[Dolly or the best in the world--a prelude to human cloning?].
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Animals↗
Biomedical subjects
M Dubois
Publications and source records attributed to M Dubois.
Losartan: a new antihypertensive drug.
Hypertension is a major risk factor for cardiovascular disease. It affects approximately one in five, or 20 per cent of Canadians. The consequences of untreated hypertension include myocardial infarction, stroke, congestive heart failure, peripheral vascular disease and renal disease. By lowering a person's diastolic blood pressure 5 to 6 mmHg, their chances of having a stroke are reduced by 35 to 40 per cent and 20 to 25 per cent for coronary heart disease. While the treatment for hypertension includes both nonpharmacological and pharmacological therapy, this article will explore losartan or Cozaar, which falls under the newest class of antihypertensive drugs, angiotensin II antagonists.
Angiotensin II↗
[Precancerous states of the endometrium: hormonal aspects].
The two types of endometrial carcinomas are preceded by precancerous lesions. Type I endometrial carcinomas are most commonly encountered in perimenopausal women with the classical risk factors associated with estrogen exposure: obesity, multiparity, diabetes, estrogen treatment, ... Hyperplasia (simple, followed by complex forms without cellular atypias and subsequently by complex hyperplasias with cellular transformation) precede such cancers. Estrogens exert a promoting effect on these lesions but do not initiate them. Progesterone and progestins exert a preventive and protective effect. However, the progressive loss of steroidal receptors is correlated to the progression of tissular anomalies and to the onset of cytogenetic anomalies and to mutations of p53 anti-oncogene. The preventive role of progestin is well established, but their curative beneficial effect on atypical precursors forms of endometrial cancers and on endometrial carcinomas remains controversial. The second type of endometrial cancer appears during the postmenopause and is characterized by an increased invasiveness and a poor prognosis, devoid of identifiable risks factors, these aggressive cancers are not preceded by hormone-sensitive precancerous lesions, but by an intra-epithelial endometrial carcinoma. This lesion appears most often in an atrophic endometrium. Finally, the two types of precancerous states are characterized by distinct gene anomalies suggesting two different pathogenic mechanisms of cancerisation.
Endometrial Neoplasms↗
Ultrastructural modifications in cultured fetal quail hepatocytes exposed to pesticides and PCBs.
There is increasing interest in cultured hepatocytes as a tool for solving toxicological and pharmacological problems while reducing laboratory animal experimentation. In the present study, fetal hepatocytes from the Japanese quail (Coturnix coturnix japonica) were used as an in vitro alternative model for evaluating the effects of PCBs and various pesticide-type chemicals on cell ultrastructure. Major alterations were demonstrated. The most striking effects of toxicants were an increase in the number of cisternae of the rough endoplasmic reticulum (RER), various alterations of mitochondrial morphology, a decreased glycogen content, vacuolization of the cytoplasm, and the appearance of concentric membrane arrays (CMA's), also called myelin-like figures. Other changes were sometimes observed, such as altered cell junctions, an increased lipid content, deformations of the nuclei, or the appearance of crystalline structures. These ultrastructural modifications seem to be dose-dependent. The present in vitro findings are validated by similar observations previously made in vivo on Japanese quail. They confirm the effectiveness of this technique as a biomonitoring tool for the evaluation of environmental quality. Yet the multiplicity of possible toxic effects, even for xenobiotics of a same category, makes it necessary to screen additional indicators of toxicity, such as the detoxifying activity of monooxygenases.
Animals↗
Hierarchical cluster analysis of environmental pollutants through P450 induction in cultured hepatic cells.
Environmental pollutants are classically associated with increased drug metabolism. Cultures of rat hepatocytes, quail hepatocytes, and human hepatoma (Hep G2) cells were used to study the effects of pesticides on drug-metabolizing enzymes. Membrane integrity and mitochondrial activity were evaluated and induction of ethoxycoumarin-O-deethylase and ethoxyresorufin-O-deethylase activities were measured. Induced P450s were identified by immunoblotting. Pentachlorophenol and lindane appeared as the strongest inducers. On the immunoblots, specific antibodies revealed induced CYP1A1 in fetal rat hepatocytes, CYP2B in quail hepatocytes, and CYP3A7 in Hep G2 cells. Pesticide effects on these different activities in each type of cultured cells were compared by cluster analysis. Results obtained under similar conditions with reference inducers phenobarbital (PB) and benzo[a]anthracene and other environmental pollutants (polychlorobiphenyls) were added to previous data prior to multivariate analysis. The tested products fell into four major groups: a first group with pentachlorophenol, identified as a CYP3A inducer; a second group containing the methylcholanthrene-type inducers that increase CYP1A-related activities; a third class represented by dieldrin, a PB-type inducer; a fourth group including inert compounds or weak inducers. Lindane shares the criteria of the second and third groups and seems to induce both CYP1A and CYP2B activities. The current study results highlight the advantage of using several types of cultured hepatocytes to evaluate the short-term toxicity of environmental pollutants in vitro and constitute a useful model for predicting the potential toxicity of pesticides in humans (Hep G2 cells) and wildlife (fetal quail hepatocytes).
