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Biomedical subjects

A Mallet

Publications and source records attributed to A Mallet.

At least 37 records · Page 2Linked to original sources
PubMed1999

Familial dilated cardiomyopathy: clinical features in French families.

UNLABELLED: The aims of the study were to analyze the clinical features, the penetrance and the mode of inheritance of 13 French families with dilated cardiomyopathy using diagnostic criteria recently established by a European collaboration. METHODS: Screening consisted of physical examination, ECG and Echo of all the probands first degree relatives (n = 118). Using major Echo criteria [ejection fraction (EF) < 45% or FS < 25% and left ventricular diameter (LVD) > 117% of the predictive value], or combined minor Echo/ECG criteria, relatives were classified as affected, unknown or healthy. RESULTS: (1) Adult affected relatives (n = 31) were identified with major Echo criteria in 74% of cases, and with combined minor Echo/ECG criteria in 26% of cases. (2) In the unknown relatives (n = 21), the most common abnormality was an isolated left ventricular dilation (67%). (3) Mode of inheritance was autosomal dominant (AD) in 11 families and possibly autosomal recessive in two. (4) In AD families, the penetrance was incomplete in adults (72%), age-related (O.R.: 1.3 per 10 years; 95% CI 1.03-1.56) and sex-related [greater in men (87%) than in women (61%), actuarial survival curve: P<0.002]. (5) Mortality related to end stage heart failure was 2.2 times as high as mortality related to sudden death (11% vs. 5%). CONCLUSIONS: (1) In the absence of a specific phenotype of FDC, the characterization of relatives appears more accurate when minor criteria were added. (2) Since high mortality (16%) and incomplete penetrance frequently give rise to small nuclei of clinically affected and alive relatives per family, the accurate model of penetrance that we proposed might be helpful in the future to enhance the statistical power of linkage analysis in this disease.

Adult↗
PubMed1999

Drug-drug pharmacodynamic interaction detection by a nonparametric population approach. Influence of design and of interindividual variability.

Population approaches are appealing methods for detecting then assessing drug-drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug-drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.

Algorithms↗
PubMed1999

Asymmetries in brain maturation and behavioral disturbances: multivariate electroencephalogram and P300 studies.

If behavior results from brain function, some evidence of dysfunction could be expected in children with major behavioral problems. Yet, neurophysiologic studies in these children are frequently normal. We hypothesized a relationship between maturational asymmetry and behavior, given the role of hemispheric imbalance in adult psychopathology. The purpose of this study was to investigate whether age-sensitive neurophysiologic measures could identify behaviorally relevant maturational asymmetries in otherwise healthy children. Ninety-five children were studied; reasons for testing were behavioral (19), academic (12), medical nonneurologic (16), and mixed (28), along with 20 control subjects. Academic, behavioral (Child Behavioral Checklist), and psychometric (Wechsler Intelligence Scale for Children-Revised; WISC-R) measures were analyzed in relation to four neurophysiologic parameters: P300 Latency, P300 Latency Asymmetry, Maturational Z-score, and Maturational Z-score Asymmetry, within a canonical design. The highest correlation was behavior with Maturational Z-score Asymmetry. Academic scores were predicted by the three-variable interaction of P300 Latency,Maturational Z-score, and Maturational Z-score Asymmetry. We concluded that behavior was strongly influenced by maturational asymmetry, while academic performance depended on both global maturation and maturational asymmetry. Our results suggest that behavioral disturbances can have a neural substrate despite apparently normal electroencephalograms (EEGs) and event-related potentials (ERPs). They open the possibility for specific therapeutic interventions to improve behavior and performance, and, perhaps, prevent major psychopathology in later life.

Achievement↗
PubMed1998

Comparison of four sib-pair linkage methods for analyzing sibships with more than two affecteds: interest of the binomial maximum likelihood approach.

