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Biomedical subjects

A Cordier

Publications and source records attributed to A Cordier.

At least 55 records · Page 3Linked to original sources
PubMed1994

No cyclosporin-induced chromosomal aberrations in human peripheral blood lymphocytes in vitro.

Continuous in vitro treatment of human peripheral blood lymphocytes with cyclosporin A for 20 h and 44 h in the absence of metabolic activation decreased the mitotic index in a concentration-dependent way (MI about 35% at 50 micrograms/ml). In the presence of 10% S9 lymphocytes were exposed to cyclosporin A at concentrations which formed cloudy suspension, i.e., above 100 micrograms/ml. A 2 h treatment in the presence of metabolic activation showed a depression of the mitotic index at the 44 h fixation time only. Based upon results concerning the depression of the mitotic index, slides of the 5, 10, 25 and 50 micrograms/ml (-S9, 20 h and 44 h continuous treatment) and 5, 150, 250 and 300 micrograms/ml (+S9, 2 h pulse treatment) treatment groups were selected to be analyzed in the chromosomal aberration assay. At no concentration and at no fixation time did cyclosporin A increase the frequency of cells with chromosomal aberrations.

Animals↗
PubMed1994

Hypertrophic osteopathy in rats following chronic administration of SDZ MNS 949, an isoquinoline.

SDZ MNS 949, 6,7-dimethoxy-3-methyl-1-(3',5'-bis (methoxyethoxy) phenyl)-isoquinoline, a bronchodilating anti-inflammatory drug that inhibits phosphodiesterase, had been proposed for the treatment of bronchial asthma. Groups of 14 male and 14 female Wistar rats were administered doses of 12, 50, and 130 mg/kg/day in feed for 26 weeks. Periodic radiographic examinations were performed in addition to clinical observations, clinical chemistry measurements and urinalysis. At study termination full necropsy and histopathological examinations were performed on all animals. The principal clinical signs observed were unilateral edematous, red and painful swelling of the distal hindlimbs in 8 of 28 high dose animals, and abdominal swelling in 19 of 28 high dose animals. At radiographic examination periosteal new bone formation was predominantly along the tibia. Lesions at necropsy included dilated small and large intestines. Microscopically, enteritis was observed, and the periosteal new bone formation was confirmed. Hematological findings consisted of thrombocytosis and lymphocytosis, especially in high dose animals. The clinical, radiographical and histological findings in treated rats were consistent with the diagnosis of "hypertrophic osteopathy" or "Marie's Disease".

Animals↗
PubMed1994

The analysis of thermal comfort requirements through the simulation of an occupied building.

Building simulation usually focuses on the study of physical indoor parameters, but we must not forget the main aim of a house: to provide comfort to the occupants. This study was undertaken in order to build a complete tool to model thermal behaviour that will enable the prediction of thermal sensations of humans in a real environment. A human thermoregulation model was added to TRNSYS, a building simulation program. For our purposes, improvements had to be made to the original physiological model, by refining the calculation of all heat exchanges with the environment and adding a representation of clothes. This paper briefly describes the program, its modifications, and compares its results with experimental ones. An example of potential use is given, which points out the usefulness of such models in seeking the best solutions to reach optimal environmental conditions for global, and specially local comfort, of building occupants.

Body Temperature Regulation↗
PubMed1994

The Y graft: myocardial revascularization with both internal thoracic arteries. Evaluation of eighty cases with coronary angiographic assessment.