7-Alkoxycoumarin O-Dealkylase↗
Specific effects of n-3 fatty acids and 8-bromo-cGMP on the cyclic nucleotide phosphodiesterase activity in neonatal rat cardiac myocytes.
The authors have previously resolved four forms of cyclic nucleotide phosphodiesterase (PDE) in neonatal rat cultured cardiomyocytes by use of high-performance liquid chromatography (HPLC) and have shown that the response of the cGMP-stimulated PDE to the effector cGMP was markedly reduced as compared to that of the corresponding isoform present in the heart ventricle of adult rat (70% v 350%). When neonatal rat ventricular myocytes were grown in a medium enriched in docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA), an increase of the basal level of cAMP and mainly cGMP was observed. The cGMP-PDE specific activity in the unfractionated cytosol of DHA-, EPA- or 8-bromo-cGMP-enriched cardiomyocytes was lower than that observed in control cells. Whereas the cAMP-PDE specific activity remained unchanged whatever the treatment used. At the same time, the response of the cGMP-stimulated PDE to cGMP was substantially increased in n-3 fatty acid-enriched cardiomyocytes and reached the same level as in the whole ventricle (340%). The treatment of neonatal cardiomyocytes with 8-bromo-cGMP also re-established the sensitivity of this cGMP-stimulated isozyme to cGMP (320%). These results suggest a common mechanism for polyunsaturated fatty acids and 8-bromo-cGMP in the regulation of the cGMP-stimulated PDE activity in cardiomyocytes from new-born rats.
3',5'-Cyclic-AMP Phosphodiesterases↗
P450 induction by Aroclor 1254 and 3,3',4,4'-tetrachlorobiphenyl in cultured hepatocytes from rat, quail and man: interspecies comparison.
Polychlorobiphenyls are potent inducers of hepatic cytochrome P450 in various species. Until now, no model based on cultured cells can be considered as a universal surrogate for in vivo metabolism. In this respect, cultured rat hepatocytes, quail hepatocytes, and human hepatoma (HepG2) cells were used to study the effects of 3,3',4,4'-tetrachlorobiphenyl (3,3',4,4'-TCB) and Aroclor 1254 on drug-metabolizing enzymes. The presence of dexamethasone in the culture medium allows the expression and the induction of several cytochrome P450 isoenzymes found in adult cells. Induction of ethoxycoumarin-(ECOD) and ethoxyresorufin-O-deethylase (EROD), activities were measured. Induced P450s were identified by immunoblotting and Northern blotting. Aroclor 1254 induced ECOD activity in all three cell types, but the effect was much stronger in fetal rat hepatocytes than in human or quail cells. Aroclor failed to induce EROD activity in quail cells, had a slight inducer effect in HepG2 cells, and a marked effect in rat hepatocytes. 3,3',4,4'-TCB had no effect in HepG2 cells but significantly increased EROD and ECOD activities, especially the latter, in rat and quail cells. On the immunoblots, specific antibodies revealed essentially CYP1A1 in fetal rat hepatocytes, CYP2B1/2 in quail hepatocytes and CYP3A1 in HepG2 cells. Analysis of Northern blots showed an hybridization with CYP1A1, 2B1 and 3A1 mRNA in fetal rat hepatocytes, CYP3A and 1A mRNA in HepG2 cells, and a form of CYP2 mRNA in fetal quail hepatocytes closely related to homolog rat CYP2E or CYP2C. In quail hepatocytes, induction did not increase proportionally with the concentration of inducer in the culture medium. Instead, the dose-response curves (for EROD activity especially) peaked sharply at 1 muM Aroclor 1254, an effect attributed to changes in membrane fluidity or lipid content. Our results highlight the advantage of using several types of cultured hepatocytes to investigate fundamental aspects of drug-metabolism-linked toxicity, the balance between xenobiotic bioactivation and detoxication being differently affected by PCBs in different animal species.