Family samples collected for sib-pair linkage studies usually include some sibships with more than two affecteds (multiplex sibships). Several methods have been proposed to take into account these multiplex sibships, and four of them are discussed in this work. Two methods, which are the most widely used, are based on the number of alleles shared by the sib-pairs constitutive of the multiplex sibship, with the first using the total number of these shared alleles ("all possible pairs" method) and the second considering a weighted number of these alleles (weighted method). The two other approaches considered the sibship as a whole, with in particular a likelihood method based on a binomial distribution of parental alleles among affected offspring. We theoretically show that, in the analysis of sibships with two affecteds, this likelihood method is expected to be more powerful than the classical mean test when a common asymptotic type I error is used. The variation of the sibship informativeness (assessed by the proportion of heterozygous parents) according to the number of affected sibs is investigated under various genetic models. Simulations under the null hypothesis of no linkage indicate that the "all possible pairs" is anticonservative, especially for type I errors < or = 0.001, whereas the weighted method generally provides satisfactory results. The likelihood method shows very consistent results in terms of type I errors, whatever the sample size, and provides power levels similar to those of the other methods. This binomial likelihood approach, which accounts in a natural way for multiplex sibships and provides a simple likelihood-ratio test for linkage involving a single parameter, appears to be a quite interesting alternative to analyze sib-pair studies.

Adult↗
PubMed1998

Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients.

OBJECTIVE: Fluindione is a vitamin K antagonist with a long half-life. This study was designed to investigate the pharmacokinetics and pharmacodynamics of multiple doses of fluindione in patients. METHODS: In a learning group of 49 patients who began fluindione treatment, blood samples were taken 12, 18, or 24 hours after one, three, and five doses. Concentration of fluindione, activity of clotting factors II, VII, IX and X, prothrombin complex activity (PCA), and international normalized ratio (INR) were measured. An indirect-response pharmacodynamic model was used for each effect. A comprehensive analysis was performed with a nonparametric population approach. The model was evaluated in 24 other patients: blood samples were taken 24 hours after two, three, four, and six doses; and PCA and INR were observed. RESULTS: Analysis of concentrations and clotting factor activities showed notably that (1) fluindione has a long half-life (median, 69 hours), and (2) concentration that inhibits the synthesis of the clotting factors by 50% varied for each factor, with a median ranging from 0.25 to 2.05 mg.L-1 for factors VII and II, respectively. The results obtained for INR and PCA were validated in the 24 subsequent patients. CONCLUSION: The population approach allowed the comparison of several pharmacodynamic submodels. This first application of the indirect-response model to multiple oral anticoagulant doses in patients confirmed that both the pharmacokinetics and the pharmacodynamics of fluindione show substantial interindividual variability.

Anticoagulants↗
PubMed1998

Population pharmacokinetic analysis of mizolastine and validation from sparse data on patients using the nonparametric maximum likelihood method.

A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.

Benzimidazoles↗
PubMed1998

Robust optimal design for the estimation of hyperparameters in population pharmacokinetics.

The expectation of the determinant of the inverse of the population Fisher information matrix is proposed as a criterion to evaluate and optimize designs for the estimation of population pharmacokinetic (PK) parameters. Given a PK model, a measurement error model, a parametric distribution of the parameters and a prior distribution representing the belief about the hyperparameters to be estimated, the EID criterion is minimized in order to find the optimal population design. In this approach, a group is defined as a number of subjects to whom the same sampling schedule (i.e., the number of samples and their timing) is applied. The constraints, which are defined a priori, are the number of groups, the size of each group and the number of samples per subject in each group. The goal of the optimization is to determine the optimal sampling times in each group. This criterion is applied to a one-compartment open model with first-order absorption. The error model is either homoscedastic or heteroscedastic with constant coefficient of variation. Individual parameters are assumed to arise from a lognormal distribution with mean vector M and covariance matrix C. Uncertainties about the M and C are accounted for by a prior distribution which is normal for M and Wishart for C. Sampling times are optimized by using a stochastic gradient algorithm. Influence of the number of different sampling schemes, the number of subjects per sampling schedule, the number of samples per subject in each sampling scheme, the uncertainties on M and C and the assumption about the error model and the dose have been investigated.

Humans↗
PubMed1998

Modeling INR data to predict maintenance fluindione dosage.

