Biomedical subjects

Flavie Mathieu

Publications and source records attributed to Flavie Mathieu.

10 recordsLinked to original sources

PubMed2006

Shared executive dysfunctions in unaffected relatives of patients with autism and obsessive-compulsive disorder.

BACKGROUND: Executive dysfunctions have been studied as a potential endophenotype associated with the genetic basis of autism. Given that recent findings from clinical and molecular genetic studies suggest that autism and obsessive-compulsive disorder (OCD) could share a common pattern of heritability, we assessed executive functions as a possible common cognitive endophenotype in unaffected family members of individuals with either autism or OCD. METHODS: Five tests assessing executive functions (Tower of London, verbal fluency, design fluency, trail making and association fluency) were proposed to 58 unaffected first-degree relatives (parents and siblings) of probands with autism and 64 unaffected first-degree relatives of OCD patients. Results were compared with those of 47 healthy controls matched for age, sex, and level of education. RESULTS: In the Tower of London test, both groups of unaffected relatives showed significantly lower scores and longer response times compared with controls. No differences were observed between autism and OCD relatives and healthy controls in the four other tasks (verbal fluency, design fluency, trail making test and association fluency). CONCLUSIONS: Our findings show the existence of executive dysfunction in the unaffected first-degree relatives of probands with OCD, similar to those observed in the relatives of patients with autism. These results support and extend previous cognitive studies on probands indicating executive dysfunctions in autism and OCD. Planning and working memory processes could thus represent a common cognitive endophenotype in autism and OCD that could help in the identification of genes conferring vulnerability to these disorders.

Adolescent↗

PubMed2006

Prefrontal cortex dysfunction in patients with suicidal behavior.

BACKGROUND: Abnormal serotonergic neurotransmission has long been demonstrated in suicidal behavior. The dorsal and median raphe nuclei housing the main serotonergic cell bodies and the prefrontal cortex (PFC), particularly the ventral part innervated by the serotonergic system, have therefore been studied extensively in suicidal behavior research. However, only a few studies have described neuropsychological function impairment in suicidal patients. We investigated PFC-related neuropsychological function in patients with suicidal behavior, separating dorsolateral PFC (DLPFC)- and orbitofrontal cortex (OFC)-related functions. METHOD: We compared 30 euthymic patients with suicidal behavior aged 18-65 years with 39 control subjects, for the following neuropsychological domains: global intellectual functioning, reward sensitivity, initiation, inhibition, and working memory. Patients and controls were compared by means of univariate and multivariate analyses, adjusting for age at interview, level of education and mood state at the time of evaluation. Trait impulsivity, measured with the Barratt Impulsivity Scale version 10 (BIS-10), was also included as a covariate in a subset of analyses. RESULTS: Multivariate comparisons demonstrated significant executive function deficits in patients with suicidal behavior. In particular, we observed impairment in visuospatial conceptualization (p<0.0001), spatial working memory (p=0.001), inhibition (Hayling B-A, p=0.04; go anticipations, p=0.01) and visual attention (or reading fluency) (p=0.002). Similar results were obtained following adjustment for motor impulsivity as a covariate, except for spatial working memory. CONCLUSIONS: These deficits are consistent with prefrontal dysfunction in patients with suicidal behavior. Differentiation between DLPFC- and OFC-related neuropsychological functions showed no specific dysfunction of the orbitofrontal region in patients with suicidal behavior in our sample.

Adult↗

PubMed2006

Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus.

We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection (TAAD) and patent ductus arteriosus (PDA) and mapped the disease locus to 16p12.2-p13.13 (ref. 3). We now demonstrate that the disease is caused by mutations in the MYH11 gene affecting the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, a specific contractile protein of smooth muscle cells (SMC). All individuals bearing the heterozygous mutations, even if asymptomatic, showed marked aortic stiffness. Examination of pathological aortas showed large areas of medial degeneration with very low SMC content. Abnormal immunological recognition of SM-MHC and the colocalization of wild-type and mutant rod proteins in SMC, in conjunction with differences in their coimmunoprecipitation capacities, strongly suggest a dominant-negative effect. Human MYH11 gene mutations provide the first example of a direct change in a specific SMC protein leading to an inherited arterial disease.

Adult↗

PubMed2006

Exploratory analysis of obsessive compulsive symptom dimensions in children and adolescents: a prospective follow-up study.