7-Alkoxycoumarin O-Dealkylase↗
Chronic effects of endothelin-3 on blood pressure and renal haemodynamics in rats.
BACKGROUND: Renal vasoconstriction and systemic hypertension are well-known effects of bolus or short-term endothelin administration. However, the role of endothelin as a circulating hormone remains largely unknown. METHODS: The present study explores the effects of endothelin-3 (ET-3) on renal haemodynamics and systemic blood pressure during a 3-h and a 3-day intravenous infusion in rats. Male Sprague-Dawley (SD) rats were infused with vehicle (group 1) or ET-3 (group 2), 10 ng/kg per min; group 3, 50 ng/kg per min) delivered via osmotic minipumps into the right jugular vein for 3 days. On day 3 after pump implantation, rats were anaesthetized with Inactin and surgically prepared for assessment of mean arterial blood pressure (MABP), renal plasma flow (RPF), glomerular filtration rate (GFR), and renal vascular resistance (RVR). The same parameters were assessed during a 3-h ET-3 infusion study in SD rats (group 4, vehicle; group 5, ET-3, 10 ng/kg per min; group 6, ET-3, 50 ng/kg per min). RESULTS: In 3-day infused rats, ET-3 induced a significant decrease in RPF (-22+/-7% and -26+/-8% for group 2 and group 3 respectively, P<0.05 vs group 1) and an increase in RVR (+40+/-11% for groups 2 and 3; P<0.05 vs group 1); 50 ng/kg per min ET-3 significantly decreased GFR (-17%, P<0.05 vs group 1). MABP was not significantly affected by endothelin infusion. In acute infusion studies a decrease of the same magnitude was seen for the renal haemodynamics values. 50 ng/kg per min ET-3 increased MABP; a systemic effect that disappeared after the 3-day infusion. CONCLUSIONS: This study suggests that intravenously administered ET-3 in the rat has only a transient effect on systemic blood pressure, whereas it induces alterations in renal haemodynamics after both acute and chronic perfusions.
Animals↗
Selective inhibition of rat heart cAMP phosphodiesterases by lipophilic C-methyl-2-phenyl-4H-1-benzopyran-4-ones (C-methylflavones).
A series of eight methoxylated C-methyl-2-phenyl-4H-1-benzopyran-4-ones 3, 6, 10-15 was evaluated as inhibitors of rat heart cytosolic cyclic nucleotide phosphodiesterase (PDE). The 2-(3,4-dimethoxyphenyl)-5,7-dimethoxy-3,8-dimethyl-4H-1-benzopyran-4-one (3) and the 2-(4-methoxyphenyl)-5,7-dimethoxy-3,8-dimethyl-4H-1-benzopyran-4-one (10) have never been previously described. Inhibition was performed on the whole cytosolic preparation and on the four PDE isoforms after HPLC purification. The flavones 3, 6, 10, 13 and 14 were selective and potent inhibitors of the isoforms, namely ROI (rolipram-sensitive) and CGI (cGMP-sensitive) PDEs specifically hydrolyzing cAMP. The di-C-methylflavones 3 and 13 have been shown to be potent inhibitors of these two isoforms, with IC50 values in the micromolar range.
3',5'-Cyclic-AMP Phosphodiesterases↗
Prevention of cyclosporin nephrotoxicity with a platelet-activating factor (PAF) antagonist.
BACKGROUND: Cyclosporin (CsA) is a potent immunosuppressive drug whose main side-effect is nephrotoxicity. In the kidney, CsA induces vasoconstriction with a decrease in renal blood flow (RBF) and glomerular filtration rate (GFR) and a significant increase in renal vascular resistance (RVR). CsA enhances platelet-activating factor (PAF) synthesis in mesangial cells in vitro. PAF, a secondary mediator of anaphylaxis and inflammation, exhibits vasoactive properties in the kidney similar to those of CsA. METHODS: The in situ autoperfused rat kidney model was used to investigate whether PAF plays a role in the haemodynamic injury induced by CsA. RESULTS: In this model, CsA (40 mg/kg and 20 mg/kg i.v.) induced a significant decrease in RBF and in GFR and an increase in RVR. BN 52021, a potent and specific PAF antagonist (20 mg/kg i.v. bolus dose) induced a significant increase in GFR (137 +/- 32% of initial value, P < 0.05). BN 52021 (20 and 10 mg/kg) also significantly prevented the decline in RBF and GFR induced by CsA. CONCLUSIONS: We have demonstrated that the PAF antagonist BN 52021 can minimize the alteration of renal function induced by CsA.
