year old subjects. Due to the fact that young subjects are exposed to the risk for longer periods, it is advisable to treat their hypercholesterolaemia even more seriously than that of older patients.

Adult↗

[Should hypercholesterolemic women be treated?].

There have been few studies designed to evaluate the problem of hypercholesterolaemia in women despite the fact that, like men, cardiovascular disease is their main cause of death. Serum cholesterol is a risk factor in women, but the increased risk appears at much higher values of serum cholesterol than observed in men. In women, low HDL-cholesterol seems to be the best predictive factor for the occurrence of a coronary event, especially if the triglycerides are raised. The absence of therapeutic data on the treatment of hypercholesterolaemia in women underlines the need for a specific trial to assess the effects of lipid-lowering drugs in this population. The cardiovascular benefits of hormone substitute therapy at the menopause have been reported in several studies and a large scale randomised trial is under way to confirm these results. The benefit of hypercholesterolaemic therapy in women with mild hypercholesterolaemia has not been proved. When the serum cholesterol level is over 3 g/l (7.77 mmol/l), early treatment is advisable.

Adult↗

Reversibility of left ventricular hypertrophy.

Left ventricular hypertrophy (LVH) is a powerful independent risk factor for coronary artery disease. This overview of 104 studies examines the ability of various types of antihypertensive therapies to reverse LVH as assessed by echocardiography. Combination therapy, angiotensin converting enzyme (ACE) inhibitors, and methyldopa were the most effective in reversing LV mass; vasodilators such as minoxidil and hydralazine had no effect on LVH. These differences were independent of the degree of fall in blood pressure and duration of therapy. beta-blockers were as effective as ACE inhibitors in decreasing LV wall thickness. Possible reasons for drug differences in reversing LVH are discussed. Preliminary evidence suggests that reversing LVH by antihypertensive drug therapy is associated with a reduction in cardiovascular complications.

Antihypertensive Agents↗

Cholesterol reduction in single and multifactor randomized trials: relationship to CHD incidence and total mortality as found by meta analysis of twenty-two trials.

This paper reports on a meta analysis in twenty-two randomized both single and multifactor trials regarding the effect of designed cholesterol reduction on total mortality and CHD incidence. Per cent reduction in CHD incidence was 2.5 for every per cent associated net reduction in total cholesterol, but was only 0.74% for total mortality. Since total net reduction in cholesterol was about 5% in all trials combined, the number of participants was far too small to demonstrate a significant expected reduction of 4% in total mortality. However, the 4% reduction lies just outside the observed 95% confidence limits of the overall estimate of effect on total mortality (OR = 1.02; CL 0.97, 1.07). It is concluded that cholesterol reduction must be much larger than 5% to be able to reduce the relative risk of CHD substantially and total mortality moderately.

Cholesterol↗

Efficacy of tianeptine in comparative trials versus reference antidepressants. An overview.

The clinical properties of tianeptine have been assessed in double-blind controlled studies, which involved depressed patients fulfilling DSM-III criteria for either major depression--single episode or recurrent (without melancholia and psychotic features)--or dysthymic disorder--with or without an additional diagnosis of alcohol abuse or dependence. Five studies have compared tianeptine with reference antidepressants: its efficacy has been found to be similar to that of amitriptyline in depressed out-patients. However, these data need to be confirmed by other controlled trials v. reference drugs and by at least two placebo-controlled studies. Tianeptine does not induce sleep disorders, anticholinergic effects, or modifications of cardiovascular variables or biological parameters (renal, haematological, or hepatic). After the end of treatment, the only signs of withdrawal have been some disturbances of sleep.

Amitriptyline↗

A quantitative assessment of oral contraceptive use and risk of ovarian cancer.

OBJECTIVE: To provide a quantitative assessment of the association between oral contraceptive (OC) use and ovarian cancer using results from the published literature. DATA SOURCES: We conducted a MEDLINE literature search for all epidemiologic studies of OC and ovarian cancer published in English between 1970-1991. The reference list for each article was reviewed to locate additional published articles. METHODS OF STUDY SELECTION: We included 20 studies in which a relative risk and either a standard error, confidence interval, or P value was reported, or sufficient data were presented to allow us to calculate these measures. DATA EXTRACTION AND SYNTHESIS: We summarized the findings using weighted averages and regression analyses. We found a summary relative risk of 0.64 (95% confidence interval 0.57-0.73) associated with ever-use of OC, indicating a 36% reduction in ovarian cancer risk. The risk of ovarian cancer decreased with increasing duration of OC use; we noted a 10-12% decrease in risk with 1 year of use and approximately a 50% decrease after 5 years of use. The reduced risk was present among both nulliparous and parous women and it appeared to last for at least 10 years after cessation of use. Although most studies assessed the use of cessation of use. Although most studies assessed the use of OC formulations from the 1960s and 1970s, data from the Cancer and Steroid Hormone Study indicate that the decreased ovarian cancer risk may also be present with current lower-dose formulations. CONCLUSION: The protective effect of OC against ovarian cancer risk should be considered in a woman's decision to use OC.

Contraceptives, Oral↗

The business of preventing African-American infant mortality.