This study was designed to construct a pharmacokinetic/pharmacodynamic model describing the evolution of International Normalized Ratio (INR) under oral anticoagulation treatment by fluindione in patients and to develop a method for individualization of fluindione dosage. Three indirect response models describing the concentration-INR relationship were tested using a nonparametric estimation method. INR was modelled as a quantity being produced and eliminated. According to a log-likelihood ratio test, the evolution of INR was best modelled as an inhibition of its elimination by fluindione. The selected model was evaluated in 24 additional patients with INR measurements (after 2, 3, 4, 6, and 10 doses). Using a Bayesian method with data until day 4, INR was correctly predicted for days 6 and 10. The population characteristics of fluindione were estimated, pooling the two groups of patients. A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state. Prescription rules for fluindione were derived using this method retrospectively on the 73 patients in this study.

Anticoagulants↗
PubMed1998

HIV-associated nephropathy: outcome and prognosis factors. Groupe d' Etudes Néphrologiques d'Ile de France.

Records of 102 patients with biopsy-proven HIV-associated nephropathy (HIVAN) admitted to 18 hospitals in the Paris area from 1984 through 1996 were retrospectively reviewed. Demographics and clinical and laboratory features of the cohort were determined, and prognostic factors of renal and patient survival were analyzed. Renal and patient survival curves were estimated with the actuarial method. Prognostic factors were assessed by uni- and multidimensional analyses based on Cox regression models. Values were expressed as median with interquartile. The total population (median age 34) included 97% blacks and 71.5% males. Median patient follow-up was 165 d (range, 43 to 493). At the time of renal biopsy, median values of serum creatinine, proteinuria, and CD4+ cell count were 496 micromol/L, 6.5 g/24 h, and 48.5 cells/mm3, respectively. Fifteen patients were given steroids after the onset of HIVAN. Overall patient survival at 0.5, 1, and 3 yr was 73 +/- 5, 55 +/- 6, and 38 +/- 7%, respectively. The proportion of patients free of dialysis at 0.5, 1, and 3 yr was 73 +/- 5, 60 +/- 7, and 18 +/- 10%, respectively. Predictors of poor patient prognosis were a low CD4+ cell count (relative risk [RR; per 50 cells/mm3 decrease] 1.35; confidence interval [CI], 1.13 to 1.6) and antiretroviral therapy before the onset of HIVAN (RR 1.9; CI, 1.05 to 3.6). Main independent factors associated with better renal outcome were: steroid therapy (RR 0.29; CI, 0.1 to 0.9); low proteinuria level (RR [per 50% decrease] 0.7; CI, 0.5 to 0.98); low serum creatinine (RR [per 1.1 mg/dl decrease] 0.78; CI, 0.7 to 0.87); and hemoglobin level (RR [per g/dl increase] 0.76; CI, 0.58 to 1.00). HIVAN is not a rare nephropathy in Paris and its suburbs. Renal prognosis and patient survival are better than what was reported previously. Steroids may delay the downward course of HIVAN. It is not certain that in the new era of HIV therapy, the possible renal benefits of corticosteroids outweigh their potential risks. The only reliable predictor of patient survival is the intensity of immunodeficiency.

Adrenal Cortex Hormones↗
PubMed1997

Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the Cardiac Insufficiency BIsoprolol Study (CIBIS).

BACKGROUND: To further evaluate the mechanism of beta-blocker-induced benefits in heart failure, the relationships between bisoprolol-induced hemodynamic effects and survival were studied during the Cardiac Insufficiency BIsoprolol Study (CIBIS). METHODS AND RESULTS: In 557 patients studied, bisoprolol significantly reduced heart rate (-16.3+/-15.3 versus -1.6+/-13.4 bpm, respectively; P<.001) compared with placebo at 2 months after inclusion in the study. Heart rate change over time had the highest predictive value for survival (P<.01). Left ventricular fractional shortening (LVFS) significantly increased in the bisoprolol group compared with the placebo group 5 months after inclusion (+0.04+/-0.06 versus -0.001+/-0.05, respectively; P<.001; n=160). LVFS change over time was also significantly correlated with further survival (P<.02 by Cox analysis). Using a nonparametric approach, we demonstrated a significant interaction between study treatment group and LVFS over time. Patients who demonstrated improvement of LVFS over time (82% and 51% of patients in the bisoprolol and the placebo groups, respectively; P<.02) were at lower risk, but the hazard did not further decrease with a further increase of fractional shortening, and there was no significant difference between study treatment groups. Finally, it could be demonstrated that each of the three factors (heart rate change over time, LVFS change over time, and bisoprolol treatment) made a specific contribution to mortality rate. CONCLUSIONS: Preservation of left ventricular function appears to play a key role in the bisoprolol-induced beneficial effects on prognosis in heart failure. Short-term beta-blocker-induced cardiac effects could provide a means to identify those patients who will experience improved survival over the long term.

