Investigation de liens de parenté à l'aide de l'ADN: lecture différentielle de rapports d'expertise

De nos jours, l'ADN apparaît fréquemment dans les affaires judiciaires et la littérature spécialisée. L'évaluation de ce type d'indice est vaste. En général, les débats restent toutefois assez théoriques. Dans la présente contribution, deux types courants d'analyse sont abordés, l'ADN nucléaire et l'ADN mitochondrial, dans le cadre d'une recherche en demi-fraternité. Deux rapports d'expertise seront décortiqués ligne par ligne pour en offrir une lecture critique et cerner la fiabilité et l'utilité des conclusions apportées par les experts.

Involvement of glial cells in the neurotoxicity of parathion and chlorpyrifos.

An in vitro model, the aggregating brain cell culture of fetal rat telencephalon, has been used to investigate the influence of glial cells on the neurotoxicity of two organophosphorus pesticides (OPs), chlorpyrifos and parathion. Mixed-cell aggregate cultures were treated continuously for 10 days between DIV 5 and 15. Parathion induced astrogliosis at concentration at which MAP-2 immunostaining, found here to be more sensitive than neuron-specific enzyme activities, was not affected. In contrast, chlorpyrifos induced a comparatively weak gliotic reaction, and only at concentrations at which neurons were already affected. After similar treatments, increased neurotoxicity of parathion and chlorpyrifos was found in aggregate cultures deprived of glial cells. These results suggest that glial cells provide neuroprotection against OPs toxicity. To address the question of the difference in toxicity between parathion and chlorpyrifos, the toxic effects of their leaving groups, p-nitrophenol and trichloropyridinol, were studied in mixed-cell aggregates. General cytotoxicity was more pronounced for trichloropyridinol and both compounds had similar toxic effects on neuron-specific enzyme activities. In contrast, trichloropyridinol induced a much stronger decrease in glutamine synthetase activity, the enzymatic marker of astrocytes. Trichloropyridinol may exert a toxic effect on astrocytes, compromising their neuroprotective function, thus exacerbating the neurotoxicity of chlorpyrifos. This is in line with the suggestion that glial cells may contribute to OPs neurotoxicity, and with the view that OPs may exert their neurotoxic effects through different mechanisms.

My older sibling was drunk - younger siblings' drunkenness in relation to parental monitoring and the parent-adolescent relationship.

This study explored the links between having older siblings who get drunk, satisfaction with the parent-adolescent relationship, parental monitoring, and adolescents' risky drinking. Regression models were conducted based on a national representative sample of 3725 8th to 10th graders in Switzerland (mean age 15.0, SD = .93) who indicated having older siblings. Results showed that both parental factors and older siblings' drinking behaviour shape younger siblings' frequency of risky drinking. Parental monitoring showed a linear dose-response relationship, and siblings' influence had an additive effect. There was a non-linear interaction effect between parent-adolescent relationship and older sibling's drunkenness. The findings suggest that, apart from avoiding an increasingly unsatisfactory relationship with their children, parental monitoring appears to be important in preventing risky drinking by their younger children, even if the older sibling drinks in such a way. However, a satisfying relationship with parents does not seem to be sufficient to counterbalance older siblings' influence.

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Family physician involvement in cancer care follow-up: the experience of a cohort of patients with lung cancer.

PURPOSE There has been little research describing the involvement of family physicians in the follow up of patients with cancer especially during the primary treatment phase We undertook a prospective longitudinal study of patients with lung cancer to assess their family physician s involvement in their follow up at the different phases of cancer METHODS In 5 hospitals in the province of Quebec Canada patients with a recent diagnosis of lung cancer were surveyed every 3 to 6 months whether they had metastasis or not, for a maximum of 18 months to assess aspects of their family physician s involvement in cancer care RESULTS Of the 395 participating patients 92% had a regular family physician but only 60% had been referred to a specialist by him/her or a colleague for the diagnosis of their lung cancer A majority of patients identified the oncology team or oncologists as mainly responsible for their cancer care throughout their cancer journey except at the advanced phase where a majority attributed this role to their family physician At baseline only 16% of patients perceived a shared care pattern between their family physician and oncologists but this pro portion increased with cancer progression Most patients would have liked their family physician to be more involved in all aspects of cancer care CONCLUSIONS Although patients perceive that the oncology team is the main party responsible for the follow up of their lung cancer they also wish their family physicians to be involved Better communication and collaboration between family physicians and the oncology team are needed to facilitate shared care in cancer follow up

Management of severe pediatric subglottic stenosis with glottic involvement.

