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Biomedical subjects

J Rouleau

Publications and source records attributed to J Rouleau.

At least 19 recordsLinked to original sources
PubMed1995

Cholesterol and Recurrent Events: a secondary prevention trial for normolipidemic patients. CARE Investigators.

Although elevated plasma cholesterol levels represent a well-established and significant risk for developing atherosclerosis, there is a wide spectrum of cholesterol levels in patients with coronary artery disease (CAD). Most secondary prevention studies have generated convincing evidence that cholesterol reduction in patients with high cholesterol levels is associated with improved clinical outcome by reducing risk of further cardiovascular events. However, other risk factors may play a prominent role in the pathogenesis of coronary disease in the majority of patients with near-normal cholesterol values. The Cholesterol and Recurrent Events (CARE) study was designed to address whether the pharmacologic reduction of cholesterol levels with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, would reduce the sum of fatal coronary artery disease (CAD) and nonfatal myocardial infarction (MI) in patients who have survived an MI yet have a total cholesterol value < 240 mg/dl (< 6.2 mmol/liter). The other inclusion criteria for this study were age 21-75 years, low density lipoprotein (LDL) cholesterol levels of 115-174 mg/dl (3.0-4.5 mmol/liter), and fasting serum triglyceride levels < 350 mg/dl (< 4.0 mmol/liter). A total of 4,159 eligible consenting patients without other study exclusions were then randomly assigned to receive either pravastatin 40 mg daily or matching placebo in addition to their individualized conventional therapy. The trial was designed to have a median follow-up of 5 years. Study endpoints will be evaluated with respect to predefined subgroups according to baseline lipid values, age, gender, prior cardiovascular risk factors, and history.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Regulation of DNA methylation by the Ras signaling pathway.

We demonstrate that DNA methylation in an adrenocortical tumor cell line, Y1, is controlled by the Ras signaling pathway. Forced expression of a cDNA encoding human GAP120 (hGAP), a down-modulator of Ras activity or delta 9-Jun a transdominant negative mutant of Jun, in Y1 cells reverts the transformed morphology of the cells and results in a reduction in the level of DNA methylation, DNA methyltransferase (MeTase) mRNA, and enzymatic activity. Introduction of an oncogenic Ha-ras into the GAP transfectants results in reversion to a transformed morphology and an increase in the levels of DNA methylation and DNA MeTase activity. Transient transfection CAT assays demonstrate that the expression of DNA MeTase promoter in Y1 cells is regulated by Ras and AP-1. These results establish a molecular link between a major signaling pathway involved in tumorigenesis and DNA methylation.

Adrenal Cortex Neoplasms↗
PubMed1995

Regulation of the DNA methyltransferase by the Ras-AP-1 signaling pathway.

Using deletion analysis and site-specific mutagenesis to map the 5' regulatory region of the DNA methyltransferase (MeTase) gene, we show that a 106-bp sequence (at -1744 to -1650) bearing three AP-1 sites is responsible for induction of DNA MeTase promoter activity. Using transient cotransfection chloramphenicol acetyl-transferase assays in P19 cells, we show that the DNA MeTase promoter is induced by c-Jun or Ha-Ras but not by a dominant negative mutant of Jun, delta 9. The activation of the DNA MeTase promoter by Jun is inhibited in a ligand dependent manner by the glucocorticoid receptor. Stable expression of Ha-Ras in P19 cells results in induction of transcription of the DNA MeTase mRNA as determined by nuclear run-on assays and the steady state levels of DNA MeTase mRNA as determined by an RNase protection assay. These experiments establish a potential molecular link between nodal cellular signaling pathways and the control of expression of the DNA MeTase gene. This provides us with a possible molecular explanation for the hyperactivation of DNA MeTase in many cancer cells and suggests that DNA MeTase is one possible downstream effector of Ras.

Animals↗
PubMed1992

Induction of myogenic differentiation by an expression vector encoding the DNA methyltransferase cDNA sequence in the antisense orientation.

