Search

ABSTRACTStudies have linked maternal pre-pregnancy obesity and hyperglycaemia with metabolic and neurodevelopmental complications in childhood. DNA methylation (DNAm) might enable foetal adaptations to environmental adversities through important gene loci. NEGR1is involved in both energy balance and behaviour regulation. The aim of this study was to investigate associations between placental DNAm at the NEGR1gene locus and childhood anthropometric and neurodevelopmental profiles in preschoolers. We analysed 276 mother-child dyads from Gen3G, a prospective birth cohort from Sherbrooke. At 3yo (40.4 ± 3.0 months), we measured body mass index (BMI) and the mothers reported on offspring neurobehavior using the Strengths and Difficulties Questionnaire (SDQ). We quantified DNAm levels at 30 CpGs at the NEGR1locus using the MethylationEPIC Array in placental biopsies. DNAm at four CpGs located before NEGR1second exon predicted child’s BMI z-score (cg26153364: β=−0.16 ± 0.04; p=0.008, cg23166710: β=0.14 ± 0.08; p=0.03) and SDQ total score (cg04932878: β=0.22 ± 1.0; p= 3.0x10−4, cg16525738: β=−0.14 ± 0.18; p=0.01, cg23166710: β=−0.13 ± 0.36; p= 0.04), explaining 4.2% (p=0.003) and 7.3% (p= 1.3 x 10−4) of BMI-z and SDQ variances. cg23166710 was associated with both childhood phenotypes and correlated with NEGR1placental expression (r=−0.22, p=0.04), suggesting its possible functional role. Together, maternal metabolic characteristics during pregnancy with NEGR1DNAm levels explained 7.4% (p=4.2 x 10−4) of BMI-z and 14.2% (p=2.8 x 10−7) of SDQ variance at 3yo. This longitudinal study suggests that placental NEGR1DNAm is associated with adiposity and neurodevelopment in preschool children and highlights its potential role in their comorbidity.

Background:Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.Participants and methods:A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Results:Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10−8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.Conclusions:We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Lors de la transition à la parentalité, l’aspect intime et sexuel de la relation conjugale des futurs et nouveaux couples parentaux est le plus affecté et le plus vulnérable ; les couples doivent s’adapter pour favoriser leur couple et leur famille. Le but de cet examen de la portée est de cerner ce que dit la littérature des 15 dernières années sur la sexualité périnatale. Au total, 123 articles empiriques ont été retenus. Ce premier article d’une série de deux concerne la sexualité pendant la grossesse. En plus de dresser un portrait des recherches sélectionnées, 23 variables sexuelles prénatales ont été analysées. Les données rassemblées esquissent un portrait sexopérinatal diversifié : les expériences intimes et sexuelles sont variables. Malgré certaines exceptions, une certaine tendance à la baisse graduelle et progressive de la plupart des comportements sexuels et de l’expression sexuelle générale pendant la grossesse a été notée, avec une diminution marquée au début de la grossesse et au 3etrimestre. Les femmes sont particulièrement affectées par un plus grand nombre de changements sexuels, mais les hommes le sont aussi. De nombreux facteurs physiologiques et psychologiques simultanés affectent l’expression sexuelle des couples. Les fluctuations sexuelles sont toutefois un phénomène naturel pendant la transition à la parentalité ; la sexualité pendant la grossesse constitue une bulle temporelle et temporaire où la sexualité se modifie et s’ajuste en fonction des nouvelles conditions. L’intervention sexopérinatale devrait faire partie du suivi holistique des soins de santé périnataux pour favoriser le maintien d’une relation intime et sexuelle saine et positive chez les couples.