The use of bilateral in situ internal thoracic arteries is restricted by the risk of sternal devascularization, the length of the pedicle, and the necessity to avoid crossing the midline. The aim of this study is to evaluate Y grafts achieved by anastomosing the proximal end of the free right internal thoracic artery to the side of the attached left internal thoracic artery. Y grafts were performed in 80 patients, aged 41 to 74 years (mean age 58.6 years) between May 1991 and September 1992. Two different techniques were used. Thirty-four patients were included in group 1 and 46 in group 2. Seventy-nine grafts were performed from the left internal thoracic artery to the left anterior descending artery. The right internal thoracic artery was anastomosed to the diagonal artery (5 times), the marginal branch (67 times), the circumflex artery (7 times) and the right coronary artery (2 times). Seventy-five complementary saphenous vein bypasses were performed in 58 patients. Operative mortality was 2.5%. Two patients had perioperative myocardial infarcts (2.5%) on nonbypassed sites. Three patients had sternal wound infections (3.7%). Sixty-two patients (80%) were reexamined by angiography at month 6-25 in group 1 and 37 in group 2. Sixty left internal thoracic artery bypass grafts (97%) were patent versus 39 right internal thoracic artery bypass grafts (63%). In group 1, 23 of 25 left internal thoracic artery bypass grafts were patient (92%) versus 12 right internal thoracic artery grafts (48%). In group 2, all 37 left internal thoracic artery bypass grafts were patent (100%) versus 27 right internal thoracic artery grafts (73%). With this procedure, particular attention must be paid to the length of the right internal thoracic artery, and extensive training is required.

Adult↗
PubMed1993

Lack of predictivity of bone marrow micronucleus test versus testis micronucleus test: comparison with four carcinogens.

In vivo somatic chromosome mutation tests are usually carried out using the bone marrow micronucleus test in the mouse. This test is also considered predictive for the study of clastogenic effects in germ cells. However, it has been reported that the sensitivity of the bone marrow micronucleus test is insufficient to detect unstable compounds or short-lived metabolites and the use of target cells with metabolic activity (hepatocytes) has been questioned. In order to analyze in vivo micronucleus induction in cells with metabolic enzyme activity, we compared the sensitivity of somatic and germ cells to four carcinogens in the bone marrow and spermatid micronucleus test in the mouse. Three procarcinogens with a complex metabolic pattern (dimethylnitrosamine, diethylnitrosamine and 1,1-dimethylhydrazine) and one direct unstable mutagen (beta-propiolactone) were tested. All four carcinogens were not detected by the bone marrow micronucleus test but were detected in the mouse spermatid micronucleus test in which they induced clear clastogenic effects, as was the case in a previous study in liver micronucleus test. In conclusion, this study demonstrates that the bone marrow micronucleus test is not sufficient for the prediction of a clastogenic hazard in germ cells. In addition to a second in vivo test in an organ with metabolic enzymes, i.e., the liver, the spermatid micronucleus test can be performed when a specific risk to the testis is likely.

Animals↗
PubMed1993

Effect of tauroursodeoxycholate on actin filament alteration induced by cholestatic agents. A study in isolated rat hepatocyte couplets.

The mechanism of the protective effect of ursodeoxycholic acid in cholestatic liver diseases remains unclear. Since there is evidence that alterations in the pericanalicular actin microfilament network play a major role in cholestasis, the aims of this study were (a) to determine the effect of the cholestatic agents, taurolithocholate (TLC) and erythromycin estolate (ERY), on F-actin distribution in isolated rat hepatocyte couplets and (b) to assess the effect of tauroursodeoxycholate (TUDC) and taurocholate on the modifications induced by these two compounds. F-actin was stained with fluorescein-isothiocyanate phalloidin and fluorimetric measurements were performed using a scanning laser cytometer ACAS 570. F-actin distribution was assessed in the couplets by the ratio of the pericanalicular area fluorescence/total couplet fluorescence (CF/TF). At non-cytotoxic concentrations, TLC (50, 100 microM) and ERY (10, 50, 100 microM) induced a significant accumulation of F-actin around the bile canaliculus as indicated by increased fluorescence in the pericanalicular area and by the increased CF/TF ratio compared with the controls. Electron microscopy studies showed significant alterations in bile canaliculi microvilli in couplets treated with 100 microM TLC. Only a few canaliculi showed an increase in pericanalicular microfilaments after treatment with 100 microM ERY. As assessed by scanning laser cytometry, TUDC prevented changes in F-actin distribution when it was added to the medium with taurolithocholate or erythromycin estolate at equimolar concentrations. However, the morphological changes observed by electron microscopy after treatment with TLC were not modified by co-treatment with TUDC. Taurocholate was ineffective. We conclude that (a) abnormalities of pericanalicular F-actin microfilaments occur in two different models of cholestasis, (b) tauroursodeoxycholate prevents the accumulation of pericanalicular F-actin detected by scanning laser cytometry but not the morphological changes of the canaliculus observed by electronic microscopy. Therefore, in these experimental conditions, the protective effect of TUDC appears to be partial.