To test the hypothesis that DNA methylation controls the state of differentiation of a mammalian cell, we transfected the stable mesenchymal line 10T1/2 with an expression vector encoding sequences from the DNA methyltransferase (DNA MeTase) cDNA in the antisense orientation. 10T1/2 cells transfected with the antisense construct (pZ alpha M), but not with the vector alone, exhibit morphological changes, convert into multinucleated tubular cells, and express the skeletal myosin heavy chain protein. The conversion to myogenic phenotype is a late event and is dependent on the number of replication events that the cell has undergone, suggesting that induction of myogenesis is a multistep process. Demethylation of sequences that are not involved in the myogenic process is detected at early passages, while demethylation and expression of the MyoD gene is a late event. This report establishes for the first time that demethylation is a very early event in commitment to myogenic differentiation, while demethylation and expression of MyoD is a late event. We suggest that other genes serve as the initial targets for demethylation and commitment of mesenchymal cells to myogenesis. The cell lines described in this report can serve as an important system for identifying these genes.

Animals↗
PubMed1992

The mouse DNA methyltransferase 5'-region. A unique housekeeping gene promoter.

We have cloned and characterized 5'-flanking sequences of the DNA methyltransferase (MeTase) gene. DNA MeTase gene transcription is initiated at a few discrete sites: 343 and 90 base pairs upstream of the translation initiation site as determined by RNase protection and primer extension assays. The promoter sequences that regulate expression of DNA MeTase, as defined by chloramphenicol acetyltransferase assays, reside between position -171 and the transcription start site. The promoter of DNA MeTase does not contain TATAA or CAAT boxes and is unusual because it does not contain the CG-rich elements characteristic of TATAA-less housekeeping genes. The 5'-flanking region of DNA MeTase contains AP-1, AP-2 and glucocorticoid response elements, suggesting possible regulation by cellular signal transduction pathways. The base composition of the DNA MeTase promoter is markedly different from that of other housekeeping genes. Whereas most housekeeping genes are characterized by CG-rich areas in their 5'-flanking regions, the TG dinucleotide is over-represented in DNA MeTase 5'-flanking sequences, including a perfect tandem repeat of T/G between positions -685 and -650. DNA methylation patterns play an important role in the developmental regulation of gene expression in vertebrates. DNA MeTase activity is probably regulated to maintain this pattern of methylation. We suggest that the DNA MeTase promoter represents a new class of housekeeping gene promoters that was designed to ensure high fidelity regulation of gene expression.

3T3 Cells↗
PubMed1992

Failure of AICA riboside to limit infarct size during acute myocardial infarction in rabbits.

This study examined whether the adenosine potentiator, 5-aminoimidazole-4-carboxamide riboside (AICAr), could limit tissue necrosis during acute myocardial infarction in rabbit hearts with minimal coronary collateral flow. Forty-four rabbits underwent 45 min of ischemia with or without coronary reperfusion for 180 min. Five groups were studied. Saline or AICAr (20 mg/kg, i.v.) was administered as a bolus either 10 min before coronary occlusion or 10 min before the onset of coronary reperfusion. The anatomic risk zone size was assessed by radiolabeled microsphere autoradiography and the area of tissue necrosis was defined using the tetrazolium staining method. Coronary collateral flow in the central ischemic zone was assessed using the radiolabeled microsphere technique. No differences were observed for tissue necrosis (normalized to risk zone size) for saline- and AICAr-treated rabbits (66.2 +/- 10.9% vs. 70.8 +/- 19.9%, p = NS) subjected to 45 min of coronary occlusion without reperfusion. Similarly, tissue necrosis in rabbit hearts with 45 min of coronary occlusion followed by 180 min of reperfusion was not significantly reduced when AICAr was administered either 10 min before ischemia or 10 min before reperfusion (79.8 +/- 17.5 and 76.4 +/- 8.1%, respectively) compared to saline-treated controls (68.1 +/- 22.7%). Coronary collateral flow in these hearts was almost nonexistent. The risk zone size and cardiac hemodynamics were similar between the treatment groups. These results demonstrate that AICAr was unable to limit myocyte necrosis when administered either before ischemia or before coronary reperfusion in this experimental preparation of acute myocardial infarction.