Lors de la transition à la parentalité, l’aspect intime et sexuel des futurs et nouveaux couples parentaux sont les plus affectés et les plus vulnérables. Le but de cet examen de la portée est de faire un portrait de l’expérience sexuelle périnatale à l’aide de 123 articles empiriques des 15 dernières années sur le sujet. Ce deuxième article d’une série de deux concerne la sexualité lors du travail et de l’accouchement, la sexualité postnatale ainsi que la sexualité et l’allaitement. Au total, 29 variables sexuelles ont été analysées. La sexualité pendant et après l’accouchement relèvent d’expériences diversifiées. Certains éléments récurrents peuvent toutefois être identifiés, dont un moment relativement inactif de sexualité dans les premiers mois postpartum, suivi d’une reprise graduelle à partir de trois à six mois postnataux et se poursuivant jusqu’à 12 mois et plus. La sexualité lors de l’accouchement est un sujet tabou et les expériences sont polarisées : certains couples ont des expériences sensuelles et érotiques à l’accouchement, alors que d’autres vivent des traumatismes à la naissance avec impact négatif sexuel durant la période postnatale. La sexualité pendant l’allaitement revêt aussi un caractère tabou et des impacts négatifs sur la sexualité des femmes sont courants. Dans tous les cas, la sexualité des femmes et des hommes est affectée et une multitude de facteurs physiologiques et psychologiques simultanés teintent les expériences. Les fluctuations intimes et sexuelles constituent des phénomènes naturels, temporels et temporaires, mais l’intervention sexopérinatale incluse dans les soins de santé périnataux holistiques peut favoriser le maintien d’une relation intime et sexuelle positive chez les couples.

Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In uteroexposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEPlocus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS10) and showed it was an adequate instrumental variable (β = 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE = 0.007; P= 7.8 × 10−11; N = 467). A higher GRS10was associated with lower methylation levels at cg12083122 located near LEP(β = −0.072 unit per additional risk allele; SE = 0.04; P= 0.05; N = 166). Direction and effect size of association between the instrumental variable GRS10and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (β = −0.17 log of cord blood leptin per unit; SE = 0.07; P= 0.01; N = 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

Placental lipoprotein lipase (LPL) is crucial for placental lipid transfer. Impaired LPLgene expression and activity were reported in pregnancies complicated by gestational diabetes mellitus (GDM) and intra-uterine growth restriction. We hypothesized that placental LPLDNA methylation is altered by maternal metabolic status and could contribute to fetal programming. The objective of this study was thus to assess whether placental LPLDNA methylation is associated with GDM and both maternal and newborn lipid profiles. Placenta biopsies were sampled at delivery from 126 women including 27 women with GDM diagnosed following a post 75 g-oral glucose tolerance test (OGTT) between weeks 24 and 28 of gestation. Placental LPLDNA methylation and expression levels were determined using bisulfite pyrosequencing and quantitative real-time PCR, respectively. DNA methylation levels within LPLproximal promoter region (CpG1) and intron 1 CpG island (CpGs 2 and 3) were lower in placenta of women with GDM. DNA methylation levels at LPL-CpG1 and CpG3 were also negatively correlated with maternal glucose (2-h post OGTT; r=–0.22; P=0.02) and HDL-cholesterol levels (third trimester of pregnancy; r=–0.20; p=0.03), respectively. Moreover, we report correlation between LPL-CpG2 DNA methylation and cord blood lipid profile. DNA methylation levels within intron 1 CpG island explained up to 26% (r?–0.51; P<0.001) of placental LPLmRNA expression variance. Overall, we showed that maternal metabolic profile is associated with placental LPLDNA methylation dysregulation. Our results suggest that site-specific LPLepipolymorphisms in the placenta are possibly functional and could potentially be involved in determining the future metabolic health of the newborn.

Obesity and insulin resistance are common features of Type 2 Diabetes. A new protein called resistin has been shown to be secreted by adipocytes in mice and to influence insulin sensitivity. The goal of the present study was to investigate the associations between one polymorphism (g-420C>G) of the human resistin gene and phenotypes related to adiposity and glucose metabolism. We genotyped 725 (including 42 diabetics) adult subjects participating in the Québec Family Study (QFS) by a minisequencing method. Forty-two were diabetic subjects. Phenotypes measured were: body mass index (BMI) and waist circumference (WC), % body fat (PFAT) and fat mass (FM) assessed by under water weighing, abdominal total, subcutaneous and visceral fat assessed by computed tomography and fasting plasma glucose, insulin and C-peptide and their responses to an oral glucose tolerance test (OGTT). Comparisons between genotypes were performed in non-diabetic men (no.=280) and women (no.=403) separately by analyses of covariance (ANCOVA). Among men, g-420 G homozygotes had less visceral fat (p<0.05), lower levels of acute insulin responses to an OGTT and lower levels of C-peptide in a fasting state and in responses to an OGTT than carriers of the C allele (p<0.01). These associations were independent of age and adiposity but were not observed in women. These results suggest that in men, the human resistin gene is associated with reduced amount of visceral obesity and lower insulin secretory responses to a glucose load.

