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Biomedical subjects

F Nicolas

Publications and source records attributed to F Nicolas.

At least 37 records · Page 2Linked to original sources
PubMed1996

Adenosine physiology and pharmacology: how about A2 receptors?

Adenosine participates in the physiology of central and peripheral tissues through several subtypes of G-protein-coupled receptors. Positively linked to adenylate cyclase, A2 receptors have been subdivided into A2a and A2b sites on the basis of their molecular, biochemical and pharmacological properties. They exhibit selective distribution, and are implicated in the modulation of psychomotor activity, circulation, respiration, and metabolism. Recent data support the evidence that adenosine A2 receptor properties may prove useful in future drug development, and selective manipulation of receptor-associated biologic effects might be relevant in the treatment of various disorders, including psychiatric diseases, hypoxia/ischemia, inflammation or erythrocytosis.

Adenosine↗
PubMed1996

[Hemodynamic changes induced by apnea test in patients with brain death].

OBJECTIVE: In France, an apnoea test is compulsory to confirm brain death. This test results in a major hypercarbia and respiratory acidosis. This study aimed to assess haemodynamic changes elicited by the apnoea test. STUDY DESIGN: Prospective clinical study. PATIENTS: Fifteen patients with brain death METHODS: Before the apnoea test, the lungs were ventilated with pure oxygen for 20 minutes. Thereafter, the test was conducted with continuous oxygen flow through the endotracheal tube, and SpO2 monitoring. Blood gases and haemodynamic parameters, including systemic arterial pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, cardiac index and right ventricular function parameters were assessed before, during and 20 minutes after the apnoea test. Mean values at the various times were compared. RESULTS: Hypercarbia and acidosis induced a major pulmonary hypertension and an increase in cardiac output, associated with a decrease in systemic vascular resistances. Despite pulmonary hypertension and acidosis, right ventricular function was maintained. All haemodynamic modifications were reversed by reventilation. CONCLUSION: Apnoea test induces a reversible pulmonary hypertension that is seemingly not deleterious for right ventricular function. Apnoea test probably does not alter viability of the donor's organs.

Acidosis, Respiratory↗
PubMed1996

Hemodiafiltration in pentobarbital poisoning.

We report the use of continuous venovenous hemodiafiltration (CVVHD) in a case of massive intentional ingestion of pentobarbital associated with severe coma and hypotension. Despite a poor hemodynamic state, toxic epuration (15% of drug ingested) was obtained. However, death occurred 7 hr after the end of treatment. This report suggests that CVVHD can be effective in the treatment of massive pentobarbital intoxication.

Acute Disease↗
PubMed1995

In vitro evaluation of donor liver preservation fluids on human hepatocyte function.

Successful liver transplantation depends on adequate preservation of cellular function. We therefore tested the effects of two currently used liver preservation fluids, Euro-Collins (EC) solution and University of Wisconsin (UW) solution, on the viability and some functional activities of hepatocytes isolated from human livers. Cells in primary culture were maintained under hypoxic (95% N2/5% CO2) and hypothermic (4 degrees C) conditions for 24 h, either in EC or UW solution. This treatment did not result in significant hepatocyte damage, as judged by phase contrast microscopy, intracellular LDH release, and the MTT mitochondrial test. However, neutral red uptake indicated that lysosomal functions were slightly affected (35% decrease) when compared to control conditions. At the end of the hypoxia/hypothermia period, hepatocyte monolayers were incubated at 37 degrees C under normoxic conditions for 24 h, in order to simulate the reperfusion of a transplanted liver. Three drugs--midazolam, diazepam, zidovudine--were used as diagnostic substrates to check the metabolic abilities of human hepatocytes replaced in normal conditions. Both phase I (hydroxylation, demethylation) and phase II (glucuronidation) metabolic reactions were affected by the hypoxia/hypothermia shock. Indeed, a 30%-50% decrease in these activities was observed as compared to values obtained in control hepatocytes. No difference could, however, be found at the cellular level regarding the solution used for cold storage. These results suggest that the superiority of UW over EC solution, already reported in clinical practice after transplantation of preserved human livers, was not due to a better preservation of the hepatocytes.