BACKGROUND: Recent statistical approaches based on factor analysis of obsessive compulsive (OC) symptoms in adult patients have identified dimensions that seem more effective in symptom-based taxonomies and appear to be more stable over time. Although a phenotypic continuum from childhood to adulthood has been hypothesized, no factor analytic studies have been performed in juvenile patients, and the stability of OC dimensions in children and adolescents has not been assessed. METHODS: This study was designed to perform an exploratory factor analysis of OC symptoms in a sample of children and adolescents with OC disorder (OCD) and to investigate the course of factors over time (mean follow-up period: four years). RESULTS: We report for the first time that four symptom dimensions, remarkably similar to those previously described in adults, underlined the heterogeneity of OC symptoms in children and adolescents. Moreover, after follow-up, the symptom dimensions identified remained essentially unmodified. The changes observed concerned the intensity of dimensions rather than shifts from one dimension to another. CONCLUSION: These findings reinforce the hypothesis of a phenotypic continuum of OC symptoms from childhood to adulthood. They also strengthen the interest for investigating the clinical, neurobiological and genetic heterogeneity of OCD using a dimension-based approach.

Adolescent↗

PubMed2005

Mapping of familial thoracic aortic aneurysm/dissection with patent ductus arteriosus to 16p12.2-p13.13.

BACKGROUND: Three loci have been shown to be responsible for nonsyndromic familial thoracic aortic aneurysms (TAAs) and aortic dissections (ADs). We recently described a large family in which TAA/AD associates with patent ductus arteriosus (PDA) and provided genetic arguments for a unique pathophysiological entity. METHODS AND RESULTS: Genome-wide scan was performed in 40 subjects belonging to 3 generations in this large pedigree. Using the 7 TAA/AD cases as affected, we observed positive 2-point LOD scores on adjacent markers at chromosome 16p, with a maximum LOD score value of 2.73 at theta=0, a value that increased to 3.56 when 5 PDA cases were included. Multipoint linkage analysis yielded a maximum LOD score of 4.14 in the vicinity of marker D16S3103. Fine mapping allowed the observation of recombinant haplotypes that delimited a critical 20-cM interval at 16p12.2-p13.13. Automatic determination of aortic compliance with cine MRI showed that all subjects bearing the disease haplotype, even asymptomatic, displayed a very low level of aortic compliance and distensibility. Aortic stiffness was strongly associated with disease haplotype with a marked effect of age, indicating subclinical and early manifestation of the disease. CONCLUSIONS: Genetic analysis of this family identified a unique locus responsible for both TAA/AD and PDA at chromosome 16p12.2-p13.13 with aortic stiffness as an early hallmark of the disease. TAA/AD with PDA is a new monogenic entity among the genetically heterogeneous group of TAA/AD disease.

Aorta↗

PubMed2005

Tests of executive functions in first-degree relatives of schizophrenic patients: a meta-analysis.

BACKGROUND: Executive dysfunctions in relatives of schizophrenic patients may be trait markers of genetic liability and thus help us to elucidate the aetiology of schizophrenia. As a large amount of data has been published, a synthesis through a meta-analysis was needed to demonstrate the existence of executive impairments in relatives of schizophrenic patients and to assess their magnitude. METHOD: We conducted a meta-analysis of articles that compared performances of controls and relatives of schizophrenic patients on the four tests most frequently used to assess executive functions: the Wisconsin Card Sorting Test (WCST), the Trail Making Test (TMT), the Stroop Test and the Verbal Fluency (VF) Test. When needed and possible, published data were supplemented with information from the authors. After assessing the homogeneity of the data, effect sizes were estimated and publication bias was tested by use of funnel plots. RESULTS: Relatives of schizophrenic patients performed less well than controls on all executive tests analysed. Effect estimates were in the small to moderate range (from 0.26 to 0.49) for Stroop, WCST and TMT, but were greater for the fluency tests (0.65 for phonological and 0.87 for semantic VF). CONCLUSION: Relatives of schizophrenic patients appear to have wide, although not severe, executive dysfunctions. As the sensitivity of the different tests for impairments in relatives is not the same, the choice of test and method used should be carefully assessed.

Cognition Disorders↗

PubMed2004

Lack of evidence for association between serotonin transporter gene (5-HTTLPR) and obsessive-compulsive disorder by case control and family association study in humans.

Association studies of the serotonin transporter (SLC6A4) gene in obsessive-compulsive disorder (OCD) have generated discrepant results. Here, we genotyped the 5-HTTLPR polymorphism in 106 French OCD patients and 171 healthy controls (case control study). We also performed a family association study on 116 trios including an OCD patient (73 French and 43 German). No association was detected between the 5-HTTLPR polymorphism and OCD in either the case control study or the family study.

Adult↗

PubMed2004

Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity.

