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J Delforge

Publications and source records attributed to J Delforge.

At least 37 records · Page 2Linked to original sources
PubMed1995

Canine myocardial beta-adrenergic, muscarinic receptor densities after denervation: a PET study.

UNLABELLED: In an effort to better understand cardiac neurotransmission, PET was serially used in dogs to assess changes in ventricular muscarinic (MR) and beta-adrenergic receptor (beta-AR) densities following chemical or surgical denervation. METHODS: Beta-adrenergic and MR receptor concentrations were studied in beagle dogs nine days after chemical sympathectomy (using the neurotoxin 6-hydroxydopamine) or 3-7 wk and 23-28 wk after surgical intrapericardial denervation. RESULTS: In control dogs (n = 13), global beta-AR and MR concentrations were 32 +/- 4 and 62.2 +/- 10.4 pmole/ml tissue, respectively. Nine days after 6-hydroxytk; 1opamine (n = 8), hemodynamic tests and MIBG scintigraphy demonstrated the destruction of cardiac sympathetic innervation. Beta-adrenergic density increased by 190% (p < 0.001) while MR density remained unchanged. Three to 7 wk after surgery (n = 5), hemodynamic tests and MIBG scintigraphy demonstrated both parasympathetic and sympathetic denervations. Beta-adrenergic density was increased by 219% while MR concentration remained unchanged. Twenty-three to 28 wk after surgery, atrial innervation was restored (hemodynamic tests) while ventricular sympathetic innervation was not (MIBG scintigraphy). Beta-adrenergic density remained high. CONCLUSION: The present study demonstrates the ability of PET to serially assess myocardial receptor concentrations. The absence of change in MR density and the prolonged up-regulation of beta-AR following heart denervation are the main findings of the present study.

3-Iodobenzylguanidine↗
PubMed1994

In vivo quantification of myocardial muscarinic receptors in heart transplant patients.

BACKGROUND: Decreased myocardial adenylate cyclase activity in response to guanine nucleotide stimulation has been recently demonstrated in denervated myocardium of transplant patients, suggesting that changes in left ventricular muscarinic receptors may occur. METHODS AND RESULTS: The concentration and affinity constants of myocardial muscarinic receptors were determined by positron emission tomography with 11C-labeled methylquinuclidinyl benzilate (MQNB), a specific hydrophilic antagonist, in six transplant patients 4.7 +/- 2.3 months after surgery and in six normal subjects. Patients had no sign of cardiac rejection at endomyocardial biopsy. After intravenous injections of MQNB, time-activity curves were obtained over different regions of interest and were fitted to a nonlinear mathematical model. No difference in the concentration of muscarinic receptors was found in transplant patients compared with control subjects: 24 +/- 4 versus 26 +/- 7 pmol/mL tissue, respectively (P = NS). The association rate constant k+1, the dissociation rate constant k-1, and thus the equilibrium-dissociation constant Kd were the same in transplant patients compared with control subjects. CONCLUSIONS: Despite known decreased GTP-stimulated adenylate cyclase activity in transplant patients, the density and affinity constants of myocardial muscarinic receptors are not altered. This suggests abnormalities of the signal-transduction function, such as a change in the guanine nucleotide binding proteins.

Adult↗
PubMed1993

Modeling analysis of [11C]flumazenil kinetics studied by PET: application to a critical study of the equilibrium approaches.

The multi-injection modeling approach was used for the in vivo quantitation of benzodiazepine receptors in baboon brain using positron emission tomography (PET) and [11C]flumazenil (RO 15-1788) as a specific ligand. The model included three compartments (plasma, free, and bound ligand) and five parameters (including the benzodiazepine receptor concentration). The plasma concentration after correction for the metabolites was used as the input function. The experimental protocol consisted of four injections of labeled and/or unlabeled ligand. This protocol allows the evaluation, from a single experiment, of the five model parameters in various regions of interest. For example, in the temporal cortex, the concentration of receptor sites available for binding (B'max) and the equilibrium dissociation constant (Kd) were estimated to be 70 +/- 15 pmol/ml and 15.8 +/- 2.2 nM, respectively. The validity of the equilibrium approach, which is the most often used quantitation method, has been studied from simulated data calculated using these model parameters. The equilibrium approaches consist of reproducing in PET studies the experimental conditions that permit the use of the usual in vitro methods such as Scatchard analysis. These approaches are often open to criticism because of the difficulty of defining the notion of equilibrium in in vivo studies. However, it appears that the basic relation of Scatchard analysis is valid over a broader range of conditions than those normally used, such as the requirement of a constant bound/free ratio. Simulations showed that the values of the receptor concentration (B'max) and the equilibrium dissociation constant (Kd) found using Scatchard analysis are always underestimated. These simulations also suggest an explanation concerning the dependency of B'max and Kd on the time point employed for the Scatchard analysis, a phenomenon found by several authors. To conclude, we propose new protocols that allow the estimation of the B'max and Kd parameters using a Scatchard analysis but based on a protocol including only one or two injections. These protocols being entirely noninvasive, it thus becomes possible to investigate possible changes in receptor density and/or affinity in patients.