African-American women are twice as likely as women from other ethnic groups to have babies with low birth weights and to experience the loss of infant death. The problem is so endemic in black communities in Alameda County, California, that numerous programs have been developed over the past decade to reduce maternal risk factors and eliminate barriers to prenatal care. Despite these efforts, African-American ethnicity continues to be a major risk factor for infant mortality for reasons that are poorly understood. We take a critical look at 3 types of studies characteristic of infant mortality research: epidemiologic, studies that advocate prenatal care, and ethnomedical (cultural). We argue that the assumptions informing this research restrict the thinking about infant mortality and the political issues involved in how prevention programs are developed and structured. The persistent focus on maternal behavioral characteristics limits more in-depth analysis of the micropolitics of perinatal bureaucracies established in response to this ongoing crisis.

Black or African American↗

Chemicals classified by IARC: their potency in tests for carcinogenicity in rodents and their genotoxicity and acute toxicity.

Chemicals classified by the IARC to its groups 1, 2A, 2B and 3 were examined in an attempt to identify characteristics of their behaviour in experimental studies of carcinogenicity, genotoxicity and acute mammalian toxicity that correlate with those categories. Only those agents for which information on carcinogenic potency was available were studied. In both mice and rats, more chemicals were potent carcinogens if they had been categorized in Group 1 (human carcinogens) than if they had been put into one of the other categories. Not surprisingly, there was a weak association between carcinogenic potency and acute toxicity. Mice were especially sensitive to tumour induction by halides; the lower sensitivity of rats to any carcinogenic effect of halides could be due in part to their higher systemic toxicity in this species: a reduced differential of toxic and carcinogenic doses decreases the dose window in which carcinogenic effects may be demonstrated. It was notable that the human carcinogens were active in those genotoxicity tests with higher specificity for identifying rodent carcinogens. Predictive assays for carcinogenicity that were considered to be highly specific were tests for cytogenetic effects in vivo, unscheduled DNA synthesis in hepatocytes, mutation in any of the five commonly used strains of Salmonella typhimurium and mutation at the hprt locus in mammalian cells. None of the relationships was strong enough to form the basis of a simple categorization, but they could serve to alert investigators to chemicals of special toxicological interest and importance.

Animals↗

Chemical toxicity and chemical carcinogenesis. Is there a causal connection? A comparative morphological evaluation of 1500 experiments.

Chemicals cause toxic and carcinogenic effects as well as beneficial and other adverse effects in animals and in humans. The purpose of this paper is to assess whether there is a direct, uniform causal relationship between toxicity and carcinogenicity. Within this context, specific issues receive attention: the influence of exposure concentrations on carcinogenesis; kidney cancer and alpha 2 mu-globulin; urinary calculi and tumours; and cell turnover or proliferation and cancer. The data used to evaluate histopathological site-specific correspondence between these two end-points comes from 130 studies of chemical carcinogenesis designed and conducted by the US National Toxicology Program (NTP). Nearly 1500 sex-species-exposure group experiments were evaluated for morphological evidence of toxicity and/or carcinogenicity, for dose-response relationships, and for site-specific correlations of toxicity and carcinogenicity. The major conclusions are that chemicals evaluated for long-term toxicity and carcinogenicity in experimental animals can be divided into three categories: (1) those that cause organ toxicity without cancer, (2) those that cause site-specific cancer with no associated toxicity and (3) those that cause toxicity and cancer in the same organ. Examples are given to illustrate each category. On the basis of this comparative analysis, in the great majority of cases the available data do not support a correlation between chemically induced toxicity and carcinogenicity. Moreover, until considerably more scientific knowledge about molecular mechanisms of carcinogenesis becomes available and accepted, attempts to use findings on toxicity to modify the risk assessment process will be fraught with uncertainty and might even have a negative impact on public health.

Animals↗

Overall safety of Arthrotec.

Data from four double-blind studies of the treatment of patients with rheumatoid arthritis or osteoarthritis were combined. For 4 to 12 weeks, 747 patients received Arthrotec, a combination of 50 mg of diclofenac and 200 micrograms of misoprostol, and 754 patients received 50 mg of diclofenac; the drugs were given twice or three times daily. The five most commonly reported adverse events were abdominal pain by 23.2% of the diclofenac/misoprostol patients and 19.8% of the diclofenac patients; diarrhea by 19.9% and 11.3%; nausea by 11.8% and 6.5%; dyspepsia by 11.2% and 7.8%; and flatulence by 8.0% and 3.1%. Other adverse events, reported by similar proportions of both treatment groups, included headache, gastritis, dizziness, vomiting, and constipation. In the diclofenac/misoprostol-treated patients, the abdominal pain and diarrhea were rated mild in 30.6% and 24.3%, moderate in 49.1% and 51.4%, and severe in 20.2% and 24.3%. Serious adverse events occurred in eight of the diclofenac/misoprostol-treated patients and in 13 of the diclofenac-treated patients; 12.6% and 10.1%, respectively, were withdrawn from the study because of adverse events. Results of laboratory tests of hepatic and renal function were similar in the two treatment groups.

Administration, Oral↗