Genetic variation in FADS genes is associated with maternal long-chain PUFA status but not with cognitive development of infants in a high fish-eating observational study

AbstractLong-chain n-6 and n-3 PUFA (LC-PUFA), arachidonic acid (AA) (20:4n-6) and DHA (22:6n-3), are critical for optimal brain development. These fatty acids can be consumed directly from the diet, or synthesized endogenously from precursor PUFA by Δ-5 (encoded by FADS1) and Δ-6 desaturases (encoded by FADS2). The aim of this study was to determine the potential importance of maternal genetic variability in FADS1 and FADS2 genes to maternal LC-PUFA status and infant neurodevelopment in populations with high fish intakes. The Nutrition Cohorts 1 (NC1) and 2 (NC2) are longitudinal observational mother-child cohorts in the Republic of Seychelles. Maternal serum LC-PUFA was measured at 28 weeks gestation and genotyping for rs174537 (FADS1), rs174561 (FADS1), rs3834458 (FADS1-FADS2) and rs174575 (FADS2) was performed in both cohorts. The children completed the Bayley Scales of Infant Development II (BSID-II) at 30 months in NC1 and at 20 months in NC2. Complete data were available for 221 and 1310 mothers from NC1 and NC2 respectively. With increasing number of rs3834458 minor alleles, maternal concentrations of AA were significantly decreased (NC1 p=0.004; NC2 p<0.001) and precursor:product ratios for linoleic acid (LA) (18:2n-6)-to-AA (NC1 p<0.001; NC2 p<0.001) and α-linolenic acid (ALA) (18:3n-3)-to-DHA were increased (NC2 p=0.028). There were no significant associations between maternal FADS genotype and BSID-II scores in either cohort. A trend for improved PDI was found among infants born to mothers with the minor rs3834458 allele.In these high fish-eating cohorts, genetic variability in FADS genes was associated with maternal AA status measured in serum and a subtle association of the FADS genotype was found with neurodevelopment

Maternal polymorphisms in glutathione-related genes are associated with maternal mercury concentrations and early child neurodevelopment in a population with a fish-rich diet

Introduction: Glutathione (GSH) pathways play a key role the metabolism and elimination of the neurotoxicant methylmercury (MeHg). We hypothesized that maternal genetic variation linked to GSH pathways could influence MeHg concentrations in pregnant mothers and children and thereby also affect early life development. Methods: The GCLM (rs41303970, C/T), GCLC (rs761142, T/G) and GSTP1 (rs1695, A/G) polymorphisms were genotyped in 1449 mothers in a prospective study of the Seychellois population with a diet rich in fish. Genotypes were analyzed in association with maternal hair and blood Hg, fetal blood Hg (cord blood Hg), as well as children's mental (MDI) and motor development (PDI; MDI and PDI assessed by Bayley Scales of Infant Development at 20 months). We also examined whether genotypes modified the association between Hg exposure and developmental outcomes. Results: GCLC rs761142 TT homozygotes showed statistically higher mean maternal hair Hg (4.12 ppm) than G carriers (AG 3.73 and GG 3.52 ppm) (p = 0.037). For the combination of GCLC rs761142 and GCLM rs41303970, double homozygotes TT + CC showed higher hair Hg (4.40 ppm) than G + T carriers (3.44 ppm; p = 0.018). No associations were observed between GSTP1 rs1695 and maternal hair Hg or between any genotypes and maternal blood Hg or cord blood Hg. The maternal GSTP1 rs1695 rare allele (G) was associated with a lower MDI among children (β = −1.48, p = 0.048). We also observed some interactions: increasing Hg in maternal and cord blood was associated with lower PDI among GCLC rs761142 TT carriers; and increasing Hg in hair was associated with lower MDI among GSTP1 rs1695 GG carriers. Conclusions: Maternal genetic variation in genes involved in GSH synthesis is statistically associated with Hg concentrations in maternal hair, but not in maternal or fetal blood. We observed interactions that suggest maternal GSH genetics may modify associations between MeHg exposure and neurodevelopmental outcomes

Polymorphisms in ATP-binding cassette transporters associated with maternal methylmercury disposition and infant neurodevelopment in mother-infant pairs in the Seychelles Child Development Study

