Biomedical subjects

Jean Maccario

Publications and source records attributed to Jean Maccario.

18 recordsLinked to original sources

PubMed2006

Interrelationships of quantitative asthma-related phenotypes in the Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy.

BACKGROUND: Delineating asthma subphenotypes is of interest to understand the cause of the disease. Few studies have addressed the interrelationships of quantitative asthma-related traits. OBJECTIVE: We sought to study the interrelationships of allergy markers and FEV(1) in relation to asthma and sex in children and adults. METHODS: Total IgE levels, skin prick test (SPT) positivity, eosinophil counts, and FEV(1) were assessed in 299 asthmatic cases (children and adults) recruited in chest clinics and 309 nonasthmatic population-based control subjects in the French Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy. RESULTS: Allergy parameters were significantly higher in asthmatic cases than in control subjects for children and adults and for both sexes. Sex and age modified the pattern of concordance of high IgE levels, SPT positivity, and eosinophilia among asthmatic cases, with the greatest overlap in male children (64%) and the lowest in male adults (18%). Patterns of change over the lifespan of IgE levels, eosinophil counts, and FEV(1)/height(2) varied, with the acceleration of FEV(1) decrease being particularly evident in asthmatic adults. In adult cases and control subjects, SPT positivity (particularly to indoor allergens) was significantly related to IgE levels but not to eosinophil counts. The association of eosinophil counts with IgE levels was evident only in children. Environmental factors (smoking, pets, and country living) did not alter the patterns observed. CONCLUSIONS: Each allergy-related phenotype showed a distinct relation with asthma, with the role for eosinophils being different than that for IgE levels and SPT responses. CLINICAL IMPLICATIONS: Taking age and sex into account is essential for understanding the interrelationships of the various allergy-related phenotypes to asthma status.

Adult↗

PubMed2006

Efficacy of siRNA nanocapsules targeted against the EWS-Fli1 oncogene in Ewing sarcoma.

The EWS-Fli1 fusion gene encodes for a chimeric oncogenic transcription factor considered to be the cause of the Ewing sarcoma. The efficiency of small interfering RNAs (siRNAs) targeted toward the EWS-Fli1 transcript (at the junction point type 1) was studied, free or encapsulated into recently developed polyisobutylcyanoacrylate aqueous core nanocapsules. Because this mRNA sequence is only present in cancer cells, it therefore constituted a relevant target. Studies of the intracellular penetration by confocal microscopy in NIH/3T3 EWS-Fli1 cells showed that nanocapsules improved the intracellular penetration of siRNA with mainly a cytoplasmic localization. These biodegradable siRNA-loaded nanocapsules were then tested in vivo on a mice xenografted EWS-Fli1-expressing tumor; they were found to trigger a dose-dependant inhibition of tumor growth after intratumoral injection. A specific inhibition of EWS-Fli1 was observed, too. These findings now open new prospects for the treatment of experimental cancers with junction oncogenes.

Animals↗

PubMed2005

Measurement of sunscreen immune protection factors in humans: a consensus paper.

It is increasingly accepted that sunscreens should protect against ultraviolet radiation (UVR)-induced immunosuppression, with an index of protection that can be compared with the sun protection factor (SPF). Five groups of immunoprotection researchers met to discuss the status of immune protection factor (IPF) evaluation in human skin in vivo. Current methods rely on a suncreen's inhibition of UVR-induced local suppression of the contact hypersensitivity (CHS) response or the delayed-type hypersensitivity (DTH) response, using either the induction or the elicitation arms of these responses. The induction arm of the CHS response has the advantage of being sensitive to a single sub-erythemal exposure of solar-simulating radiation (SSR) that allows a direct comparison with the SPF. This approach, which necessitates sensitization, requires a large number of volunteers and is too labor intensive and time consuming to become a routine method. The elicitation arm of the CHS or DTH responses exploits prior sensitization to contact or recall antigens and has the advantage of being possible to apply on small groups of volunteers. Some current protocols, however, require repeat SSR exposures, which invalidates a direct comparison with SPF that is based on a single exposure. There is a need for a new simpler method of IPF that will have to be validated against existing models.

Dermatitis, Contact↗

PubMed2004

Asthma severity is associated with body mass index and early menarche in women.