Thoracic aortic aneurysm and aortic dissection (TAA and AD) are an important cause of sudden death. Familial cases could account for 20% of all cases. A genetic heterogeneity with two identified genes (FBN1 and COL3A1) and three loci (3p24-25 or MFS2/TAAD2, 5q13-q14 and 11q23.2-24) has been shown previously. Study of a single family composed of 179 members with an abnormally high occurrence of TAA/AD disease. A total of 40 subjects from three generations were investigated. In addition to five cases of stroke and three cases of sudden death, there were four cases of AD and four cases of TAA in adults. In all, 11 cases of patent ductus arteriosus (PDA) were observed, two of which were associated with TAA and one with AD. Segregation analysis showed that the distribution of these vascular abnormalities was more likely compatible with a single genetic defect with an autosomal dominant pattern of inheritance. There were no clinical signs of Marfan, Elhers-Danlos vascular type or Char syndromes. Genetic linkage analysis was performed for seven genes or loci implicated in familial TAA/AD disease (COL3A1, FBN1, 3p24-25 or MFS2/TAAD2, 5q13-q14 and 11q23.2-q24), Char syndrome (TFAP2B) or autosomal recessive PDA (12q24). Using different genetic models, linkage with these seven loci was excluded. Familial TAA/AD with PDA is likely to be a particular heritable vascular disorder, with an as yet undiscovered Mendelian genetic basis.

Aortic Dissection↗

PubMed2003

Altered cocaine-induced behavioral sensitization in adult mice exposed to cocaine in utero.

Behavioral sensitization induced by psychostimulants is characterized by increased locomotion and stereotypy and may reflect aspects of neuronal adaptations underlying drug addiction in humans. To study the developmental contributions to addictive behaviors, we measured behavioral responses in adult offspring to a cocaine sensitization paradigm following prenatal cocaine exposure. Pregnant Swiss-Webster (SW) mice were injected twice daily from embryonic days 8 to 17 (E8-E17, inclusive) with cocaine (20 or 40 mg/kg/day; COC20 and COC40, respectively), or saline vehicle (SAL and SPF40) subcutaneously (s.c.). A nutritional control group of dams were 'pair-fed' with COC40 dams (SPF40). P120 male offspring from each prenatal treatment group were assigned to a behavioral sensitization group and injected with cocaine (15 mg/kg) or saline intraperitoneally (i.p.) every other day for seven doses. Locomotor activity and stereotypy were measured during habituation, cocaine initiation, and following a cocaine challenge 21 days after the last initiation injection. As expected, animals demonstrated significantly more locomotion and stereotypic behavior following acute and recurrent injection of cocaine compared to saline-injected animals. However, for each prenatal treatment group, cocaine-sensitized animals showed unique temporal profiles for the increase in locomotor sensitization and stereotypy over the course of the sensitization protocol. Two features that distinguished the altered behavioral progression of prenatally cocaine-exposed animals (COC40) from control (SAL) animals included blunted augmentation of locomotion and enhanced patterns of stereotypic behavior. These findings provide evidence that the behavioral activating effects of cocaine in adult animals are altered following exposure to cocaine in utero.

Animals↗

PubMed2002

Functionality of two new polymorphisms in the human renin gene enhancer region.

BACKGROUND: The production of renin, which catalyses the rate-limiting step of the renin-angiotensin system, is strongly stimulated by a 225 bp enhancer element in the distal region of the promoter of the human gene (-5777 to -5552). OBJECTIVE: To demonstrate the major role played by this enhancer in decoy experiments, to identify variants in this region, and to determine their effects on renin gene transcription. METHODS AND RESULTS: We used this element as a decoy for transcription factors in human choriodecidual cells. The activity of the renin gene promoter was inhibited by 95% in the presence of this 225 bp enhancer element. This confirmation of the key role of this element suggested that changes in this region would be likely to affect renin gene expression. We therefore sequenced 70 genomic DNAs to identify variations in this region. We identified two new single nucleotide polymorphisms (SNPs) downstream from the 225 bp enhancer element at positions -5434 and -5312. We transfected choriodecidual cells with the four variants and found that a 592 bp region (-5870 to -5312) including the 225 bp element and the two SNPs had stronger enhancer activity than the 225 bp element alone, and that levels of transcription were 45% greater with the -5312T variant than with the -5312C variant, whereas none of the -5434 variants had an effect on renin transcription. Cis-regulatory elements close to the -5312 variant were identified in gel mobility shift assays on the basis of specific interactions between human choriodecidual cell nuclear extracts and an oligonucleotide including this polymorphism. CONCLUSION: This study demonstrates that the human renin enhancer not only comprises the 225 bp element, but also extends to the region containing the -5312 SNP.

Amino Acid Sequence↗