Aminoimidazole Carboxamide↗
PubMed1991

Amiodarone antagonizes the effects of T3 at the receptor level: an additional mechanism for its in vivo hypothyroid-like effects.

Amiodarone is a diiodinated benzofuran derivative that has some structural similarities to the thyroid hormones and contains two iodine atoms per molecule. It has exhibited hypothyroid-like effects that are thought to be the result of an inhibition of thyroid hormone synthesis due to iodine load, a decrease in the T4 to T3 conversion, and (or) a competitive binding for T3 receptors. The aim of this study was to determine if this third mechanism contributes to the hypothyroid-like effects of amiodarone in vivo. To do so, some characteristic features known to be influenced by hypothyroidism were determined in surgically thyroidectomized rats (n = 48), which received replacement doses of T3 (0.5 and 1.0 microgram.100 g-1.day-1) with or without amiodarone (60 mg.kg-1.day-1). Thyroidectomy produced a hypothyroid state upon which amiodarone had no detectable effects except a negative body weight gain. T3 (0.5 microgram) nearly normalized the thyroid status of the animals, but the concomitant administration of amiodarone induced hypothyroid-like effects suggesting that these effects are dependent on T3. Higher doses of T3 (1.0 microgram) produced hyperthyroid-like effects and attenuated the effects of amiodarone. Unexpectedly, amiodarone decreased T3 plasma concentrations. To determine if the effects of amiodarone were the results of a decrease in T3 plasma and myocardial concentrations or a competition with T3 for its receptors, exogenous T3 pharmacokinetics were studied in thyroidectomized rats receiving T3 (0.5 microgram) with or without amiodarone. The results suggested that amiodarone increased T3 cardiac concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1990

Predictors of survival and sudden death in patients with stable severe congestive heart failure due to ischemic and nonischemic causes: a prospective long term study of 200 patients.

This prospective study of 200 stable outpatients with New York Hospital Association (NYHA) class III congestive heart failure on maximal medical therapy was done to determine which factors affect survival, to record the incidence of sudden death, and to identify prognostic features which characterize patients at high risk of sudden death. Congestive heart failure was due to coronary artery disease in 151 patients (76%). After an average follow-up of 40 months, 96 patients (48%) had died: 30 (15%) suddenly, 41 (22%) of low output, and 25 (13%) of other causes. Of the 30 patients dying suddenly 12 had autopsies, and acute myocardial infarction was found in nine. Of the 41 patients dying of low output 15 had autopsies, and recent myocardial infarction was found in five. Nine of the 25 patients dying of other causes died of acute myocardial infarction. Multivariate stepwise analysis revealed that severity of ventricular arrhythmias (modified Lown classification), exercise tolerance and left ventricular ejection fraction were the most important determinants of survival. In patients with coronary artery disease, complex ventricular arrhythmias detected by ambulatory Holter monitoring were frequent in all groups and were not clinically useful in predicting which of these patients were at a higher risk of dying suddenly. In contrast, patients without coronary artery disease who died suddenly had a higher incidence of nonsustained ventricular tachycardia and a tendency towards more frequent ventricular arrhythmias in general. The authors conclude that in ambulatory patients with stable NYHA class III heart failure, the severity of ventricular arrhythmias is a predictor of survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1985

Role of mediastinoscopy in pretreatment staging of patients with primary lung cancer.

