Impact of socio-economic deprivation on endometrial cancer survival in the North West of England: a prospective database analysis.

OBJECTIVE: To assess the impact of socio-economic deprivation on endometrial cancer survival. DESIGN: Single-centre prospective database study. SETTING: North West England. POPULATION: Women with endometrial cancer treated between 2010 and 2015. METHODS: Areal-level socio-economic status, using the English indices of multiple deprivation from residential postcodes, was analysed in relation to survival using Kaplan-Meier estimation and multivariable Cox regression. MAIN OUTCOME MEASURES: Overall survival, cancer-specific survival and patterns and rates of recurrence. RESULTS: A total of 539 women, with a median age of 66 years (interquartile range, IQR 56-73 years) and a body mass index (BMI) of 32 kg/m2 (IQR 26-39 kg/m2 ), were included in the analysis. Women in the most deprived social group were younger (median 64 years, IQR 55-72 years) and more obese (median 34 kg/m2 , IQR 28-42 kg/m2 ) than women in the least deprived group (median age 68 years, IQR 60-74 years; BMI 29 kg/m2 , IQR 25-36 kg/m2 ; P = 0.002 and <0.001, respectively). There were no differences in endometrial cancer type, stage or grade between social groups. There was no difference in recurrence rates, however, women in the middle and most deprived social groups were more likely to present with distant/metastatic recurrence (80.6 and 79.2%, respectively) than women in the least deprived group (43.5%, P < 0.001). Women in the middle and most deprived groups had a two-fold (adjusted hazard ratio, HR = 2.00, 95% CI 1.07-3.73, P = 0.030) and 53% (adjusted HR = 1.53, 95% CI 0.77-3.04, P = 0.221) increase in cancer-specific mortality compared with women in the least deprived group. There were no differences in overall survival. CONCLUSIONS: We found that socio-economically deprived women with endometrial cancer were more likely to develop fatal recurrence. Larger studies are needed to confirm these findings and to identify modifiable contributing factors. TWEETABLE ABSTRACT: Socio-economic deprivation is linked to an increased risk of death from endometrial cancer in the North West of England.

Management and cleanup of legacy radium-contaminated sites in the United States.

The hazards associated with radium-containing materials were largely unknown when they were first introduced into household and other products over a century ago. Radium was also originally thought to have beneficial health properties, leading to confusion amongst the public about the safety of radium in household products and food items. When the adverse health effects associated with radium were discovered and became well known, radium products became unpopular and were prohibited in some countries. In the United States, after the hazards associated with radium became known, radium was first regulated by individual states in the late 1920s and early 1930s. Later, the US Nuclear Regulatory Commission (NRC) was given a role in the regulation of discrete sources of radium with the passage of the Energy Policy Act of 2005. After passage of the Act, the NRC began to systematically identify sites around the country where radium was used and reached out to site owners to determine whether existing radium contamination could pose a risk to public health and safety and the environment. The NRC devised a graded approach in response to its new regulatory responsibilities to address potential public health and safety issues at legacy radium sites. By September 2019, the NRC had dispositioned all the sites that were identified as having potential contamination from historical radium within its regulatory purview in non-Agreement States. The staff worked with site owners and federal, state and local officials, as needed, to properly disposition the sites to ensure that each site either meets the applicable criteria for unrestricted use or has controls in place to limit access during remediation so that no site poses an unacceptable risk to public health and safety and the environment.

Examining the initial usability, acceptability and feasibility of a digital mental health intervention for college students in India.

Generalised anxiety disorder (GAD) is prevalent among college students in India; however, barriers like stigma, treatment accessibility and cost prevent engagement in treatment. Web- and mobile-based, or digital, mental health interventions have been proposed as a potential solution to increasing treatment access. With the ultimate goal of developing an engaging digital mental health intervention for university students in India, the current study sought to understand students' reactions to a culturally and digitally adapted evidence-based cognitive behavioural therapy (CBT) for GAD intervention. Specifically, through theatre testing and focus groups with a non-clinical sample of 15 college students in India, the present study examined initial usability, acceptability and feasibility of the "Mana Maali Digital Anxiety Program." Secondary objectives comprised identifying students' perceived barriers to using the program and eliciting recommendations. Results indicated high usability, with the average usability rating ranking in the top 10% of general usability scores. Participants offered actionable changes to improve usability and perceived acceptability among peers struggling with mental health issues. Findings highlight the benefits of offering digital resources that circumvent barriers associated with accessing traditional services. Results build on existing evidence that digital interventions can be a viable means of delivering mental healthcare to large, defined populations.

Long-term fracture rates seen with continued ibandronate treatment: pooled analysis of DIVA and MOBILE long-term extension studies.