AbstractBackgroundATP-binding cassette (ABC) transporters have been associated with methylmercury (MeHg) toxicity in experimental animal models.AimsTo evaluate the association of single nucleotide polymorphisms (SNPs) in maternal ABC transporter genes with 1) maternal hair MeHg concentrations during pregnancy and 2) child neurodevelopmental outcomes.Materials and methodsNutrition Cohort 2 (NC2) is an observational mother-child cohort recruited in the Republic of Seychelles from 2008–2011. Total mercury (Hg) was measured in maternal hair growing during pregnancy as a biomarker for prenatal MeHg exposure (N=1313) (mean 3.9ppm). Infants completed developmental assessments by Bayley Scales of Infant Development II (BSID-II) at 20months of age (N=1331). Genotyping for fifteen SNPs in ABCC1, ABCC2 and ABCB1 was performed for the mothers.ResultsSeven of fifteen ABC SNPs (ABCC1 rs11075290, rs212093, and rs215088; ABCC2 rs717620; ABCB1 rs10276499, rs1202169, and rs2032582) were associated with concentrations of maternal hair Hg (p<0.001 to 0.013). One SNP (ABCC1 rs11075290) was also significantly associated with neurodevelopment; children born to mothers with rs11075290 CC genotype (mean hair Hg 3.6ppm) scored on average 2 points lower on the Mental Development Index (MDI) and 3 points lower on the Psychomotor Development Index (PDI) than children born to mothers with TT genotype (mean hair Hg 4.7ppm) while children with the CT genotype (mean hair Hg 4.0ppm) had intermediate BSID scores.DiscussionGenetic variation in ABC transporter genes was associated with maternal hair Hg concentrations. The implications for MeHg dose in the developing child and neurodevelopmental outcomes need to be further investigated

Plasma-Metanephrines in Patients with Autoimmune Addison’s Disease with and without Residual Adrenocortical Function

Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison’s disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. Conclusion: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD

Residual Corticosteroid Production in Autoimmune Addison Disease

Context - Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. Objective - To determine frequencies and clinical features of residual corticosteroid production in patients with AAD. Design - Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography–tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. Results - Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P P P P P P P  Conclusion - In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life

Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study

Objective - Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood. Methods - We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH. Results - Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = −0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (−0.15 normalized protein expression [NPX], P = .0001, and −0.25 NPX, P = .0003, respectively). Conclusions - We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small

Comparison of cisplatin sensitivity and the 18F fluoro-2-deoxy 2 glucose uptake with proliferation parameters and gene expression in squamous cell carcinoma cell lines of the head and neck

<p>Abstract</p> <p>Background</p> <p>The survival of patients with locally advanced head and neck cancer is still poor, with 5-year survival rates of 24–35%. The identification of prognostic and predictive markers at the molecular and cellular level could make it possible to find new therapeutic targets and provide "taylor made" treatments. Established cell lines of human squamous cell carcinoma (HNSCC) are valuable models for identifying such markers.</p> <p>The aim of this study was to establish and characterize a series of cell lines and to compare the cisplatin sensitivity and 18F fluoro-2 deoxy 2 glucose (18F-FDG) uptake of these cell lines with other cellular characteristics, such as proliferation parameters and TP53 and CCND1 status.</p> <p>Methods</p> <p>Explant cultures of fresh tumour tissue were cultivated, and six new permanent cell lines were established from 18 HNSCC cases. Successfully grown cell lines were analysed regarding clinical parameters, histological grade, karyotype, DNA ploidy, and index and S-phase fraction (Spf). The cell lines were further characterized with regard to their uptake of 18F-FDG, their sensitivity to cisplatin, as measured by a viability test (crystal violet), and their TP53 and CCND1 status, by fluorescence in situ hybridization (FISH), polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) with DNA sequencing and, for cyclin D1, by immunohistochemistry.</p> <p>Results</p> <p>Patients with tumours that could be cultured in vitro had shorter disease-free periods and overall survival time than those whose tumours did not grow in vitro, when analysed with the Kaplan-Meier method and the log-rank test. Their tumours also showed more complex karyotypes than tumours from which cell lines could not be established. No correlation was found between TP53 or CCND1 status and 18F-FDG uptake or cisplatin sensitivity. However, there was an inverse correlation between tumour cell doubling time and 18F-FDG uptake.</p> <p>Conclusion</p> <p>In vitro growth of HNSCC cells seem to be an independent prognostic factor, with cell lines being more readily established from aggressive tumours, a phenomenon more dependent on the molecular genetic characteristics of the tumour cells than on tumour location or TNM status.</p