Background & Aims: A 50% dysfunction rate at 1 year is one of the main drawbacks of the transjugular intrahepatic portosystemic shunt procedure. Preliminary experimental and clinical studies suggest that the use of stents covered with polytetrafluoroethylene could tremendously decrease this risk. Methods: Eighty patients with cirrhosis and uncontrolled bleeding (n = 23), recurrent bleeding (n = 25), or refractory ascites (n = 32) were randomized to be treated by transjugular intrahepatic portosystemic shunts with either a polytetrafluoroethylene-covered stent (group 1; 39 patients) or a usual uncovered prosthesis (group 2; 41 patients). Follow-up Doppler ultrasound was scheduled at day 7, at 1 month, and then every 3 months for 2 years. Angiography and portosystemic pressure gradient measurements were performed 6, 12, and 24 months after the transjugular intrahepatic portosystemic shunt procedure and whenever dysfunction was suspected. Dysfunction was defined as a >50% reduction of the lumen of the shunt at angiography or a portosystemic pressure gradient >12 mm Hg. Results: After a median follow-up of 300 days, 5 patients (13%) in group 1 and 18 (44%) in group 2 experienced shunt dysfunction (P < 0.001). Clinical relapse occurred in 3 patients (8%) in group 1 and 12 (29%) in group 2 (P < 0.05). Actuarial rates of encephalopathy were 21% in group 1 and 41% in group 2 at 1 year (not significant). Estimated probabilities of survival were 71% and 60% at 1 year and 65% and 41% at 2 years in groups 1 and 2, respectively (not significant). Conclusions: The use of polytetrafluoroethylene-covered prostheses improves transjugular intrahepatic portosystemic shunt patency and decreases the number of clinical relapses and reinterventions without increasing the risk of encephalopathy.

Several divinyl ether and diepoxide monomers bearing an azobenzene moiety were synthesized and used to investigate the photoalignment of a ferroelectric liquid crystal (FLC) with no use of surface orientation layers. Azobenzene polymer networks, obtained by cationic polymerization of the monomers dissolved in the FLC host and exposed to linearly polarized irradiation, were found to be able to induce and stabilize a bulk alignment of FLC. Photoinduced reorientation of the FLC can also be achieved by changing the polarization of irradiation light, but in contrast with the use of chiral azobenzene poly(meth)acrylates,¹ the results suggest a mechanism based on the formation of an anisotropic azobenzene polyether or polyepoxide network for the commanding effect on the FLC alignment.

A recent study from our laboratory has shown that significant amounts of nitric oxide are released by somatic cells recovered during endotoxin-induced mastitis. The present study was undertaken to investigate which cell type(s) among milk somatic cell population can produce nitric oxide under inflammatory conditions. Nitric oxide release from mammary epithelial cell lines and from bovine neutrophils and monocytes extracted from blood was measured in response to cytokines and Escherichia colilipopolysaccharides. An epithelial cell line isolated from bovine mammary gland, FbE cells, was found to release nitric oxide after exposure to interleukin-1β. This nitric oxide production was completely abolished by addition of L-N6-(1-iminoethyl) lysine, a potent inducible nitric oxide synthase inhibitor. Bovine monocytes produced nitric oxide in response to recombinant bovine interferon-γalone or in combination with E. colilipopolysaccharides. In these cells, nitric oxide release was reduced by the addition of inducible nitric oxide synthase inhibitors L-N6-(1-iminoethyl) lysine and aminoguanidine. Lipopolysaccharides and recombinant bovine interferon-γincreased nitric oxide synthase mRNA in neutrophils, but nitric oxide release could not be detected under any of the experimental conditions used. These results show that bovine epithelial cells and mononuclear phagocytes produce nitric oxide under inflammatory conditions and suggest that these cell populations are responsible for nitric oxide release observed during mastitis.