Animals↗
PubMed1993

Positron emission tomography with 11C CGP-12177 to assess beta-adrenergic receptor concentration in idiopathic dilated cardiomyopathy.

BACKGROUND: Positron emission tomography (PET) with 11C-labeled CGP-12177 (CGP) has been shown to have the potential to noninvasively measure beta-adrenergic receptor concentration in dog heart. The present study was undertaken to evaluate the clinical value of this technique. METHODS AND RESULTS: Eight normal subjects and 10 patients with heart failure related to an idiopathic cardiomyopathy were studied. Estimation of beta-receptor concentration was based on a graphic method applied on myocardial PET time-concentration curves obtained after an intravenous injection of 11C-CGP followed 30 minutes later by a coinjection of labeled and unlabeled CGP. The clinical tolerance of these injections was good. Left ventricular concentration of beta-receptors was decreased in patients compared with controls (3.12 +/- 0.51 versus 6.60 +/- 1.18 pmol/mL, respectively; p < 0.001). This 53% decrease agrees with previous in vitro data. In eight of the 10 patients, the beta-receptor concentration obtained from PET was compared with the beta-receptor density determined on left ventricular endomyocardial biopsy samples by in vitro binding technique using 3H-CGP-12177. Results obtained with both techniques were correlated (r = 0.79, p = 0.019). Moreover, decreased beta-receptor concentration correlated with the beta-contractile responsiveness to intracoronary dobutamine infusion (r = 0.83, p = 0.003), indicating a direct link between changes in the receptor number and its biological function. CONCLUSIONS: PET appears to be a safe and reliable method of assessing in vivo changes in the number of left ventricular beta-adrenergic receptor sites of patients with idiopathic cardiomyopathy.

Adrenergic beta-Antagonists↗
PubMed1993

Quantification of myocardial muscarinic receptors with PET in humans.

The potential for noninvasive quantification of myocardial muscarinic receptors using PET data, a mathematical model, multi-injection protocols and 11C-labeled methylquinuclidinyl benzilate (MQNB) as a radioligand was previously demonstrated in dogs. The present study examines the possibility of optimizing the experimental protocol to make this approach suitable for human studies. For six normal subjects, the protocol included three injections: a tracer injection, followed 30 min later by an injection of an excess of unlabeled MQNB (displacement) and then 30 min later by a simultaneous injection of unlabeled and labeled MQNB (coinjection). The model input function was estimated from the PET data corresponding to the left ventricular cavity. This protocol enables a separate evaluation of all parameters of a ligand-receptor model which includes three compartments and seven parameters. The complexity of this three-injection protocol, however, appears to be inconvenient for clinical use. A simplified two-injection protocol (tracer injection and coinjection) was evaluated in five other normal subjects and the results were compared to those obtained with the three-injection protocol. In regions of interest over the left ventricle, the mean value of the receptor concentration B'max and the equilibrium dissociation constant Kd were 26 +/- 7 pmole/ml tissue and 2.0 +/- 0.5 pmole/ml tissue, respectively. The possible existence of nonspecific binding was studied in two subjects using a double-displacement protocol. The corresponding rate constant was found to be very low (0.03 min-1).

Adult↗
PubMed1991

Kinetic analysis of central [76Br]bromolisuride binding to dopamine D2 receptors studied by PET.

The in vivo kinetic analysis of dopamine D2 receptors was obtained in baboon brain using positron emission tomography (PET) and [76Br]bromolisuride [( 76Br]BLIS) as radioligand. An injection of a trace amount of [76Br]BLIS was followed 3 h later by an injection of a mixture of [76Br]BLIS and BLIS in the same syringe (coinjection experiment). A third injection performed at 6 h was either an excess of unlabeled ligand (displacement experiment) or a second coinjection. This protocol allowed us to evaluate in the striatum of each animal and after a single experiment the quantity of available receptors (B'max) and the kinetic parameters including the association and dissociation rate constants (k + 1VR and k-1, respectively, where VR is the volume of reaction). The cerebellum data were fitted using a model without specific binding. All the parameters were estimated using nonlinear mathematical models of the ligand-receptor interactions including or not including nonspecific binding. The plasma time-concentration curve was used as an input function after correction for the metabolites. An estimate of standard errors was obtained for each PET study and for each identified parameter using the covariance matrix. The average values of B'max and KdVR were 73 +/- 11 pmol/ml tissue and 1.9 +/- 0.9 pmol/ml, respectively. The nonspecific binding was identifiable in the experiment where the last injection corresponded to a second coinjection. We found that approximately 6% of the striatal binding was nonspecific after a tracer injection of [76Br]BLIS. The nonspecific binding appeared to be reversible in the striatum but irreversible in the cerebellum.