Actins↗
PubMed1993

Initial experience of peroperative electrocochleography monitoring in stapedectomy.

Clinical experience of intraoperative ECochG monitoring during stapes surgery is reported. Selected surgical phases have been taken into consideration, laying particular stress on the phase corresponding to the opening of the labyrinthine spaces. Compound action potential (CAP) amplitude and latency showed, a supposed, an inversely proportional relationship in most of the cases. Abnormal findings were also recorded in some patients, thus giving rise to different electrophysiological hypotheses. A proposal for an "in vivo" model for the study of the electrophysiological changes due to the opening of labyrinthine spaces is made.

Adult↗
PubMed1992

A method for measuring H2O2 based on the potentiation of peroxidative NADPH oxidation by superoxide dismutase and scopoletin.

NADPH oxidation catalyzed by horseradish peroxidase is considerably increased by scopoletin and superoxide dismutase. These effects were used to develop a method for measuring H2O2 in a horseradish peroxidase, superoxide dismutase, and scopoletin system by measuring the NADPH oxidation rate. The optimal concentration of each reactant was determined. H2O2 could be detected and measured when it was present free in the medium or when it was produced by an H2O2-generating system, such as glucose-glucose oxidase or NADPH oxidase from thyroid plasma membranes. H2O2 was measured either by taking aliquots of the incubation medium or by placing NADPH directly in the medium and following the kinetics of NADPH oxidation. This latter approach required smaller amounts of biological material. In contrast to other methods, the H2O2 which is measured is regenerated. This method is 10 times more sensitive than the standard scopoletin method for H2O2 measurement and will detect a H2O2 production rate as low as 0.2 nmol per hour. The method is particularly suitable for biological systems in which small quantities of biological material are available.

Animals↗
PubMed1992

Male rat hepatic UDP-glucuronosyltransferase activity toward thyroxine. Activation and induction properties--relation with thyroxine plasma disappearance rate.

Detergent-activation of UDP-glucuronosyltransferase (UGT) isoenzyme(s) involved in thyroxine (T4) glucuronidation in control, phenobarbital (PB)- and 3-methylcholanthrene (3-MC)-treated rats showed that between the four tested detergents, i.e. Triton X-100, Brij 58, Lubrol Px and 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acid (CHAPS), optimal activation of T4 UGT was displayed by the zwitterion CHAPS. "Native" versus optimal detergent-activated T4 UGT activity determination revealed that the latency of T4 UGT in microsomes from 3-MC-treated rats was decreased while the latency of T4 UGT in microsomes from PB-treated rats was increased compared to control, and suggest that the UGT isoenzyme(s) involved in the hepatic glucuronidation of T4 is (are) different in PB-treated rats than in 3-MC-treated rats. After a 7-day treatment with 20 mg/kg 3-MC, the activity of T4 UGT was increased 5-fold when determined in "native" and 4-fold when determined in optimal detergent-activated microsomes compared to controls. After a 7-day treatment with 75 mg/kg PB, T4 UGT was equivalent to the control when determined in "native", and increased 1.3-fold when determined in optimal detergent-activated microsomes. The results thus extend evidence that both 3-MC and PB induce the synthesis of UGT protein(s) involved in the glucuronidation of T4, 3-MC being a strong and PB a weak inducer. Hyperthyroid and hypothyroid status, achieved respectively by a 7-day treatment with 100 microns/kg T4 or a 7-day treatment with 10 mg/kg of one of the antithyroid drugs propylthiouracile or methymazole, did not modify T4 UGT activity, suggesting that the isoenzyme(s) conjugating T4 in microsomes from control rats is (are) unlikely to be either 4-nitrophenol or bilirubin UGT isoenzymes. After 14 days of treatment with 75 mg/kg PB, the hepatic glucuronidation rate of T4 was not different from the control when enzyme activity was expressed per mg microsomal protein but was significantly increased 1.4-fold when expressed per whole liver. A significant (1.5-fold) increase in the 125I-T4 plasma elimination rate was also observed in PB-treated rats compared to controls. A strong (3.6-fold) increase in the T4 glucuronidation rate was observed in rats treated with 5 mg/kg 3-MC for 14 days while the 125I-T4 plasma elimination rate was equivalent to the controls. These results demonstrate that there is no direct relation between T4 UGT activity (and subsequent biliary secretion of T4-glucuronides) and T4 plasma clearance and suggest an important contribution of the intestinal exchangeable thyroid hormone pool to the maintenance of blood thyroid hormone levels.