Nitric oxide production was measured during endotoxin-induced mastitis. One hour after morning milking, the right hind quarters of 15 cows were infused with saline containing Escherichia coliendotoxin. Left hind control quarters were infused with saline only. At varying intervals before and after infusion, diagnostic markers of mastitis were recorded and nitric oxide production was evaluated by measuring nitrite plus nitrate levels in milk. In endotoxin-infused quarters, a significant increase in nitrite plus nitrate concentrations was observed 3h postinfusion; concentrations decreased to preinfusion levels within 48h. This change indicates that significant amounts of nitric oxide are released during endotoxin-induced mastitis. At 3 different time points, somatic cells were harvested from milk samples, plated, and maintained in culture for 24h. The concentration of nitrite plus nitrate in medium from cells harvested 12h postinfusion was increased, suggesting that nitric oxide is released, at least in part, by milk somatic cells. In a second set of experiments, we evaluated nitric oxide production when animals were infused with endotoxin and aminoguanidine, a specific inhibitor of the inducible form of nitric oxide synthase. In cows treated with aminoguanidine, the increase in nitrite plus nitrate observed after endotoxin infusion was prevented. These results suggest that nitric oxide production during endotoxin-induced mastitis resulted from the activity of the inducible form of nitric oxide synthase. They also support a possible involvement for nitric oxide in the inflammatory reaction observed during mastitis.

Les benzodiazépines (BZD) produisent leurs effets cliniques en se liant à des récepteurs spécifiques du système nerveux central. Le récepteur BZD fait partie d'un complexe supramoléculaire qui possède également des sites allostériques pour les barbituriques et le GABA. En facilitant l'unité de couplage GABA-canal à CL-, les BZD potentialisent l'inhibition neuronale. Les recherches actuelles visent à préciser le fonctionnement moléculaire des récepteurs et à identifier leurs ligands endogènes.

Lauryl sucrose has recently been shown to decrease the toxicity of amphotericin B (AmB), a widely used antifungal agent, probably through a modulation of its physical state. In this paper, we demonstrate using a lymphoproliferative assay, that lauryl sucrose and monosubstituted analogs in addition to their effects on AmB also possess significant immune enhancer properties. An anti-bell shape relationship was observed between stimulation of lymphoproliferation and chain length of ester's fatty acid, lauryl sucrose being the less active of the tested derivatives. These properties of sucrose esters are discussed in the specific context of antifungal therapy.

Viewing a real-world scene (picture) from several perspectives enhanced recognition of 16 and 36 college students of that scene from a new perspective but reduced detection of the new perspective as such. The accuracy of recognition for mirror-image transformed scenes declined slowly in comparison to the accuracy of detecting the transformed scenes as such. These findings support the notion that prototypes are abstracted from real-world scenes.

We investigated the mechanism by which the large T antigen (T-Ag) of both polyomavirus and simian virus 40 (SV40) promotes homologous recombination in mammalian cells. To this end, we constructed a rat cell line, designated Hy5, that carries two mutated copies of the polyomavirus middle-T-Ag (pmt) oncogene lying as direct repeats on the same chromosome. The structure of the viral insert was devised so that intrachromosomal recombination between the pmt repeats reconstitutes wild-type pmt and yields cell populations amenable to selection for the transformed phenotype. Correction of pmt by gene conversion occurred spontaneously at a rate of ca. 1.7 x 10(-7) per cell generation and was masked by another recombination event that also led to the transformation of the Hy5 cell line. This event was identified as chromosomal inversion and overexpression of the upstream pmt copy as a result of homologous recombination between adjacent pBR322 sequences. Both events were promoted by the polyomavirus large T-Ag by several orders of magnitude, as well as by mutants defective in the initiation of viral DNA synthesis. Large T-Ag also promoted reconstitution of wild-type pmt by unequal exchange between sister chromatids, yielding structures compatible with some of the chromosomal aberrations commonly observed in transformed cells. Our data indicate that large T-Ag has a recombination-promoting activity that can be dissociated from its replicative function.