Animals↗
PubMed1991

Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177, and a new graphical method.

The in vivo quantification of myocardial beta-adrenergic receptor has been obtained in five closed-chest dogs using positron emission tomography (PET). The ligand was racemic (+/-)[11C] CGP 12177, a very potent hydrophilic antagonist of the beta-adrenergic receptor. A kinetic method appeared unsuitable because of the presence of metabolites which made the input function difficult to measure and also inaccurate. Therefore, a graphical method, based on a particular protocol, was proposed. The animals were injected with a trace amount of (+/-)[11C]CGP 12177, which was followed 40 min later by a second injection of radioligand with a low-specific activity. An additional injection of an excess of unlabeled CGP 12177 was administered after 90 min and allowed for the estimation of the dissociation rate constant. The main advantage of this graphical approach is that the results are obtained without having to measure the input function and therefore without estimating the metabolites. The average value of Bmax was 31 +/- 4 pmole/ml of tissue and the dissociation constant was 0.014 +/- 0.002 min-1.

Adrenergic beta-Antagonists↗
PubMed1990

Identifiability analysis and parameter identification of an in vivo ligand-receptor model from PET data.

Identifiability problem is a very important topic in the framework of model justification and not accounting for it during the modeling procedure can lead to meaningless results. While studying the receptor-ligand model parameter estimation from dynamic positron emission tomography data, each of the three possible conclusions to the identifiability problem (i.e., unidentifiable model, multiple solutions, or unique solution) are reached depending on the experimental protocol used. The identification of the model parameters from data obtained with a single tracer injection leads to disappointing numerical results since most of the parameters have to be considered as unidentifiable. A protocol including two injections, a first injection of the labeled ligand and a second injection of the cold ligand (displacement experiment) leads to two very different numerical solutions, which is surprising since such multiplicity of solutions was not indicated by a preliminary theoretical identifiability study. We show that a three-injections protocol, including both a displacement and coinjection experiment, allows to determine which of these two solutions is biologically valid.

Animals↗
PubMed1990

Noninvasive quantification of muscarinic receptors in vivo with positron emission tomography in the dog heart.

The in vivo quantification of myocardial muscarinic receptors has been obtained in six closed-chest dogs by using positron emission tomography. The dogs were injected with a trace amount of 11C-labeled methylquinuclidinyl benzilate (MQNB), a nonmetabolized antagonist of the muscarinic receptor. This was followed 30 minutes later by an injection of an excess of unlabeled MQNB (displacement experiment). Two additional injections of unlabeled MQNB with [11C]MQNB (coinjection experiment) and without [11C]MQNB (second displacement experiment) were administered after 70 and 120 minutes, respectively. This protocol allowed a separate evaluation of the quantity of available receptors (B'max) as well as the association and dissociation rate constants (k+1 and k-1) in each dog. The parameters were calculated by using a nonlinear mathematical model in regions of interest over the left ventricle and the interventricular septum. The average value of B'max was 42 +/- 11 pmol/ml tissue, the rate constants k+1, k-1, and Kd were 0.6 +/- 0.1 ml.pmol-1.min-1, 0.27 +/- 0.03 ml.pmol-1.min-1, and 0.49 +/- 0.14 pmol.ml-1, respectively, taking into account the MQNB reaction volume estimated to 0.15 ml/ml tissue. Although [11C]MQNB binding would appear irreversible, our findings indicate that the association of the antagonist is very rapid and that the dissociation is far from negligible. The dissociated ligand, however, has a high probability of rebinding to a free receptor site instead of escaping into the microcirculation. We deduce that the positron emission tomographic images obtained after injecting a trace amount of [11C]MQNB are more representative of blood flow than of receptor density or affinity. We also suggest a simplified protocol consisting of a tracer injection of [11C]MQNB and a second injection of an excess of cold MQNB, which is sufficient to measure B'max and Kd in humans.

Animals↗
PubMed1989

Experimental design optimisation: theory and application to estimation of receptor model parameters using dynamic positron emission tomography.

The general framework and various criteria for experimental design optimisation are presented. The methodology is applied to the estimation of receptor-ligand reaction model parameters with dynamic positron emission tomography data. The possibility of improving parameter estimation using a new experimental design combining an injection of the beta+-labelled ligand and an injection of the cold ligand is investigated. Numerical simulations predict a remarkable improvement in the accuracy of the parameter estimates with this new experimental design and particularly the possibility of separate estimations of the association constant (k+1) and of the receptor density (B'max) in a single experiment. Simulation predictions are validated using experimental PET data in which parameter uncertainties are reduced by factors ranging from 17 to 1000.