Adrenergic beta-Antagonists↗
PubMed1997

Pharmacokinetic analysis of mizolastine in healthy young volunteers after single oral and intravenous doses: noncompartmental approach and compartmental modeling.

This paper presents the analysis of the kinetics of a new antihistamine, mizolastine, in 18 healthy volunteers, from concentrations measured after an intravenous infusion and two different oral administrations: tablet and capsule. Two approaches were used to analyze these data: (i) a noncompartmental approach implemented in PHARM-NCA; (ii) a compartmental modeling approach implemented in a new S-PLUS library, NLS2, which allows the estimation of variance parameters simultaneously with the kinetic parameters. For the compartmental modeling approach, two-compartment open models were used. According to the Akaike criterion, the best model describing the kinetics of mizolastine after oral administration was the zero-order absorption model. The kinetic parameters obtained with PHARM-NCA and NLS2 were similar. The estimated duration of absorption was greater for the tablets than for the capsules (with means equal to 1.13 hr and 0.84 hr respectively). After an intravenous infusion, the mean estimated clearance was 4.9 L/hr, the mean lambda 2-phase apparent volume of distribution was 89.6 L and the mean terminal half-life was 12.9 hr.

Administration, Oral↗
PubMed1997

Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method.

AIMS: To evaluate the distribution of population kinetic parameters for clozapine and their relationship to age and gender in patients on continuous treatment with the drug. METHODS: Retrospective therapeutic drug monitoring data (391 samples from 241 patients) were evaluated using the nonparametric maximum likelihood method. Patients treated concomitantly with drugs known to interact with clozapine were not included. The distribution of clozapine clearance was compared with the distribution of the activity of the drug metabolic enzyme CYP1A2 found in other populations, as recent studies indicate that CYP1A2 is a major determinant for clozapine elimination. The kinetic linearity for clozapine was studied in 41 patients who each provided data from more than one dose level. RESULTS: Clozapine clearance was highly variable in the population and skewed towards high values. Men had higher clearances CL/F (median with 25% and 75% quartiles 38.2 (22.0, 60.0) vs 28.3 (15.2, 48.6) l h(-1)) and a larger volume of distribution V/F (694 (224, 970) vs 401 (189, 932) l) than women. Clearance did not decrease with age in any gender. Clozapine clearance was similarly distributed as the indices of CYP1A2-activity found in other populations by other authors. Evidence of nonlinear kinetics was not found. CONCLUSION: The large kinetic variability for clozapine found in this study implies that the dose of clozapine needs to be individualised over a wide dose range. The similarity of the distribution of clozapine clearance in this study and the CYP1A2-activity in other populations support the assumption that CYP1A2 is a major determinant for clozapine elimination.

Administration, Oral↗
PubMed1997

Penetrance of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant cardiac disease for which the penetrance remains a much-debated issue. Since the recent identification of the genes involved in the disease, the penetrance of FHC has not been reassessed in a large genotyped population. The aim of our study was therefore to evaluate it, according to age and sex, in ten families with previously identified mutations. Among 178 individuals we studied, 90 were genetically affected (9 different mutations in 3 genes). We found that penetrance, assessed by classical echocardiographic and electrocardiographic criteria, was (1) incomplete: 69%; (2) age-related: 55% between 10 and 29 years old, 75% between 30 and 49 y. and 95% over 50 y.; (3) greater in males than in females: 77% vs 58%, age-adjusted odds ratio: 3.98, CI 95%: 1.34 to 11,48; (4) similar for the genes analyzed. The consequences of these results for genetic counseling and linkage analyses are discussed.