Since the introduction of mediastinoscopy, there has been a great deal of discussion regarding indications for this technique and the significance of positive findings. We undertook this study to determine the role of clinical staging and the value of routine mediastinoscopy in the treatment selection of patients with primary lung cancer. From 1975 to 1983, 1,259 consecutive patients with proven and operable lung cancer underwent preresection mediastinoscopy. Nodes were sampled at three levels, and findings were recorded by location, invasiveness, and histology. There were no operative deaths, but 3 patients had a major complication. Mediastinoscopy was positive in 339 (27%) patients and negative in 920 (73%). In the group with positive findings, 303 patients had no operation because a curative resection was not possible (extranodal metastases, 180; location, 76; histology, 47). No patient survived 5 years, and only 4% survived 2 years. Of the 36 patients considered to have operable disease, 28 underwent resection with a projected 5-year survival of 18%. In the group with negative findings, 89% had a curative resection with a hospital mortality of 3.2% and 5-year survival of 53%. When results of mediastinoscopy were correlated with findings at thoracotomy, the sensitivity of the test was 93% on nodes in the superior mediastinum and the specificity, 100%. This study shows that mediastinoscopy is safe and is an accurate indicator of the presence or absence of tumor in superior mediastinal nodes. If positive nodes are found, a curative resection is generally not possible, thoracotomy is avoided, and the overall survival is low.

Adult↗
PubMed1981

Hemodynamic effects of prazosin in chronic heart failure.

Three series of investigations were carried out with prazosin (PZN) hydrochloride. In the first, hemodynamic effects of PZN were compared with those of hydralazine (HDZ) in 11 patients with chronic congestive heart failure (CHF). In doses up to 5 mg, PZN increased cardiac output (CO) 20% accompanied by a 20% decrease in pulmonary capillary wedge pressure (LVFP). HDZ increased CO by 50% with little or no effect on LVFP. An additional 12 patients were given multiple 5 mg doses of PZN at 6-hour intervals with measurements of hemodynamic and plasma blood levels. Results suggested an attenuation of the effects of PZN on increasing CO but not on decreasing LVFP. This attenuation of CO was not due to inadequate plasma levels. Acute exercise studies (supine bicycle) were performed in 10 patients with severe CHF before and after the administration of several doses of PZN. There appeared to be a greater effect of PZN during exercise than at rest, with a beneficial increase in CO and reduction in LVFP. These data suggest that, despite hemodynamic attenuation of its effects on CO at rest, PZN may still be beneficial to active patients with CHF. In vitro studies with various vasodilators were performed to evaluate potential intropic effects. Isometric force (cat papillary muscle) increased 2% with 10-4M and 31% with 10-3M HDZ. PZN increased force 4% at 10-6M and 18% at 10-4M. Captopril did not increase force development at any dose level. The doses of HDZ and PZN that increased force development were higher than usual clinical doses.

Adult↗
PubMed1981

Cholesterol potentiates the coronary artery response to norepinephrine in anesthetized and conscious dogs.

We investigated the effect of hypercholesterolemia on coronary and cardiac hemodynamic responses to intracoronary norepinephrine (NE) (0.01 to 10.0 micrograms/min as the bitartrate) in a Gregg cannula autoperfusion system. Coronary blood flow was measured by the radioactive microsphere technique in two groups of open-chest dogs anesthetized with pentobarbital: 10 controls and 8 that were fed a cholesterol-rich diet (CD) which doubled the serum cholesterol level. In the control dogs, NE in doses of 0.01 to 1.0 micrograms/min had no effect on coronary vascular resistance (CVR) but 10 micrograms/min caused a significant decrease to 0.58 +/- 0.12 of control. In the CD dogs, NE at doses of 1.0 and 10.0 micrograms/min significantly reduced CVR, to 0.72 +/- 0.06 and 0.52 +/- 0.11 of control, respectively. There was no consistent effect of NE, at these doses, on myocardial oxygen uptake, left ventricular stroke work index, or maximal positive dP/dt. In a second series of experiments we measured coronary flow with electromagnetic flowmeters in 11 chronically instrumented conscious dogs, 5 controls, and 6 CD. In the control dogs, intravenously administered NE hydrochloride, 0.01 microgram/min, reduced CVR to 0.74 +/- 0.07 of control, and 1.0 microgram/min increased CVR to 1.26 +/- 0.09 of control. In the CD animals, these effects were seen at a 10-fold lower NE dose, 0.001 microgram/min (0.83 +/- 0.11 of control) and 0.1 microgram/min (1.32 +/- 0.06 of control). The vasodilation was blocked by propranolol, and vasoconstriction by phentolamine. We conclude that NE at low doses activates beta-adrenoreceptors to reduce CVR and at higher doses activates alpha-adrenoreceptors to increase CVR; the vasoconstrictor response is inhibited in pentobarbital anesthetized dogs, and hypercholesterolemia sensitizes coronary vessels to both the dilator and constrictor effects of NE.