Computer Simulation↗
PubMed1986

[Pulsed and continuous Doppler in qualitative and quantitative diagnosis of mitral insufficiency].

The aim of this study was to assess the diagnostic value of pulsed and continuous wave Doppler in mitral regurgitation. One hundred and twenty-one patients (64 women and 57 men aged 13 to 76 years, average 54 years) investigated for mitral regurgitation or ischaemic heart disease underwent left ventricular angiography and continuous wave and pulsed Doppler echocardiography. In addition to clinical examination, they also underwent M mode, 2D echocardiography and phonocardiography. They were divided into two groups according to the presence or absence of mitral regurgitation on angiography, chosen as the reference method. Group I comprised 51 patients with angiographic regurgitation, and Group II 70 patients without mitral regurgitation. The sensitivity of the Doppler examination was 98%. Of the 51 patients in Group I there was only one false negative in a patient with doubtful angiographic regurgitation in the context of an endocardial cushion defect. In comparison, the sensitivity of clinical examination and phonocardiography were 74.5% and 80% respectively; 13 cases of mitral regurgitation on angiography and Doppler echocardiography had no auscultatory signs. The specificity of the Doppler examination was 92.8%; 5 of the 70 patients in Group II had unquestionable systolic turbulence in the left atrium and 2D echocardiography showed the possible mechanism of these valvular leaks in 3 cases: 1 bivalvular prolapse, 1 rheumatic valvular thickening and 1 papillary muscle dysfunction. We interpret these 5 cases as being true mitral regurgitation but intermittent or too slight to be visible on angiography. The positive predictive value of systolic turbulence in the left was 90.9% and the negative predictive value was 98.4%.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗
PubMed1985

[New criteria for a positive exercise test].

In this paper, the author reviews the recently developed criteria for a positive stress test. The "nearly ischaemic" appearance in which the ST segment is depressed by greater than or equal to 1.5 mm and slowly rises (slope of less than or equal to 1 millivolt/second) to a value which is predictive in symptomatic patients, of 70 p. cent in favour of coronary artery disease and 40 p. cent in favour of multiple vessel disease. The increased amplitude of the R wave in V5 immediately after effort is more a sign of left ventricular dysfunction than of coronary artery disease. The decreased amplitude of the Q wave in V5 and V6 at maximal effort is a very sensitive (82%) and very specific (88%) sign of left coronary or anterior interventricular artery disease. Similarly, inversion of the U wave in V5 on effort is a very sensitive and specific (97%) sign of left coronary or anterior interventricular artery disease. The major value of these new criteria is to help recognise the false negative results of the stress test, which can be as high as 50% of cases in patients with one vessel disease.

Arrhythmias, Cardiac↗
PubMed1981

Brain uptake of 11C-methionine in phenylketonuria.

The brain uptake of 11C-methionine was studied in 26 children with classical phenylketonuria; one adult was used as a control. Labelled methionine uptake in brain was first measured during a low phenylalanine diet and again one week later after a load of phenylalanine. Ten children aged 1 to 30 months were studied twice at intervals of several months. In children having a phenylalaninemia less than or equal to 0.3 mumoles . ml-1, a decrease in methionine brain uptake was observed with increasing age, with the largest change occurring during the first year of life. After the phenylalanine load, a mean increase in phenylalaninemia by a factor of ten was accompanied by a mean decrease in brain methionine uptake by a factor of two while blood methionine remained unchanged. Brain activity curves increased with time for children younger than one year and having phenylalaninemia less than 0.6 mumoles . ml-1. After the age of 2 most patients had a decreasing curve regardless of the blood phenylalanine level. This study indicates that 11C-methionine brain uptake may be taken as an index of blood barrier permeability to essential amino acids, and of brain maturation. The results obtained suggest that an increase in phenylalaninemia to levels greater than 0.6 mumole . ml-1 induces a modification in brain uptake of amino acids, primarily during the first two years of life.

Adult↗
PubMed1975

The regulation of arginine biosynthesis in Saccharomyces cerevisiae. The specificity of argR- mutations and the general control of amino-acid biosynthesis.

The regulation of arginine biosynthetic enzymes in yeast is subjected to a double control. One level of arginine enzyme synthesis is under the control of an apo-repressor, called ARGR. ARGR molecules control specifically the arginine pathway. A second level of control of arginine biosynthesis has been disclosed. It also controls tryptophan, histidine, lysine, isoleucine-valine and probably many more biosyntheses. The general mechanism is turned on in leaky mutants in any of the amino acid pathways mentioned above.

Amino Acids↗