Asthma severity in relation to body mass index (BMI) has rarely been studied. The relation between BMI and asthma severity was studied by sex in 366 adults with asthma from the Epidemiological Study on the Genetics and Environment of Asthma, a case-control and family study on asthma. Factors related to asthma severity and BMI such as smoking, FEV(1), bronchial hyperresponsiveness, and dyspnea were taken into account. The influence of early menarche was studied to assess the potential role of hormonal factors. Clinical asthma severity in the last 12 months was assessed by a score (0-7) based on the frequency of asthma attacks, persisting symptoms between attacks, and hospitalization. Asthma severity, which was unrelated to sex, increased with BMI in women (p = 0.0001) but not in men (p = 0.3). In women, the association remained after adjustment for age, FEV(1), smoking habits, and BMI-adjusted dyspnea and taking into account familial dependence (p = 0.0001). The association between BMI and severity was stronger in women with early menarche than in women without early menarche (p interaction = 0.02). Findings support the hypothesis of hormonal factors involved in the severity of asthma.

Adult↗

PubMed2004

Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families.

A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P</=0.001): 6q14 for %FEV(1), 12p13 for IgE, 17q22-q24 for SPT and 21q21 for both SPTQ and %FEV(1). Nine other regions indicated smaller linkage signals (0.001<P</=0.005). While most of these regions have been reported by previous asthma and lung function screens, 6q14 appears to be a new region potentially linked to %FEV(1). To determine which of these various asthma phenotypes are more likely to share common genetic determinants, a principal component analysis was applied to the genome-wide LOD scores. This analysis revealed clustering of LODs for asthma, SPT and Phadiatop on one axis and clustering of LODs for %FEV(1), BR and SPTQ on the other, while LODs for IgE and eosinophils appeared to be independent from all other LODs. These results provide new insights into the potential sharing of genetic determinants by asthma-related phenotypes.

Adolescent↗

PubMed2004

MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients.

BACKGROUND: Cyclosporine A (CsA) is characterized by high interindividual variations in oral bioavailability and a narrow therapeutic index. CsA is a substrate for P-glycoprotein, a member of the ABC transporter family encoded by the multiple drug-resistant gene MDR1. METHODS: Because MDR1 gene exon 26 C3435T polymorphism influences intestinal P-glycoprotein expression, we investigated whether this polymorphism was correlated with variation in CsA dose requirement and concentration/dose ratio in 44 liver-transplant recipients during 1 month after transplantation. CsA concentration was measured 2 hours after administration (C2), according to international recommendations. RESULTS: The MDR-1 wild-type genotype (3435CC) was observed in 15 patients (34%), whereas 21 (48%) patients were heterozygous (3435CT), and 8 (18%) patients were homozygous for the mutation (3435TT). There was no significant difference between the three groups regarding corticosteroids treatment or renal function during this period. One to 3 days after liver transplantation, when every patient received a similar CsA weight-adjusted dose, the concentration/dose ratio was correlated with exon 26 single nucleotide polymorphism and was significantly higher in subjects homozygous for the mutation (P=0.012). This was confirmed 1 month after transplantation (P=0.049), when the dose was adjusted to maintain the C2 target level of 1,000 microg/L and we observed that TT patients required approximately 50% lower weight-adjusted CsA dose than wild-type patients (P=0,033). CONCLUSIONS: These findings demonstrate that the MDR1 exon 26 C3435T polymorphism is a major determinant of CsA concentration/dose ratio in liver-transplant recipients and is predictive of the dose of CsA to be administered to achieve the target C(2) concentration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Role of gender and hormone-related events on IgE, atopy, and eosinophils in the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy.

BACKGROUND: The pattern of asthma over the lifespan is different in male and female patients, but etiologic differences according to gender are only partially understood. In women, information regarding factors explaining perimenstrual asthma and the role of hormone-related aspects on asthma-related phenotypes is scanty. OBJECTIVE: To assess the relationships of eosinophils, IgE, and atopy with (1) asthma according to gender and age of onset and (2) hormone-related events. METHODS: Using data from the Epidemiological study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness and Atopy, adults and children with asthma recruited in chest clinics (n=313) and first-degree relatives of patients with asthma (n=214) were compared with nonasthmatic controls (n=334) and first-degree relatives without asthma (n=595). RESULTS: Among asthmatic women, eosinophilia was significantly associated with perimenstrual asthma independently from age, smoking, and asthma severity (eosinophils/mm(3) 330 vs 194; P=.01). In nonasthmatic women, IgE level was significantly decreased (by half) and atopy decreased with menopause, and IgE increased with oral contraceptive use, independently from age and smoking. Considering both genders, the increase of eosinophil counts with asthma was significantly greater in women with childhood-onset asthma than in women with adulthood-onset or in men in general. No interaction between gender and asthma was observed for eosinophils in children and for IgE level and atopy in children and adults. CONCLUSION: Results suggest a role of hormone-related events on asthma-related traits and support the hypothesis of the role of eosinophils in the persistence and severity of asthma.

