[Renin and aldosterone in human arterial hypertension (excluding Conn's syndrome)].
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Adult↗
Biomedical subjects
G Tremblay
Publications and source records attributed to G Tremblay.
EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium.
Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)
Animals↗
Bronchial responsiveness to methacholine in swine confinement building workers.
Bronchial responsiveness to methacholine was measured in 60 swine confinement building workers selected from 461 subjects who participated in a recent epidemiologic survey on the respiratory impact of exposure to this environment. Subjects were divided into the following four groups: group 1, asymptomatic with normal spirometry (n = 16); group 2, asymptomatic with forced expiratory volume in one second/forced vital capacity (FEV1.0/FVC) < 95% predicted (n = 17); group 3, presence of chronic bronchitis with normal respiratory function (n = 13); and group 4, both symptomatic and FEV1.0/FVC < 95% predicted (n = 14). Each subject answered a questionnaire and had a physical examination, PA and lateral chest films, lung volumes and DLCO measurements, and a methacholine bronchoprovocation test. Ages were similar in each group. Physical examination, chest x-rays, and DLCO were normal in all subjects. Values of total lung capacity (TLC) for subjects in group 4 were higher than those of subjects in group 3, and respiratory volume (RV) values of group 4 subjects were higher than those found for all other groups. The provocation dose of methacholine (PC20) was lower for group 4, and the number of subjects with PC20 < 16 mg/ml was greater in this group than in the other groups. We conclude that only swine confinement building workers with both symptoms of chronic bronchitis and abnormal spirometry have an increased bronchial responsiveness to methacholine; however, it is uncertain whether the bronchial responsiveness demonstrated is directly related to the subjects' employment.
Adult↗
Maternal and child reports of behavioral compensation in response to safety equipment usage.
OBJECTIVE: To assess maternal and child risk compensation behaviors in response to several commonly used safety measures. METHODS: We administered a previously validated self-report measure of risk tolerance to a total of 151 mothers and their children in grades 3-7. Mothers indicated the level of risk they would permit their child to assume; children were questioned regarding the degree of physical risk they would typically assume while unsupervised by an adult. Participating families were randomly assigned to conditions in which safety equipment either was or was not present during assessments of risk tolerance. RESULTS: Mothers who viewed the stimulus materials depicting the use of safety precautions reported significantly higher levels of tolerance for risky behavior on the part of their children than did mothers who viewed identical materials without the safety precautions. No significant differences in estimated risk taking emerged between children in the two experimental conditions. CONCLUSIONS: These data may reveal a compensatory mechanism by which parents escalate their threshold for acceptable risk behavior in the presence of safety precautions for their children. Such tendencies have the potential to offset some of the protection provided by the use of safety equipment.
Adolescent↗
Utilization of an antibody specific for human dystrophin to follow myoblast transplantation in nude mice.
Human myoblasts were transplanted in nude mice. The efficacy of these transplantations was analyzed using a monoclonal antibody (NCLDys3) specific for human dystrophin. This antibody did not reveal any dystrophin in nude mice that did not receive a human myoblast transplantation. However, about 30 days after a human myoblast transplantation, dystrophin-positive muscle fibers were observed. They were not abundant, and were present either in small clusters or isolated. This technique follows the fate of myoblast transplantation in animals that already have dystrophin, and distinguishes between new dystrophin-positive fibers due to the transplantation and the revertant fibers in mdx mice. Moreover, this technique does not require any labelling of the myoblasts before transplantation. It can also be used to detect dystrophin produced following the fusion of myoblasts transfected with the human dystrophin gene.
Adolescent↗
[The role of beta-2 stimulators in cardiac insufficiency].
Beta-2 adrenergic stimulators, a class of drugs which has been used for a long time in the treatment of bronchial asthma and in tocolysis, have recently become part of the therapeutic arsenal for congestive heart failure. Their action seems to be essentially vasodilator, although they do have a mild positive inotropic effect. In the short term, they improve the cardiac output and they decrease the peripheral vascular resistance. Their long term haemodynamic effects are still controversial. However, their are some arguments in favour of the persistence of the beneficial effects observed in the short term. They have a contradictory action on the capacity for exercise; one study states that they improve exercise capacity and another study finds that they do not. Their action on the length of survival is still unknown. Some reports suggest that they may aggravate ventricular arrhythmias. At the moment, then, this class of drugs is only used experimentally in congestive heart failure. We need to wait for the results of larger studies on the long-term benefits, the exercise capacity and the survival. Possible side effects also need to be studied in more detail.
Adrenergic beta-Agonists↗
Adherence to management of high blood pressure: recommendations of the Canadian Coalition for High Blood Pressure Prevention and Control.
Adherence or compliance, in the context of medical treatment, refers to how well a patient follows and sticks to the management plan developed with her/his health care provider, which may include pharmacologic agents as well as changes in lifestyle. Adherence is of great concern in asymptomatic conditions such as hypertension, where lack of control may have serious ramifications including end organ damage and premature mortality. To address this issue, the Canadian Coalition for High Blood Pressure Prevention and Control established a national Advisory Committee on Adherence to the Management of High Blood Pressure. The Advisory Committee consisted of 11 members from different disciplines of health care providers. The Committee reviewed all evidences to date and drew up four practical recommendations with respect to patient, provider and environment. Based on Canadian Task Force on Periodic Health Examination's guidelines, all four recommendations can be classified as 'level C' with a quality of evidence of II.
Canada↗
Adherence to non-pharmacologic therapy for hypertension: problems and solutions.
The efficacy of a number of non-pharmacologic interventions in the therapy of primary hypertension has been firmly established. Most prominently, weight reduction, sodium restriction, and alcohol restriction have significant effects on lowering blood pressure. Increased physical activity contributes to management of hypertensive patients in a variety of ways: apart from having a direct impact on blood pressure level, it is an important supportive factor in a weight-reducing regime. The success in applying these non-pharmacologic measures in standard patient population is rather limited. A salient example is the lack of success in weight reduction. Reduction of sodium in the diet is somewhat more successful, however, the problem is that most of the salt intake is non-discretionary. Adherence to physical activity regimes is in the range of what has been observed in pharmacologic therapy. Research and experience in the past few years are providing a better understanding of the factors determining compliance with prescribed therapeutical regimes. Further research is needed to develop innovative strategies for providing efficacious non-pharmacologic measures to hypertensive patients.
Alcohol Drinking↗