Animals↗
PubMed1992

Regulation of the Escherichia coli lac operon expressed in human cells.

We have investigated the use of various Epstein-Barr virus (EBV)-based vectors bearing the two components of the Escherichia coli lac operator-repressor (lacO, lacI) complex. Our aim was to develop a model system of gene expression by looking at the transcription of the bacterial beta-galactosidase coding gene (lacZ) in 293 human embryonic kidney cells. Several vectors have been built carrying different promoters upstream of the lacI and lacZ genes and in which natural or synthetic operator sequences were inserted in the 5' part of the lacZ gene. In transient expression assays we achieved efficient lacZ gene repression which could be released by the specific inducer isopropyl beta-D-thiogalactoside (IPTG). A stable transformed cell line carrying two EBV-derived plasmids with the building blocks of the lac operator/repressor system was established. This cell line allowed us to achieve a wide range of lacZ gene regulation. In this cell line IPTG alone could remove the repression to trigger a 5-fold increase of lacZ expression. Heavy metal ions, which induced the mouse metallothionein I promoter located upstream of the lacZ gene, added together with IPTG gave rise to a 40-fold induction of lacZ expression.

Base Sequence↗
PubMed1992

Establishment of a human cell line for the detection of demethylating agents.

To detect xenobiotics affecting the DNA methylation pattern we have established a human clonal cell line (A4/4) derived from the 293 epithelial cells. This cell line is stable after more than 1 year in culture and we report here its characteristics. The A4/4 cells carry the Escherichia coli lacI gene and the symmetric lacO sequence upstream of the beta-galactosidase coding gene (lacZ). Both sequences have been independently integrated into the genomic DNA. The lacZ gene is under the control of the metal-inducible mouse metallothionein-I (mMT-I) promoter. Vector integration followed by cell ageing in culture gave rise to the methylation of the 5'CpG3' sites in the mMT-I promoter and the 5' part of the lacZ gene. The reactivation of the lacZ gene by 5-azacytidine (5-Aza-CR) treatment allowed a tremendous lacZ expression which is correlated with demethylation in the mMT-I promoter and its neighboring regions. This enhanced transcription is easily quantified by measuring the beta-galactosidase activity in cell extracts. 5-Aza-CR, the specific isopropyl beta-D-thiogalactoside inducer, and heavy metal ions added together trigger an increase of the beta-galactosidase activity up to 600-fold over the basal level. These cells can be used for a rapid assessment of the demethylating potential of environmental chemicals.

Cell Line↗
PubMed1992

Detection of micronuclei after exposure to mitomycin C, cyclophosphamide and diethylnitrosamine by the in vivo micronucleus test in mouse splenocytes.