Adolescent↗
PubMed1996

Beta-1,2-linked oligomannosides inhibit Candida albicans binding to murine macrophage.

Interaction of Candida albicans with cells of the macrophage lineage was examined by using heat-killed (HK) and live yeast cells. Laminarin, an analogue of the cell wall beta-glucans, strongly inhibited HK yeasts adherence to J774 cell line but had no effect on live yeast binding. Phosphopeptidomannan (PPM) from Saccharomyces cerevisiae had a limited effect on the binding of both HK and live yeasts but significant inhibition was achieved by the use of C. albicans PPM. The role of beta-1,2-oligomannosides was examined with regard to their exclusive presence within C. albicans PPM. PPM acid labile beta-1,2-oligomannosides or a synthetic beta-1,2-mannotetraose, inhibited yeasts binding in a manner comparable to the original PPM. These latter results were confirmed by using mouse peritoneal macrophages, thus suggesting a general role for beta-1,2-oligomannosides in the adherence of the yeast to the macrophage membrane.

Animals↗
PubMed1995

Cognitive function and assessment of lung function in the elderly.

The feasibility of spirometry or respiratory impedance measurements for assessing lung function in the elderly was compared in 208 institutionalized patients with various degrees of cognitive function impairment. Respiratory impedance was determined by the forced oscillation technique. Cognitive function was assessed by the score for the mini-mental state (MMS) examination. Of the 208 patients, 126 had severe cognitive impairment (MMS < or = 17), 36 had mild impairment (18 < or = MMS < or = 23), and 46 had no impairment (MMS > or = 24). Of the 208 patients, respiratory impedance measurements were possible in 159, whereas in only 85 was spirometry possible. The overall difference between the feasibility rates for the spirometric and respiratory impedance measurements was highly significant (chi 2 = 71.4; p < 10(-6)). The difference between the feasibility rates for the two techniques was higher in the group of subjects with severe cognitive impairment than in the groups with mild impairment and no impairment, respectively. Among the 84 patients able to complete both tests, significant correlations were found between the spirometric and respiratory impedance measurements. These results indicate that respiratory impedance measurement seems a more useful tool than spirometry for assessing lung function in elderly patients whenever cognitive function is impaired.

Aged↗
PubMed1995

[Tools for the assessment of tobacco dependence: comparison with questionnaires and marker assays].

Fagerström Tolerance Questionnaire has been questioned in some respects for the purpose of the evaluation of tobacco dependence. In a sample of 208 smokers attempting to quit, we measured on urinary samples the levels of nicotine metabolites via their thiobarbituric acid derivatives comparatively to the levels of nicotine and cotinine by high performance liquid chromatography. Urinary concentration of nicotine metabolites was 77.1 +/- 50.0 mumol/l. Nicotine and cotinine levels were respectively 8.2 +/- 12.0 mumol/l and 12.9 +/- 9.8 mumol/l. Spearman correlation coefficients were used to examine the relationships among various measures of exposure to cigarette smoke, tobacco markers and tobacco addiction scores obtained through the Fagerström Questionnaire and a Simplified Questionnaire. Nicotine metabolites are correlated with the score obtained with the Simplified Questionnaire (rho = 0.39) better than with the score of Fagerström (rho = 0.28) (p < 0.01). These moderate correlations suggest that the measurement of tobacco markers provide a more valuable information than questionnaires for the appreciation of the depth of tobacco intake. The questionnaires should not serve as a substitute for tobacco markers determination.

Adult↗
PubMed1994

Designing an optimal experiment for Bayesian estimation: application to the kinetics of iodine thyroid uptake.

We consider the problem of designing an optimal experiment for Bayesian estimation of the parameters of a non-linear model. When their distribution is known, the Bayesian approach allows individual estimation from a small number of measurements; the design determines the accuracy of the estimates. We propose to optimize this design by maximizing a general criterion: the expectation of the information supplied by the experiment. This approach is applied to optimize the two sampling times for Bayesian estimation of the kinetics of radioiodine thyroid uptake from an estimated non-parametric prior distribution.

Bayes Theorem↗