Adolescent↗

PubMed2004

Familial correlations and inter-relationships of four asthma-associated quantitative phenotypes in 320 French EGEA families ascertained through asthmatic probands.

Asthma is a complex disease, associated with biological and physiological phenotypes including immunoglobulin E (IgE) levels, sum of positive skin prick tests to allergens (SPTQ), eosinophil counts (EOS) and percent predicted forced expiratory volume in 1 s (%FEV1). We investigated the patterns of familial correlations and the inter-relationships of these four quantitative phenotypes, using the general class D regressive model, in 320 French EGEA nuclear families ascertained through 204 offspring (set A) and 116 parents (set B). Familial correlations of IgE and SPTQ were consistent with a model including no spouse correlation and equal parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.25 for IgE and 0.15 for SPTQ), this model being compatible with an additive polygenic model in the whole sample and the two family subsets A and B. Different patterns of familial correlations of EOS and %FEV1 were observed in these two sets. In set A, the best fitting model included no spouse correlation and equality of parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.14 for EOS and 0.23 for %FEV1). In set B, EOS had only a significant rhoSS of 0.28, while %FEV1 had significant rhoMO of 0.28 and rhoSS of 0.16. Analysis of shared familial determinants between these phenotypes indicated an overlap of at most 30% in rhoFO for IgE and SPTQ and in both rhoFO and rhoMO for IgE and EOS, while determinants of %FEV1 and atopy-related phenotypes appear distinct. These results may have implications for further linkage and association studies with genetic markers.

Adolescent↗

PubMed2003

Complex dispersions of multilamellar vesicles: a promising new carrier for controlled release and protection of encapsulated molecules.

Multilamellar vesicles called Spherulites have recently been discovered and are being developed for encapsulation applications. In this study, we present new systems of Spherulites called complex dispersions. These are prepared by dispersing Spherulites within an oily medium, and then emulsifying this oily dispersion of Spherulites within an aqueous solvent. The ability of complex dispersions to reduce the release of encapsulated ions under variable osmotic dilutions was evaluated and compared with Spherulites directly dispersible in an aqueous medium, and with multiple emulsions. An advantage of complex dispersions over Spherulites is to present an additional oily barrier. Indeed, this barrier retarded the release of encapsulated ions. Complex dispersions also proved to be less sensitive to osmotic pressure than multiple emulsions. It appeared that the dilution of a complex dispersion formulated with no external aqueous phase containing a hydrophilic surfactant provided the slowest release of encapsulated ions. Furthermore, this formulation maintained a difference of pH between the internal and external aqueous phases for a few hours. In conclusion, these new systems of Spherulites known as complex dispersions show great potential for pharmaceutical applications such as controlled release and protection of encapsulated substances.

Capsules↗

PubMed2003

In vivo and in vitro peripheral-type benzodiazepine receptor polymerization: functional significance in drug ligand and cholesterol binding.

Peripheral-type benzodiazepine receptor (PBR) is an 18 kDa high-affinity drug ligand and cholesterol binding protein involved in various cell functions. Antisera for distinct PBR areas identified immunoreactive proteins of 18, 40, and 56 kDa and occasionally 72, 90, and 110 kDa in testicular Leydig and breast cancer cells. These sizes may correspond to PBR polymers and correlated to the levels of reactive oxygen species. Treatment of Leydig cells with human chorionic gonadotropin rapidly induced free radical, PBR polymer, and steroid formation. UV photoirradiation generates ROS species, which increased the size of intramembraneous particles of recombinant PBR reconstituted into proteoliposomes consistent with polymer formation, determined both by SDS-PAGE and by freeze-fracture electron microscopy. Spectroscopic analysis revealed the formation of dityrosines as the covalent cross-linker between PBR monomers. Moreover, photoirradiation increased PK 11195 drug ligand binding and reduced cholesterol binding capacity of proteoliposomes. Further addition of PK 11195 drug ligand to polymers increased the rate of cholesterol binding. These data indicate that reactive oxygen species induce in vivo and in vitro the formation of covalent PBR polymers. We propose that the PBR polymer might be the functional unit responsible for ligand-activated cholesterol binding and that PBR polymerization is a dynamic process modulating the function of this receptor in cholesterol transport and other cell-specific PBR-mediated functions.

Animals↗

PubMed2003

Two-treatment comparison based on joint toxicity and efficacy ordered alternatives in cancer trials.