A micronucleus detection test using mouse splenocytes has been adapted from a method previously carried out using human lymphocytes. An ex vivo protocol was chosen: male C57B16 mice were treated with various compounds. Splenocytes were then isolated and placed in culture for 48 h and stimulated with concanavalin A and conditioned medium. The cytokinesis-block method reported by Fenech and Morley was used to detect and score micronuclei in the proliferating lymphocytes (3 micrograms/ml of cytochalasin B for 16 h). Three mutagenic clastogens, mitomycin C (MMC), a direct alkylating agent (0.4, 0.8 and 1.6 mg/kg), cyclophosphamide (CP), an indirect alkylating agent (25, 50 and 100 mg/kg) and diethylnitrosamine (DEN), an indirect alkylating agent with labile metabolites (25, 50 and 100 mg/kg), were tested at four sampling times (2, 4, 8 and 15 days). All three compounds were detected from 48 h after treatment. This method was indeed able to detect clastogenic compounds normally detected by the mouse bone marrow micronucleus test (MMC, CP) as well as a compound with labile metabolites which is not usually detected by this test (DEN). Maximum micronucleus induction was observed after 4 days for MMC, 2 days for CP and 15 days for DEN. This method thus appears to offer a potentially useful toxicological test for assessing in vivo clastogenicity.

Animals↗
PubMed1991

Rat adult hepatocytes in primary pure and mixed monolayer culture. Comparison of the maintenance of mixed function oxidase and conjugation pathways of drug metabolism.

The stabilities of several drug oxidation and conjugation pathways in adult rat hepatocytes were investigated in two systems: a primary pure culture lasting 3 days and a primary mixed culture (hepatocytes co-cultured with epithelial cells) lasting 10 days. The cytochrome P450 content in hepatocytes drastically declined within 48 hr in both culture systems. Cytochrome P450-dependent mixed function oxidase was measured by the O-dealkylation of ethoxyresorufin (EROD) and of pentoxyresorufin (PROD). UPD-glucuronosyl transferase (UDP-GT) activity was measured using 1-naphthol and morphine as substrates. In both culture systems, the activities of enzymes belonging to the 3-methylcholanthrene-inducible family, namely EROD and 1-naphthol UDP-GT, were much better maintained than those of PROD and morphine UDP-GT, which belong to the phenobarbitone-inducible family: in pure cultures, EROD and 1-naphthol UDP-GT activities declined to 60% of initial values within 3 days; in mixed cultures, EROD activity was stable throughout the 10 day culture period, whereas that of 1-naphthol UDP-GT was stable until day 4 but had declined to 70% of the initial value by day 8. In contrast, PROD and morphine UDP-GT activities declined to approx. 30% of the initial values within 2 days in both culture systems, and had dropped to approx. 10% of the initial value within 8 days in mixed culture. Reduced glutathione (GSH) levels fluctuated, but remained high throughout culture. GSH conjugation declined to 40% of initial values within 3 days in pure culture, whereas it remained relatively constant in mixed culture. Comparison of these two culture systems therefore showed that although the inclusion of epithelial cells did prolong hepatocyte viability, there was a change in relative enzyme activities in both systems, suggesting a shift towards a more de-differentiated drug metabolism pattern.

Animals↗
PubMed1991

Comparison of the effects of propylthiouracil, amiodarone, diphenylhydantoin, phenobarbital, and 3-methylcholanthrene on hepatic and renal T4 metabolism and thyroid gland function in rats.