Antimetabolites↗
PubMed1995

Analysis of glutamate receptors in primary cultured neurons from fetal rat forebrain.

In order to further analyze the development of glutamatergic pathways in neuronal cells, the expression of excitatory amino acid receptors was studied in a model of neurons in primary culture by measuring the specific binding of L-[3H]glutamate under various incubation conditions in 8-day-old intact living neurons isolated from the embryonic rat forebrain, as well as in membrane preparations from these cultures and from newborn rat forebrain. In addition, the receptor responsiveness to glutamate was assessed by studying the uptake of tetraphenylphosphonium (TPP+) which reflects membrane polarization. In the presence of a potent inhibitor of glutamate uptake, the radioligand bound to a total number of sites of 36.7 pmol/mg protein in intact cells incubated in a Tris buffer containing Na+, Ca2+, and Cl-, with a Kd around 2 microM. In the absence of the above ions, [3H]glutamate specific binding diminished to 14.2 pmol/mg protein with a Kd-value of 550 nM. Under both of the above conditions, similar Kd were obtained in membranes isolated from cultures and from the newborn brain. However, Bmax-values were significantly lower in culture membranes than in intact cells or newborn membranes. Displacement studies showed that NMDA was the most potent compound to inhibit [3H]glutamate binding in membranes obtained from cultured neurons as well as from the newborn brain, whereas quisqualate, AMPA, kainate and trans-ACPD were equally effective.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Increased plasma levels of human interleukin for DA1.a cells/leukemia inhibitory factor in sepsis correlate with shock and poor prognosis.

Animal study results have suggested a role in sepsis for human interleukin for DA1.a cells/leukemia inhibitory factor (HILDA/LIF). HILDA/LIF and interleukin-6 (IL-6) levels were prospectively studied by serial ELISAs in 34 septic patients. HILDA/LIF was detected in 11 of 34 patients at plasma levels of 100-37,000 pg/mL. Peak HILDA/LIF levels correlated with increased temperature and creatinine and IL-6 and with decreased arterial CO2 (P < .05). Multivariate analysis showed that shock and decreased arterial CO2 accounted for 75% of peak HILDA/LIF plasma variations (R2 = .753). Fatal outcome was most often associated with detectable HILDA/LIF (> 56 pg/mL) and peak IL-6 plasma levels > 850 pg/mL (sensitivity, 83%; specificity, 87%), but both (at respective levels of > 480 and > 850 pg/mL) were associated with fatal outcome. HILDA/LIF was detected in septic patients exhibiting shock, and its levels correlated with higher mortality and shorter survival.

APACHE↗
PubMed1995

Comparative metabolism of 3'-azido-3'-deoxythymidine in cultured hepatocytes from rats, dogs, monkeys, and humans.

3'-Azido-3'-deoxythymidine (AZT), the main antiretroviral drug used against Human Immunodeficiency Virus, was approved by the Food and Drug Administration in 1987 with only little knowledge concerning its metabolism. The aim of our study was to evaluate the interspecies variability of AZT metabolism in primary cultures of hepatocytes, freshly isolated from rats, dogs, monkeys, and humans. Cultures were exposed to 10 or 100 microM [3H]AZT. Extracellular and intracellular compartments were analyzed using a HPLC method. Intracellular and extracellular metabolic patterns were qualitatively similar, but very low amounts of AZT and metabolites were detected within hepatocytes. In all species, the 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine (GAZT) was identified as the major metabolite of AZT. In addition to this glucuronide, two minor peaks were detected: one coeluting with 3'-amino-3'-deoxythymidine(AMT); and the other with a retention time corresponding, on the basis of the publications in this field, to 3'-amino-3'-deoxythymidine glucuronide. However, further investigation allowed this compound to be characterized as tritiated water, possibly representing a catabolic endproduct of AZT. Although glucuronidation was the main metabolic pathway in the four species studied, AZT biotransformation rate was much lower in rat and dog hepatocytes than in monkey and human ones. Finally, an excellent correlation was obtained between in vivo and in vitro metabolic data.