OBJECTIVE: We sought to describe our experience in the management of complex glotto-subglottic stenosis in the pediatric age group. METHODS: Between 1978 and 2008, 33 children with glotto-subglottic stenosis underwent partial cricotracheal resection, and they form the focus of this study. They were compared with 67 children with isolated subglottic stenosis (no glottic involvement). The outcomes measured were need for revision open surgical intervention, delayed decannulation (>6 months), and operation-specific and overall decannulation rates. Fisher's exact test was used for comparison of outcomes. RESULTS: Results of preoperative evaluation showed Myer-Cotton grade III or IV stenosis in 32 (97%) patients and grade II stenosis in 1 patient. All patients with glotto-subglottic stenosis were treated with partial cricotracheal resection and simultaneous repair of the glottic pathology. Bilateral fixed vocal cords were seen in 19 (58%) of 33 patients, bilateral restricted abduction was seen in 7 (21%) of 33 patients, and unilateral fixed vocal cord was seen in 7 (21%) of 33 patients. Ten patients underwent single-stage partial cricotracheal resection with excision of interarytenoid scar tissue. The endotracheal tube was kept for a mean period of 7 days as a stent. Twenty-three patients underwent extended partial cricotracheal resection with LT-Mold (Bredam S.A., St. Sulpice, Switzerland) or T-tube stenting. The overall decannulation rate included 26 (79%) patients, and the operation-specific decannulation rate included 20 (61%) patients. CONCLUSIONS: Glotto-subglottic stenosis is a complex laryngeal injury associated with delayed decannulation and decreased overall and operation-specific decannulation rates when compared with those after subglottic stenosis without glottic involvement after partial cricotracheal resection.

Myocardial impairment in chronic hypoxia is abolished by short aeration episodes: involvement of K+ATP channels.

In vivo exposure to chronic hypoxia is considered to be a cause of myocardial dysfunction, thereby representing a deleterious condition, but repeated aeration episodes may exert some cardioprotection. We investigated the possible role of ATP-sensitive potassium channels in these mechanisms. First, rats (n = 8/group) were exposed for 14 days to either chronic hypoxia (CH; 10% O(2)) or chronic hypoxia with one episode/day of 1-hr normoxic aeration (CH+A), with normoxia (N) as the control. Second, isolated hearts were Langendorff perfused under hypoxia (10% O(2), 30 min) and reoxygenated (94% O(2), 30 min) with or without 3 microM glibenclamide (nonselective K(+)(ATP) channel-blocker) or 100 microM diazoxide (selective mitochondrial K(+)(ATP) channel-opener). Blood gasses, hemoglobin concentration, and plasma malondialdehyde were similar in CH and CH+A and in both different from normoxic (P < 0.01), body weight gain and plasma nitrate/nitrite were higher in CH+A than CH (P < 0.01), whereas apoptosis (number of TUNEL-positive nuclei) was less in CH+A than CH (P < 0.05). During in vitro hypoxia, the efficiency (ratio of ATP production/pressure x rate product) was the same in all groups and diazoxide had no measurable effects on myocardial performance, whereas glibenclamide increased end-diastolic pressure more in N and CH than in CH+A hearts (P < 0.05). During reoxgenation, efficiency was markedly less in CH with respect to N and CH+A (P < 0.0001), and ratex pressure product remained lower in CH than N and CH+A hearts (P < 0.001), but glibenclamide or diazoxide abolished this difference. Glibenclamide, but not diazoxide, decreased vascular resistance in N and CH (P < 0.005 and < 0.001) without changes in CH+A. We hypothesize that cardioprotection in chronically hypoxic hearts derive from cell depolarization by sarcolemmal K(+)(ATP) blockade or from preservation of oxidative phosphorylation efficiency (ATP turnover/myocardial performance) by mitochondrial K(+)(ATP) opening. Therefore K(+)(ATP) channels are involved in the deleterious effects of chronic hypoxia and in the cardioprotection elicited when chronic hypoxia is interrupted with short normoxic aeration episodes.

Involvement of the CXCR7/CXCR4/CXCL12 Axis in the Malignant Progression of Human Neuroblastoma.

Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapies for high-risk tumors are not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumor progression and dissemination. While CXCR4 expression is associated to undifferentiated tumors and poor prognosis, the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated in NB. In this report, CXCR7 and CXCL12 expressions were evaluated using a tissue micro-array including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In contrast to CXCR4, CXCR7 expression was low in undifferentiated tumors, while its expression was stronger in matured tissues and specifically associated to differentiated neural tumor cells. As determined by RT-PCR, CXCR7 expression was mainly detected in N-and S-type NB cell lines, and was slightly induced upon NB cell differentiation in vitro. The relative roles of the two CXCL12 receptors were further assessed by overexpressing CXCR7 or CXCR4 receptor alone, or in combination, in the IGR-NB8 and the SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK1/2 cascade, but not Akt pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4, and impaired CXCR4/CXCL12-mediated chemotaxis. Subcutaneous implantation of CXCR7-expressing NB cells showed that CXCR7 also significantly reduced in vivo growth. Moreover, CXCR7 affected CXCR4-mediated orthotopic growth in a CXCL12-producing environment. In such model, CXCR7, in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCR7 and CXCR4 receptors revealed specific expression patterns and distinct functional roles in NB. Our data suggest that CXCR7 elicits anti-tumorigenic functions, and may act as a regulator of CXCR4/CXCL12-mediated signaling in NB.

Gene deletion of dopamine beta-hydroxylase and alpha1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling.