The primary goal of anticancer treatments is to attain efficacy, however toxicity could affect the course of the therapy. Methods have been proposed for comparing two treatments on the basis of the joint distribution for safety and efficacy outcomes, but they do not take into account the cumulative doses of drugs (chemotherapy) or radiation (radiotherapy) received by each patient. Moreover, these methods assume a parametric form for the joint distribution. In this paper we define a multi-dimensional parameter including toxicity and efficacy outcomes and the dose at which one, none or both occur. Each patient is classified into an ordered category depending on the order of occurrence of these two criteria: the sooner the patient benefits from efficacy and/or the later he/she experiences toxicity, the better is the treatment. We then apply likelihood ratio tests with ordered alternatives. This procedure requires constrained maximum likelihood estimation via isotonic regression. A large set of simulations compares the proposed tests to other more usual tests and the results show a good power and a satisfactory type I error control. Our approach is illustrated with a multi-centre randomized clinical trial involving patients with metastatic non-seminomatous germ cell tumours.

Antineoplastic Agents↗

PubMed2003

A Bayesian analysis of pharmacoeconomic data from a clinical trial on schizophrenia.

Pharmacoeconomic studies are performed in a higher frequency to assess the economic interest of new drugs. However, a standard methodology does not still completely exist. We present here the principles and results of a cost-effectiveness Bayesian analysis on data from 146 patients (interim analysis) collected during a clinical trial. This trial was originally planned to enrol 245 patients with predominantly negative schizophrenia symptoms and involved four treatment groups (a new treatment given at low dose and high dose, a comparator and a placebo). First, some prior distributions of the cost-effectiveness ratio were numerically deduced from the effectiveness parameter clinical priors (based on investigators' opinions and questionnaires before going to blind breaking) and from cost function priors. The costs taken into account were hospitalizations, sick leave days, treatments, visits to the doctor, laboratory exams and suicide attempts. The effectiveness parameter was the change from baseline on SANS (scale for the assessment of negative symptoms). Posterior distributions were elaborated for the cost-effectiveness ratio by combining the cost-effectiveness ratio priors and likelihood together using the Bayes theorem. Results lead to a conclusion in favour of the new treatment given at high dose.

Antipsychotic Agents↗

PubMed2003

Oligonucleotides targeted against a junction oncogene are made efficient by nanotechnologies.

PURPOSE: Antisense oligonucleotides (AON) against junction EWS-Fli-1 oncogene (which is responsible for the Ewing Sarcoma) are particularly interesting for targeting chromosomal translocations that are only found in tumor cells. However, these AON have proved in the past to be ineffective in vivo because of their susceptibility to degradation and their poor intracellular penetration. The aim of this study was to improve the delivery of these molecules through the use of nanotechnologies. METHOD: Two different AONs, and their controls, both targeted against the junction area of the fusion gene EWS-Fli-1 were used. Nanocapsules were employed to deliver a phosphorothioate AON and its control. The nanospheres were used to deliver a chimeric phosphorothioate, phosphodiester AON, with 5 additional bases in 5' which allow this AON to be structured with a loop. These formulations were injected intratumorally to nude mice bearing the experimental EWS-Fli-1 tumor. The tumour volume was estimated during the experiments by two perpendicular measurements length (a) and width (b) of the tumour and was calculated as ab(2)/2. Northern blot analysis was also performed after removing the tumors 24 h after the treatment with a single dose of AON either free or associated with nanotechnologies. RESULTS: This study shows for the first time that AON against EWS-Fli-1 oncogene may inhibit with high specificity the growth of an EWS-Fli-1 dependent tumor grafted to nude mice provided they are delivered by nanocapsules or nanospheres. In this experience, the antisense effect was confirmed by the specific down regulation of EWS-Fli-1 mRNA. CONCLUSION: Thus, both nanocapsules and nanospheres may be considered as promising systems for AON delivery in vivo.

Animals↗

PubMed2003

Methodologic aspects of the quantification of skin prick test responses: the EGEA study.

BACKGROUND: The expression of responses of allergy skin prick tests is not standardized. Usual definitions of atopy are not quantitative. OBJECTIVE: We sought to perform a biometric analysis of responses to various allergens to propose synthetic, quantitative indices independent of the heterogeneity of responses to various allergens. METHODS: Adults (N = 1286) from the Epidemiological Study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA) were included in the analysis. The first step, conducted for 678 subjects with at least 1 wheal >0, was to perform a standardization of wheal diameters to obtain comparable figures for 10 allergens through use of the means of the squares of wheal size as a scaling factor. The second step was a factor analysis of the standardized responses conducted not only for all subjects but also separately for asthmatic case and nonasthmatic control subjects. Finally, the strength of the link between various dichotomous and quantitative scores was assessed with multiRAST, total IgE, and asthma. Analyzed quantitative scores were based on the number of positive responses and on the nonstandardized and standardized sizes of the wheals. RESULTS: The standardization was efficient. Among asthmatic subjects but not other subjects, factor analysis evidenced a pattern with 3 factors, corresponding to outdoor, indoor, and mold allergens. The link study showed that all scores performed very similarly. CONCLUSION: The number of positive tests is a quantitative score with valid biometric properties. It should be used more widely in clinical settings and in epidemiology to assess the severity of atopy.