Animals↗
PubMed1994

Opposite effects of cyclohexyladenosine and theophylline on hypoxic damage in cultured neurons.

To study the central effects of adenosine on hypoxia, the influence of treatment by the A1 receptor agonist cyclohexyladenosine (1 microM) or by the antagonist theophylline (10 microM) was tested on cell damage in a model of neuronal culture. Whereas theophylline enhanced cell injury induced by 8 h hypoxia, cyclohexyladenosine decreased lactate dehydrogenase leakage, abolished the transient increase in 2-D-deoxyglucose transport and improved cell morphology. Such actions might involve regulation of excitatory amino acid release and maintenance of calcium homeostasis.

Adenosine↗
PubMed1994

Characterization of adenosine receptors in a model of cultured neurons from rat forebrain.

The neuromodulator adenosine is acting through specific receptors coupled to adenylate cyclase via G-proteins. The expression of both adenosine receptors A1 and A2 as well as forskolin binding sites was investigated by radioligand binding techniques in 8-day-old neurons isolated from fetal rat forebrain and cultured in chemically-defined medium. Adenosine A1 receptors were specifically labeled with [3H]chloro-N6-cyclopentyladenosine (CCPA), whereas [3H]CGS 21680 was used for the analysis of A2 receptors. Cultured neurons exhibited high affinity binding sites for CCPA (Bmax = 160 fmol/mg protein; Kd = 2.9 nM), and for CGS 21680 (Bmax = 14 fmol/mg protein; Kd = 1.7 nM). These data correlate well with those obtained in crude membranes isolated from the newborn rat forebrain. The incubation of culture membranes in the additional presence of guanylyl-5'-imidodiphosphate (Gpp(NH)p, a GTP analogue) led to significantly increased Kd-values, suggesting the association of adenosine receptors with G-proteins. Finally, cultured neurons also bound specifically [3H]forskolin with characteristics close to those found in the newborn brain, indicating that cultured neurons appear as an appropriate model for studying the neuromodulatory properties of adenosine.

Adenosine↗
PubMed1994

Pulmonary circulation evaluation before cavopulmonary connections: the cavopulmonary bypass.

The outcome of Fontan-type procedures is dependent on several risk factors, among which pulmonary vascular resistances (PVRs) are an important component. Preoperative calculation of PVR entails several potential sources of error, particularly in patients with pulmonary atresia or multiple sources of pulmonary blood flow. In an attempt to develop a reliable test that accurately assesses the hemodynamic patterns of the pulmonary vascular bed before a Fontan procedure, a simulation of Fontan-type circulation was achieved in 13 patients by a partial cardiopulmonary bypass between the main pulmonary artery and both venae cavae (cavopulmonary bypass). During cavopulmonary bypass, pressures and resistances were recorded. Immediately after cavopulmonary bypass, the circulation was converted to standard cardiopulmonary bypass and the cavopulmonary connection was carried out. Preoperative pulmonary vascular resistance indexes were assessed roughly by the arteriovenous oxygen difference in systemic and pulmonary beds. There was no correlation between preoperative and perioperative calculations of pulmonary vascular resistance indexes (r = 0.24; p = not significant). Hemodynamic data available for all patients then were correlated to the early postoperative outcome assessed by a subjective four-point scale. A positive, significant correlation was found with intraoperative PVR (r = 0.90; p < 0.001), indexed PVR (r = 0.90; p < 0.001), and the pulmonary to systemic vascular resistance ratio (r = 0.98; p < 0.0001). Two of 13 patients had a 4-mm fenestration in the atrial baffle. No mortality or morbidity was related to the procedure. The absolute values of PVR and pulmonary vascular resistance indexes were strikingly higher than generally admitted for this type of procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Conventional cardiopulmonary bypass in neonates. A physiological approach--10 years of experience at Marie-Lannelongue Hospital.