In vitro studies have shown that stimulation of alpha1-adrenoceptors (ARs) directly induces proliferation, hypertrophy, and migration of arterial smooth muscle cells and adventitial fibroblasts. In vivo studies confirmed these findings and showed that catecholamine trophic activity becomes excessive after experimental balloon injury and contributes to neointimal growth, adventitial thickening, and lumen loss. However, past studies have been limited by selectivity of pharmacological agents. The aim of this study, in which mice devoid of norepinephrine and epinephrine synthesis [dopamine beta-hydroxylase (DBH-/-)] or deficient in alpha1-AR subtypes expressed in murine carotid (alpha1B-AR-/- and alpha1D-AR-/-) were used, was to test the hypothesis that catecholamines contribute to wall hypertrophy after injury. At 3 wk after injury of wild-type mice, lumen area and carotid circumference increased significantly, and hypertrophy of media and adventitia was in excess of that needed to restore circumferential wall stress to normal. In DBH-/- and alpha1B-AR-/- mice, increases in lumen area, circumference, and hypertrophy of the media and adventitia were reduced by 50-91%, resulting in restoration of wall tension to nearly normal (DBH-/-) or normal (alpha1B-AR-/-). In contrast, in alpha1D-AR-/- mice, increases in lumen area, circumference, and wall hypertrophy were unaffected and wall thickening remained in excess of that required to return tension to normal. When examined 5 days after injury, proliferation and leukocyte infiltration were inhibited in DBH-/- mice. These studies suggest that the trophic effects of catecholamines are mediated primarily by alpha1B-ARs in mouse carotid and contribute to hypertrophic growth after vascular injury.

Long-term voice outcome following partial cricotracheal resection in children for severe subglottic stenosis.

OBJECTIVE: To correlate the postoperative voice outcome to preoperative glottic involvement, following partial cricotracheal resection (PCTR) in children. The glottic involvement was analysed based on the extent of subglottic stenosis (SGS) in the endoscopic image and functional dynamic assessment using flexible endoscopy. METHODS: We conducted an interobserver study in which two ENT surgeons, blinded to one another's interpretation, independently rated the extent of SGS based on the endoscopic image along with the dynamic functional airway assessment, of 108 children who underwent PCTR for grade III or IV stenosis. Based on the observation, the glottic involvement was rated into 4 categories: Evaluation of the voice was based on a parent/patient proxy questionnaire sent in 2008 to assess the current functional status of the patient's voice. RESULTS: Among the 77 patients available for long-term outcome with a minimum 1-year follow-up, 31 patients had isolated SGS free from vocal cords (group A) and 30 had SGS reaching the under surface of vocal cords with partial or no impairment of abduction of vocal cords (group B). Twelve patients belonged to group C with posterior glottic stenosis and/or vocal cord fusion (without cricoarytenoid ankylosis) and 4 patients had transglottic stenosis and or/bilateral cricoarytenoid ankylosis (group D). The long-term voice outcome following PCTR as perceived by the parent or patient was normal in 18% (14 of 77 patients) and the remaining 63 patients demonstrated mild to severe dysphonia. Patients belonging to group A and B exhibited either normal voice or mild dysphonia. Patients in group C demonstrated dysphonia, which was moderate in severity in the majority (83%). All patients in group D with transglottic stenosis and/or CAA showed severe dysphonia. CONCLUSION: Children with associated glottic involvement are at high risk for poor voice outcome following PCTR. The severity of dysphonia was found to be proportional to the preoperative glottic involvement. Preoperative rating of the extent of glottic involvement based on endoscopic image and dynamic assessment was found to be useful in prognosticating the voice outcome.

Mutational and computational analysis of the alpha(1b)-adrenergic receptor. Involvement of basic and hydrophobic residues in receptor activation and G protein coupling.

To investigate their role in receptor coupling to G(q), we mutated all basic amino acids and some conserved hydrophobic residues of the cytosolic surface of the alpha(1b)-adrenergic receptor (AR). The wild type and mutated receptors were expressed in COS-7 cells and characterized for their ligand binding properties and ability to increase inositol phosphate accumulation. The experimental results have been interpreted in the context of both an ab initio model of the alpha(1b)-AR and of a new homology model built on the recently solved crystal structure of rhodopsin. Among the twenty-three basic amino acids mutated only mutations of three, Arg(254) and Lys(258) in the third intracellular loop and Lys(291) at the cytosolic extension of helix 6, markedly impaired the receptor-mediated inositol phosphate production. Additionally, mutations of two conserved hydrophobic residues, Val(147) and Leu(151) in the second intracellular loop had significant effects on receptor function. The functional analysis of the receptor mutants in conjunction with the predictions of molecular modeling supports the hypothesis that Arg(254), Lys(258), as well as Leu(151) are directly involved in receptor-G protein interaction and/or receptor-mediated activation of the G protein. In contrast, the residues belonging to the cytosolic extensions of helices 3 and 6 play a predominant role in the activation process of the alpha(1b)-AR. These findings contribute to the delineation of the molecular determinants of the alpha(1b)-AR/G(q) interface.