Animals↗
Psychodynamic aspects of smoking cessation among physicians.
After approximately 10 years of research on smoking habits with an emphasis on prevention and dishabituation, we focused on the training of teachers and general practitioners. A fairly wide-ranging inquiry within the Communauté francaise de Belgique was conducted among nearly 2000 doctors. The study showed that the proportion of smokers, although lower than the average in the general population, was higher among the doctors than other socio-professional categories. A comparison of the results registered in 1983 and 1991 revealed a decrease in the number of smokers and an increase in the number of non-smokers (those who have never smoked). This change stemmed largely from a sharply lower smoking rate among young doctors. These findings impelled us to study the resistance to dishabituation among doctors who smoked. The inquiry was comprised of non-authoritative, Rogerian-style talks that enabled us to isolate a number of motivating factors and some rather typical defense mechanisms that, until recently, went partly unnoticed. The denial, indeed the placation, of anxieties in the medical profession fostered by the constant confrontation with illness and the challenge of and victory over death apparently plays a crucial role, albeit on the unconscious plane.
Drug Evaluation↗
Effect of inducers and PCBs on the cytochrome P450 enzymes in cultured quail hepatocytes.
Hepatocytes isolated from fetal quail livers (Coturnix coturnix japonica) were cultured in vitro. Their capacity to metabolize drugs and xenobiotics was explored with typical cytochrome P450 substrates: ethoxycoumarin (known to be metabolized by several P450s), ethoxyresorufin (essentially dealkylated by P450IA1), and testosterone (specifically hydroxylated at several positions by several P450s). The cells could be kept metabolically active in culture for at least 4 days. Their drug-metabolizing activities were inducible by the usual P450 inducers, like phenobarbital and benzanthracene, but also by Aroclor 1254, a PCB mixture. The results obtained indicate that this experimental model could certainly be very helpful in ecotoxicological studies.
7-Alkoxycoumarin O-Dealkylase↗
DNA adducts and P450 induction in human, rat and avian liver cells after exposure to polychlorobiphenyls.
Polychlorinated biphenyls (PCBs) are industrial chemicals which have been detected in fish, birds and humans. They are known to exert marked effects on the liver. They induce hepatocellular carcinoma in rats and birds, and are suspected of being carcinogenic to humans. To better understand the genotoxic effects of PCBs, we used 32P-postlabelling to investigate DNA adduct formation, after exposure to PCBs (Aroclor 1254 and 3,3',4,4'-tetrachlorobiphenyl), in primary cultures of fetal hepatocytes from two animal species and in a human cell line (Hep G2). We also studied the induction of 7-ethoxyresorufin-O-deethylase (EROD) in these PCB-treated cells. The three cell types used are known to express different cytochrome P450 families. The aim was to see whether a correlation could be established between EROD activity (a CYP1A1-related activity) and DNA adduct formation. DNA adducts were found in all three models after exposure to 50 microM 3,3',4,4'-tetrachlorobiphenyl. The number of adducts was higher in quail hepatocytes (37 adducts per 10(9) nucleotides) than in rat hepatocytes or Hep G2 cells (20 adducts per 10(9) nucleotides in both cases). The major adduct was the same in all three cell types, but some adducts were found in only one or two species. These inter-species differences probably reflect metabolic differences leading to different ultimate carcinogens. Exposure to Aroclor 1254 failed to produce significant levels of DNA adducts, suggesting that pre-treated cells are required to magnify Aroclor 1254 metabolism. No correlation was found between adduct formation and the level of EROD induction.
Analysis of Variance↗
Developmental differences in distribution of cyclic nucleotide phosphodiesterase isoforms in cardiomyocytes and the ventricular tissue from newborn and adult rats.
We characterized cyclic nucleotide phosphodiesterase (PDE) activities in neonatal rat cardiomyocytes and in whole ventricle from newborn and adult rats, to determine whether cyclic nucleotide hydrolytic activities might be influenced by the developmental stage of the animal or by cell isolation and culture procedures. Using anion-exchange high-performance liquid chromatography (HPLC), we obtained four soluble PDE activities from adult rat ventricle. Peak 1, a cyclic GMP-specific PDE was stimulated by Ca2+/calmodulin; peak 2 hydrolyzed cyclic AMP and cyclic GMP, the addition of cyclic GMP stimulating the hydrolysis of cyclic AMP. Peaks 3 and 4 selectively hydrolyzed cyclic AMP, peak 3 being very sensitive to inhibition by rolipram and peak 4 consisting of two different enzyme activities, one inhibited by cyclic GMP (peak 4b) and the other inhibited by rolipram (peak 4a). In cardiomyocytes and whole ventricle from newborn rats, the response of the two cyclic GMP-sensitive PDE isoforms (cyclic GMP-stimulated and cyclic GMP-inhibited PDE) to the effector cyclic GMP was markedly reduced as compared with that of the corresponding isoforms (peaks 2 and 4b) present in the heart ventricle of adult rats. The other peaks were analogous to peaks 1, 3, and 4a of the whole ventricle. The profile of PDE activities in nonmyocardial cells did not differ from that of myocytes. Therefore, the lack of cyclic GMP effects was not due to culture conditions. Differences in PDE activities observed between cardiomyocytes from newborn rats and ventricle from adult rats might be age dependent.