Adolescent↗

PubMed2003

Manual skill, hand skill asymmetry, and cognitive performances in young children.

A total of 1022 children aged 3 to 6 years were examined in their preschools and 27% of them were followed up for 2 years. A computerised version of the peg-moving task was used repeatedly to assess hand skill of the dominant and the nondominant hand. Cognitive performance was repeatedly evaluated by tasks involving speech, vocabulary, phonological memory, and visual-spatial skills. Results showed that: (i) age, sex, and handedness effects on hand skill asymmetry generally confirmed previous reports, especially by Annett (2002); (ii) visual-spatial and vocabulary tasks were significantly related to hand skill but speech and phonological memory tasks were not, and the role of the dominant and nondominant hand were similar; (iii) overall, manual laterality indexes were only weakly associated to some cognitive abilities; (iv) early manual skill was more strongly associated to cognitive tasks than later manual skill. These results fit the assumption of a significant role of early manual behaviour in aspects of cognitive development not relying exclusively on phonology, and raise questions about cognitive development and rehabilitation of children with early occurring manual deficiencies.

Journal Article↗

PubMed2002

Familial resemblance of asthma severity in the EGEA* study.

Familial resemblance of asthma is well known but epidemiological research focused on familial resemblance of asthma severity is scanty. We studied whether asthma and asthma severity in first-degree relatives of cases with asthma were related to asthma severity of the index case. The analysis was based upon the examination of 944 subjects (348 cases, 239 relatives with asthma, and 357 subjects without asthma) and upon the information on 3467 first- degree relatives of probands. The risks of asthma in relatives of adult and pediatric cases were significantly higher than in relatives of subjects without asthma (OR 3.4 [95% CI 2.5-4.7] and 4.5 [2.6- 8.1], respectively). Proportions of asthma in relatives were not related to the asthma severity of cases for the three severity criteria studied (clinical score, FEV(1) % predicted, and inhaled corticosteroid use). Using both regression models and intraclass correlation coefficients, there was a significant familial resemblance for the clinical severity score (ICC = 0.23 and 0.23) and for FEV(1) (ICC = 0.19 and 0.25) among families of pediatric and adult probands, respectively. In conclusion, asthma occurrence in relatives may be independent of the severity of the cases with asthma, but results suggest familial resemblance in the severity of asthma when it occurs.

Administration, Inhalation↗

PubMed2002

Non-parametric optimal design in dose finding studies.

We describe a non-parametric optimal design as a theoretical gold standard for dose finding studies. Its purpose is analogous to the Cramer-Rao bound for unbiased estimators, i.e. it provides a bound beyond which improvements are not generally possible. The bound applies to the class of non-parametric designs where the data are not assumed to be generated by any known parametric model. Whenever parametric assumptions really hold it may be possible to do better than the optimal non-parametric design. The goal is to be able to compare any potential dose finding scheme with the optimal non-parametric benchmark. This paper makes precise what is meant by optimal in this context and also why the procedure is described as non-parametric.

Journal Article↗

PubMed2002

The incubation period of kuru.

BACKGROUND: Kuru is a transmissible spongiform encephalopathy that was identified in Papua New Guinea in the late 1950s. Several thousand cases of the disease occurred during a period of several decades. Epidemiologic investigations implicated ritual endocannibalistic funeral feasts as the likely route through which the infectious agent was spread. METHODS: We estimated the incubation period distribution of kuru using a back-calculation model and explored the relation among sex, age at infection, and incubation period. Key assumptions in the model were that the number of new kuru infections in a year was proportional to the number of kuru cases dying that year, and that the epidemic arose from a single case of sporadic Creutzfeldt-Jakob Disease occurring around 1900. RESULTS: The mean incubation period of kuru was estimated at between 10.3 and 13.2 years. Point estimates of the 90th percentile ranged from 21.1 to 27.0 years. The incubation period in females was estimated to be shorter than that in males. The shortest incubation periods were estimated in adult women, who may have been exposed to the largest doses of infectious material. CONCLUSIONS: Our findings suggest that the relatively young age of cases of variant Creutzfeldt-Jakob disease probably reflects increased levels of exposure in young people, rather than age-dependency in the incubation period.

Adolescent↗