We applied the Luria and Delbruck fluctuation test to analyze high-frequency changes in the phenotype of rat cells transformed by a plasmid carrying the polyomavirus middle T (pmt) gene. All of the transformed cell lines analyzed were capable of switching to the normal state with rates ranging from 10(-3) to 10(-2) per cell per generation. Analysis of both middle T antigen and middle T transcripts indicated that the reversion occurred by a mechanism involving a transcriptional block of the pmt locus. Cell lines containing two separate loci reverted with a lower rate, suggesting that phenotypic switching in these cells involved two independent events affecting each locus. The flat revertants mutated to the transformed state with rates in the range of 10(-5) to 5 X 10(-5) per cell per generation. To determine whether changes in pmt expression would affect neighboring sequences, we transfected a hybrid plasmid carrying pmt linked to the neo marker and selected either for morphological transformants or for G418-resistant cells. Although their coordinate regulation was not absolute, both genes were usually subject to the same changes, reflected by loss and reacquisition of transcriptional activity.

To investigate the mechanism by which the large T antigen (T-Ag) of polyomavirus and simian virus 40 can promote recombination in mammalian cells, we analyzed homologous recombination events occurring between two defective copies of the polyomavirus middle T (pmt) oncogene lying in close proximity on the same chromosome in a rat cell line. Reconstitution of a functional pmt gene by spontaneous recombination occurred at a rate of about 2 x 10(-7) per cell generation. Introduction of the polyomavirus large T (plt) oncogene into the cell line by DNA transfection promoted recombination very efficiently, with rates in the range of 10(-1) to 10(-2) per cell generation. Recombination was independent of any amplification of viral sequences and could even be promoted by the large T-Ag from simian virus 40, which cannot activate polyomavirus DNA replication. To explain the role of large T-Ag, we propose a novel mechanism of nonconservative recombination involving slipped-strand mispairing between the two viral repeats followed by gap repair synthesis.

The pan-B and B cell-specific sIg and CD19 antigens are functionally and physically associated in the presence of anti-Ig mAb. Incubation of B cells with anti-Ig antibodies causes rapid, specific, reversible, concentration-dependent, and unidirectional comodulation of CD19 on every mature B cell studied. Comodulation is produced by mAbs specific for the gamma, mu, kappa, and lambda chains of Ig, and by at least one idiotype-specific mAb. Comodulation is observed using 15 CD19-specific mAbs that detect at least three different CD19 epitopes. Of 18 surface antigens studied, only CD19 is comodulated. Loss of sIg and CD19 occurs concurrently during anti-Ig modulation and demonstrates a comparable dependence on anti-Ig concentration, suggesting that these are parallel rather than serial events. Incubation with anti-Ig specifically cocaps and suggests internalization of anti-CD19 mAb. Comodulation of sIg and CD19 by anti-Ig but not anti-CD19 mAbs suggests that ligand binding enables sIg to then interact with CD19. We propose that CD19 is a component of the B cell antigen receptor and suggest that it could facilitate signal transduction by sIg-antigen complexes.

La calciphylaxie (artériolopathie calcique, AC) est une vasculopathie thrombosante rare responsable d’une calcification des vaisseaux de petit et moyen calibre à l’origine de nécroses cutanées et pouvant mettre en jeu le pronostic vital. Elle touche principalement, mais non exclusivement, l’insuffisant rénal hémodialysé. Sa prise en charge est difficile et comprend le traitement local des ulcères, l’éviction des facteurs déclenchants, la correction des troubles phospho-calciques et/ou la diminution du taux de parathormone (dialyse, parathyroïdectomie, cinacalcet). Récemment, le thiosulfate de sodium (TSS) a montré son efficacité. Il est administré en intraveineux (IV) au long cours. Nous rapportons l’efficacité de TSS en injections intra-lésionnelles (TSS/IL) chez 4 patientes.

The proximal portion of the polyoma virus early region as well as the complete viral genome were cloned in pBR322. Recombinant plasmids induced tumors in newborn rats but only after linearization of the DNA by various restriction endonucleases.