3',5'-Cyclic-AMP Phosphodiesterases↗
Prevention of acute cyclosporin nephrotoxicity by verapamil and atrial natriuretic factor in the rat.
Nephrotoxicity is the most common and important side-effect of cyclosporin (CsA) therapy. CsA alters renal haemodynamics with a reduction in renal blood flow (RBF) and glomerular filtration rate (GFR) and a significant increase in renal vascular resistances (RVR). The present experimental study investigates whether verapamil or atrial natriuretic factor (ANF) are able to prevent the nephrotoxicity of CsA. All studies were conducted in an in-situ autoperfused rat kidney model which allows continuous measurement of renal blood flow without dissection of the renal artery. CsA as a 40 mg/kg bolus dose significantly decreased RBF (from 2.15 +/- 0.1 and 2.19 +/- 0.1 before CsA, to 1.29 +/- 0.16 ml/min/100 g BW, 60 min after CsA administration) (P < 0.05), and GFR (from 0.14 +/- 0.1 and 0.13 +/- 0.01 before CsA, to 0.08 +/- 0.01 ml/min/100 g BW, 60 min after CsA administration) (P < 0.05). CsA significantly increased RVR (from 9.5 +/- 0.73 and 9.8 +/- 0.78 before CsA, to 16.7 +/- 2.9 mmHg x min/ml 60 min after CsA administration) (P < 0.05). Verapamil pretreatment (as continuous intrarenal infusion at the rate of 1.25 micrograms/kg/min) attenuated the fall in GFR (from 0.16 +/- 0.01 and 0.19 +/- 0.03 ml/min/100 g before CsA to 0.20 +/- 0.05 ml/min/100 g BW, 60 min after CsA administration) (NS) and in RBF (from 2.42 +/- 0.2 and 2.6 +/- 0.22 ml/min/100 g before CsA to 1.79 +/- 0.17 ml/min/100 g BW, 60 min after CsA administration (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Renal tolerance of gadolinium-DOTA and gadolinium-DTPA in rats.
RATIONALE AND OBJECTIVES: Although gadolinium chelates are mainly eliminated by the kidney, there is limited information about their effects. The renal tolerance of these compounds on renal function in an in vivo rat model are evaluated. METHODS: A combination of renal ischemia and intrarenal iodinated contrast agent infusion (diatrizoate) led to a reproducible and reversible model of acute renal failure (n = 5). Using this model, the renal tolerance of gadolinium DOTA (Gd-DOTA) (n = 10) and gadolinium DTPA (Gd-DTPA) (n = 10) were evaluated. The effects of the association of Gd-DOTA with diatrizoate (n = 5) on renal function also were assessed. RESULTS: Gadolinium DOTA induced no change in serum creatinine and creatinine clearance. Gadolinium DTPA induced a significant increase in serum creatinine (50 to 83 +/- 5 and 70 +/- 6 mumol/L) before and at 24 and 48 hours, respectively (P < .05), and a decrease in creatinine clearance from 1.6 +/- 0.1 to 0.8 +/- 0.1; 1.2 +/- 0.1 mL/mL before and at 24 and 48 hours, respectively (P < .05). In this model, Gd-DOTA did not modify the renal tolerance of diatrizoate as assessed with serum creatinine and creatinine clearance. CONCLUSIONS: Gadolinium DOTA is not nephrotoxic and can be infused in association with iodinated contrast media. In this model, Gd-DTPA induced reversible renal failure.
Acute Kidney Injury↗
Analytical one-dimensional model to study the ultrasonic precursor generated by a laser.
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Journal Article↗
The team approach.
Cardiovascular disease continues to be the major cause of death and illness in Canada. But the news is not all bad. The incidence can be reduced by minimizing one or more cardiovascular risk factors.
Cardiovascular Diseases↗