Adrenergic beta-Antagonists↗
PubMed1981

Pre-exposure to the first dental treatment.

The present study attempts to verify the relative efficacy of two forms of pre-exposure which are identical in content and parallel in mode of exposure (in vivo or videotape). These two forms of pre-exposure were given to 38 children, aged four to six years old, before their first dental visit. The results showed that all groups manifested relatively little negative behavior while seeing the dentist. The theoretical and methodological implications of this study are discussed.

Behavior Therapy↗
PubMed1981

Does pericardial drainage decrease the frequency of postpericardiotomy syndrome?

The postpericardiotomy syndrome occurs in 10% to 40% of patients who undergo open-heart surgery. Its frequency is reportedly decreased when pericardial drainage is used. To challenge this, 50 consecutive patients (1 was disqualified) were randomly assigned to two groups: one in which only the anterior mediastinum was drained (group 1) and the other in which the anterior mediastinum and posterior pericardium were drained (group 2). The surgical procedures performed were: coronary artery bypass grafting in 14 patients, valve surgery in 23 and repair of congenital defects in 12. The two groups were similar with respect to age and the volume of blood drained. Significant differences were found only for the duration of bypass and volume of blood given. At 7 to 10 days there were no differences in the frequency of fever, thoracic pain or presence of arthralgia. Findings were similar in both groups for leukocyte count, sedimentation rate, serum lactic dehydrogenase value and for the frequency of positive blood, urine and sputum cultures. Six patients (three in each group) had a postpericardiotomy syndrome that required steroid treatment and prolonged hospitalization for 10 more days. However, none had postpericardiotomy syndrome complicating coronary artery bypass surgery. None of the patients had cardiac tamponade. This study demonstrates that pericardial drainage has no effect on the frequency of postpericardiotomy syndrome and appears to be unnecessary after open-heart surgery.

Cardiac Surgical Procedures↗
PubMed1977

Thallium-201 myocardial perfusion imaging at rest and during exercise. Comparative sensitivity to electrocardiography in coronary artery disease.

The sensitivity of myocardial perfusion imaging (MPI) using thallium-201 injected both at rest and during peak exercise was compared to simultaneously recorded 12 lead electrocardiography (ECG) for the detection of transient ischemia in 20 normal subjects and 63 patients with coronary artery disease (CAD). No significant perfusion defects or ECG changes were seen on either the rest or exercise studies in any of the normal subjects. Fifty-six percent of patients with CAD developed new perfusion defects with exercise compared to 38% who developed ischemic ST-segment depression (P less than 0.02). However, when chest pain and/or ST depression were considered indices of ischemia, the sensitivity of exercise testing and thallium-201 MPI was similar. The increased sensitivity of MPI compared to ST-segment depression on the ECG was due to patients with baseline ECG abnormalities and those who failed to achieve 85% of predicted maximum heart rate with exercise. Analysis of the exercise results according to the extent of coronary artery disease revealed a progressive increase in both positive ECGs and MPI with the number of vessels involved. In patients with single vessel disease the MPI was more sensitive than the ECG (P less than 0.02). The combination of the rest and exercise ECG, MPI and chest pain during exercise failed to identify 11% of patients with CAD. Exercise thallium-201 MPI is a useful adjunct to conventional exercise testing particularly when evaluating patients with abnormal resting ECGs, those who develop ventricular conduction defects of arrhythmias during exercise, and those who fail to achieve their predicted heart rate because of fatigue or breathlessness.

Adult↗