Particle-induced pulmonary acute phase response correlates with neutrophil influx linking inhaled particles and cardiovascular risk

BACKGROUND: Particulate air pollution is associated with cardiovascular disease. Acute phase response is causally linked to cardiovascular disease. Here, we propose that particle-induced pulmonary acute phase response provides an underlying mechanism for particle-induced cardiovascular risk. METHODS: We analysed the mRNA expression of Serum Amyloid A (Saa3) in lung tissue from female C57BL/6J mice exposed to different particles including nanomaterials (carbon black and titanium dioxide nanoparticles, multi- and single walled carbon nanotubes), diesel exhaust particles and airborne dust collected at a biofuel plant. Mice were exposed to single or multiple doses of particles by inhalation or intratracheal instillation and pulmonary mRNA expression of Saa3 was determined at different time points of up to 4 weeks after exposure. Also hepatic mRNA expression of Saa3, SAA3 protein levels in broncheoalveolar lavage fluid and in plasma and high density lipoprotein levels in plasma were determined in mice exposed to multiwalled carbon nanotubes. RESULTS: Pulmonary exposure to particles strongly increased Saa3 mRNA levels in lung tissue and elevated SAA3 protein levels in broncheoalveolar lavage fluid and plasma, whereas hepatic Saa3 levels were much less affected. Pulmonary Saa3 expression correlated with the number of neutrophils in BAL across different dosing regimens, doses and time points. CONCLUSIONS: Pulmonary acute phase response may constitute a direct link between particle inhalation and risk of cardiovascular disease. We propose that the particle-induced pulmonary acute phase response may predict risk for cardiovascular disease

Matematik i vardagen : sexton elever i de tidigare skolåren och deras förståelse för matematikens användningsområden genom matematisk problemlösning som arbetsmetod

Validerat; 20101217 (root

Cooperation between home and school : The importance of collaboration between pupils, parents and teachers. Observations gained from a primary school, year one up to and including year three

The main purpose of this study was to shed light upon several questions regarding co -operation between the home and school, based upon earlier research and empirical studies. The study focused on the opportunities and drawbacks as well as on the motives for home and school cooperation. The first section deals with the questions at issues, and the bases the dissertation was dealt with. The second part covers the empirical studies which were carried out within the first three years of the primary school, and in the third part the limitations, most important results, and future research were discussed. The aim of the first section was to identify the starting points for the study, based on earlier research, and to review, via the main body of the study, how co-operation between the home and the school developed. An analysis of the review suggested that the goal formulations of the main body of the paper allowed for opportunities for home and school collaboration. Not only had interesting possibilities come to light, throughout the earlier research, but so too, a number of problems concerning the concrete collaboration between home and school. An very important conclusion, as a result of this review focused on the importance of proceeding from the unit that a class of pupils, parents and teachers represents. The purpose of the empirical studies was to describe and to try to understand why co-operation between home and school developed as it did. A longitudinal study was carried out by means of on-site research in the primary school itself, among pupils in years 1-3. This was proceeded by questionnaires and prestudies of selected classes. The data was collected mainly by means of questionnaires, interviews and written documents. The results showed that parents could function as a valuable resource within the work of the school and that it was relatively easy to take advantage of them, as such. It became clear that pupils, parents and teachers were extremely inventive and resourceful with regard to ideas on cooperation, and indeed on carrying through those ideas. Parents saw themselves and other parents as an important resource for the work of the school. The teacher emerged as a key figure for intensified collaboration. In the concluding discussion the results from the microlevel formed the starting point for the discussion concerning the context of cooperation between home and school at the macrolevel. As a conclusion, the discussion was about collaboration between home and school in terms of some of the effects of cooperation opportunities and obstacles, the interest shown by parents together with the content and forms of collaboration. Here it was pointed out that an important condition for achieving society's objectives was that pupils, parents and teachers together should interpret this in order to connect them to the cultural economic and social reality that was relevant to that particular class.digitalisering@um