There is still controversy about the optimal method of venoarterial cardiopulmonary bypass (CPB) for correction of congenital heart disease in neonates and young infants. High rates of CPB-related morbidity and mortality are still reported. Since 1980, conventional CPB with double caval cannulation with right-angled cannulae has been used in the high majority of neonates at Marie-Lannelongue Hospital. The extracorporeal circuit was miniaturized to be primed with a volume as small as possible. Priming (500 ml) was done with packed red cells and fresh frozen plasma. CPB was conducted at 30% haematocrit and normal ranges of flow rate, arterial pressure, systemic vascular resistances and oxygen delivery. These normal physiological parameters were also maintained during hypothermia. During the last two years, 151 neonates below 15 days old who underwent open-heart surgery were reviewed. The overall hospital mortality was 7.24%. None of the survivors had postoperative complications related to CPB. All physiological and biological values remained within normal ranges during the postoperative course.

Cardiopulmonary Bypass↗
PubMed1994

GPI membrane anchor is determinant in intracellular accumulation of apical plasma membrane proteins in the non-polarized human colon cancer cell line HT-29 18.

We have compared the intracellular localization of plasma membrane proteins anchored either with a transmembrane segment or with a glycosylphosphatidylinositol moiety to estimate the effects of membrane anchor on protein segregation in the non-polarized form of the human colon cancer cell line HT-29 18. We have monitored two endogenous proteins: the carcinoembryonic antigen, a glycosylphosphatidylinositol protein and the transmembrane protein dipeptidyl peptidase IV, and two transfected proteins: the glycosylphosphatidylinositol protein Thy-1 and an engineered transmembrane form of Thy-1. Using immunocytochemistry on ultra-thin cryosections and confocal microscopy, we detected a carcinoembryonic antigen-rich vesicular compartment, excluding classical pre-lysosomal and lysosomal markers such as mannose 6-phosphate receptor, lamp-1 and cathepsin D. This compartment, where carcinoembryonic antigen accumulated, excluded the transmembrane protein dipeptidyl peptidase IV and was reduced during the polarization of the cells. Moreover, the glycosylphosphatidylinositol form of Thy-1 also accumulated in the carcinoembryonic antigen-rich compartment whereas the transmembrane form of Thy-1 was excluded. We proposed that, in the non-polarized HT-29 18 cells, accumulation of glycosylphosphatidylinositol proteins independently of transmembrane proteins reveals different intracellular fates for proteins according to their anchor in the plasma membrane.

Carcinoembryonic Antigen↗
PubMed1993

Expression of adenosine A1 receptors in cultured neurons from fetal rat brain.

The expression of adenosine A1 receptors was investigated using [3H]2-chloro-N6-cyclopentyladenosine (CCPA) in 8-day-old cultured neurons from fetal rat forebrain grown in serum-free medium. [3H]CCPA bound specifically and with high affinity (Kd = 2.9 nM) to a homogeneous population of sites. Displacement of CCPA binding by various adenosine derivatives indicated that A1 receptors were selectively labeled. The presence of Gpp(NH)p, a GTP analogue, reduced significantly the binding affinity (Kd = 12.2 nM), suggesting that A1 receptors detected in intact cultured cells are linked to associated G proteins.

Adenosine↗
PubMed1991

Physiological and pharmacological properties of adenosine: therapeutic implications.

Adenosine is a nucleoside which has been shown to participate in the regulation of physiological activity in a variety of mammalian tissues, and has been recognized as a homeostatic neuromodulator. It exerts its actions via membrane-bound receptors which have been characterized using biochemical, electrophysiological and radioligand binding techniques. Adenosine has been implicated in the pharmacological actions of several classes of drugs. A number of studies strongly suggest that the nucleoside may regulate cellular activity in many pathological disorders and, in that respect, adenosine derivatives appear as promising candidates for the development of new therapeutic compounds, such as anticonvulsant, anti-ischemic, analgesic and neuroprotective agents.

Adenosine↗