We studied the effects of propylthiouracil (PTU), amiodarone (AMIO), diphenylhydantoin (DPH), phenobarbital (PB), and 3-methylcholanthrene (MC) on thyroid histomorphology, on the hepatic and renal enzymes involved in endogenous and exogenous metabolism, and on the plasma levels and pharmacokinetics of thyroid hormones after 7 and 14 days of treatment. PTU and PB, by decreasing both serum tetraiodothyronine (T4) and triiodothyronine (T3), induced a massive increase in serum thyrotropin (TSH) and thus induced thyroid hypertrophy. AMIO and MC, by decreasing respectively serum T3 and T4, also induced an increase of TSH, but to a lesser extent, not sufficient to induce thyroid hypertrophy. Hepatic 5'-deiodinase activity was decreased in all treated rats. Inhibition of this enzyme by PTU was demonstrated in vitro; AMIO also decreased the enzyme activity by a still unelucidated mechanism, which probably requires intact cell plasma membranes, whereas in PB- and MC-treated rats the decrease in enzyme activity certainly resulted from decreased serum concentrations of T4. In PTU-treated rats, and probably in MC-treated rats, decreases in circulating thyroid hormones were primarily due to impairment of synthesis and/or of secretion by the thyroid. In contrast, in PB-treated rats, the decrease in serum thyroid hormone levels seems to be due to increased excretion of these hormones, as T4 serum clearance was significantly increased. PB, a microsomal enzyme inducer, increased the cytochrome b5 and P450 content as well as the cytochrome P450-dependent O-depentylation of pentoxyresorufin. The other type of enzyme inducer, MC, did not affect cytochrome b5 and P450 levels, but did increase the cytochrome P450 dependent O-deethylation of ethoxyresorufin. PB increased the glucuronidation of morphine, whereas MC increased the glucuronidation of 1-naphthol. However, serum T4 clearance, mainly determined by its hepatic conjugation rate, was increased only in PB-treated rats. It appears from this study that the close metabolic relationship between the liver/kidney and the thyroid should be taken into consideration when the findings of chronic toxicology and carcinogenicity studies are interpreted.

Amiodarone↗
PubMed1991

Pig Leydig cell culture: a useful in vitro test for evaluating the testicular toxicity of compounds.

In vivo studies have shown that the testis is a target organ for drugs and chemicals. In order to evaluate the testicular toxicity of compounds and to identify the mechanisms of their toxicity, we have developed a miniaturized primary culture of immature pig Leydig cells. Five well-known drugs with differing mechanisms of toxicity on testicular functions were tested to validate the model. Testosterone and progesterone secretion were measured to evaluate testicular function. Cell viability was assessed quantitatively using a colorimetric assay based on the reduction of a tetrazolium salt (3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide) which stains viable cells only, thus allowing discrimination between specific inhibitors of Leydig cell function and nonspecific cytotoxic drugs. Ketoconazole and aminoglutethimide inhibited both testosterone and progesterone secretion, but without modifying cell viability. Spironolactone specifically blocked testosterone secretion and increased progesterone concentration without inducing cell mortality. Cycloheximide altered testicular steroid secretion by another mechanism of action. Chlorpromazine, which interferes with the secretion of gonadotropins in vivo, produced a significant inhibition of progesterone and testosterone secretion as a result of the cytotoxic effects of the drug. In conclusion, this in vitro test enables one to discriminate accurately between specific and nonspecific inhibitors of steroidogenesis and could reduce the number of false positives when screening for potential testicular toxins.

Aminoglutethimide↗
PubMed1991

Optimum associations of tester strains for maximum detection of mutagenic compounds in the Ames test.

The Ames test is now widely used as a short-term test for the detection of mutagens. Different strains are available with various genetic characteristics, and in the past decade various authors have recommended different associations of strains to give maximum detection potential. However, few studies have been done to compare the sensitivity of individual strains towards a wide range of compounds in a single study. In order to define the best association of strains for screening or regulatory purpose, we have tested 103 direct mutagens (reference genotoxins or in-house compounds) on 7 strains of Salmonella typhimurium: TA1535, TA1537, TA1538, TA97, TA98, TA100 and TA102. 126 different associations of strains have been studied in terms of sensitivity and percentage overlap. Optimum associations of 2, 3, 4 or 5 strains included strains both with and without plasmid pKM101. However, the specificity of detection is greatly diminished by the presence of plasmid pKM101 in the strain, as shown by the high degree of overlap in associations constituted entirely of strains containing the plasmid. The association of strains TA1538 and TA100 detected 86% of the chemicals tested and is therefore recommended for large-scale screening. A rate of detection of 100% was obtained when 6 strains were used. The best associations of 4 and 5 strains, which detected 97 and 99% chemicals respectively, all contained strains TA1537, TA1538 and TA102. Finally, the associations of 4 strains (TA1537, TA1538, TA100, TA102) or 5 strains (TA1535, TA1537, TA1538, TA97, TA102) seemed well adapted to the optimum detection of mutagenic compounds.

Mutagenicity Tests↗