UNLABELLED: Ibandronate reduces the risk of vertebral and non-vertebral fractures versus placebo in postmenopausal women with osteoporosis. This analysis, in which fractures were reported as safety events, showed that long-term use of ibandronate was associated with low fracture rates over 5 years of treatment. INTRODUCTION: A previous post-hoc meta-analysis of 2-3 year studies found that ibandronate regimens with annual cumulative exposure (ACE) of ≥10.8 mg reduced the risk of vertebral and nonvertebral fractures (NVFs) versus placebo in postmenopausal women. This post-hoc analysis used individual patient data from the 2-year monthly oral ibandronate in ladies (MOBILE) and dosing intravenous administration (DIVA) studies, including the 3-year long-term extensions (LTEs), to assess fracture risk in patients treated with ibandronate for 5 years. METHODS: Patients treated for 2 years in MOBILE with monthly oral ibandronate 150 mg (n = 176) and in DIVA with IV ibandronate every 2 months 2 mg (n = 253) or quarterly 3 mg (n = 263) who continued on the same regimens for 3 additional years in the LTEs were included. Three-year placebo data (n = 1,924) were obtained from the ibandronate osteoporosis vertebral fracture trial in North America and Europe (BONE) and IV Fracture Prevention trials. The primary endpoint was clinical fracture rate; clinical fracture data were collected as adverse events. Time to fracture was analyzed using Kaplan-Meier and statistical analysis was conducted using the log-rank test. All clinical fractures included all NVFs and symptomatic vertebral fractures. RESULTS: For ibandronate regimens with ACE ≥10.8 mg, time to fracture was significantly longer for all clinical fractures, NVFs, and clinical vertebral fractures versus placebo (P = 0.005). For all fracture types, the rate of fracture appeared stable during the 5-year treatment period. CONCLUSION: In women with postmenopausal osteoporosis, continuous treatment with ibandronate over 5 years results in low sustained clinical fracture rate.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

A family-based association analysis and meta-analysis of the reading disabilities candidate gene DYX1C1.

Reading disabilities (RD) have a significant genetic basis and have shown linkage to multiple regions including chromosome 15q. Dyslexia susceptibility 1 candidate gene 1 (DYX1C1) on chromosome 15q21 was originally proposed as a candidate gene with two potentially functional polymorphisms at the -3G/A and 1249G/T positions showing association with RD. However, subsequent studies have yielded mixed results. We performed a literature review and meta-analysis of the -3G/A and 1249G/T polymorphisms, including new unpublished data from two family-based samples. Ten markers in DYX1C1 were genotyped in the two independently ascertained samples. Single marker and -3G/A:1249G/T haplotype analyses were performed for RD in both samples, and quantitative trait analyses using standardized reading-related measures was performed in one of the samples. For the meta-analysis, we used a random-effects model to summarize studies that tested for association between -3G/A or 1249G/T and RD. No significant association was found between the DYX1C1 SNPs and RD or any of the reading-related measures tested after correction for the number of tests performed. The previously reported risk haplotype (-3A:1249T) was not biased in transmission. A total of 9 and 10 study samples were included in the meta-analysis of the -3G/A and 1249G/T polymorphisms, respectively. Neither polymorphism reached statistical significance, but the heterogeneity for the 1249G/T polymorphism was high. The results of this study do not provide evidence for association between the putatively functional SNPs -3G/A and 1249G/T and RD.

N-Acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to determine whether oral dosing with N-acetylcysteine (NAC) increases intraplatelet levels of the antioxidant, glutathione (GSH), and reduces platelet-monocyte conjugation in blood from patients with type 2 diabetes. METHODS: In this placebo-controlled randomised crossover study, the effect of oral NAC dosing on platelet-monocyte conjugation and intraplatelet GSH was investigated in patients with type 2 diabetes (eligibility criteria: men or post-menopausal women with well-controlled diabetes (HbA(1c) < 10%), not on aspirin or statins). Patients (n = 14; age range 43-79 years, HbA(1c) = 6.9 ± 0.9% [52.3 ± 10.3 mmol/mol]) visited the Highland Clinical Research Facility, Inverness, UK on day 0 and day 7 for each arm of the study. Blood was sampled before and 2 h after oral administration of placebo or NAC (1,200 mg) on day 0 and day 7. Patients received placebo or NAC capsules for once-daily dosing on the intervening days. The order of administration of NAC and placebo was allocated by a central office and all patients and research staff involved in the study were blinded to the allocation until after the study was complete and the data fully analysed. The primary outcome for the study was platelet-monocyte conjugation. RESULTS: Oral NAC reduced platelet-monocyte conjugation (from 53.1 ± 4.5% to 42.5 ± 3.9%) at 2 h after administration and the effect was maintained after 7 days of dosing. Intraplatelet GSH was raised in individuals with depleted GSH and there was a negative correlation between baseline intraplatelet GSH and platelet-monocyte conjugation. There were no adverse events. CONCLUSIONS/INTERPRETATION: The NAC-induced normalisation of intraplatelet GSH, coupled with a reduction in platelet-monocyte conjugation, suggests that NAC might help to reduce atherothrombotic risk in type 2 diabetes. FUNDING: Chief Scientist Office (CZB/4/622), Scottish Funding Council, Highlands & Islands Enterprise and European Regional Development Fund. TRIAL REGISTRATION: isrctn.org ISRCTN89304265.

Cytoplasmic male sterility in Mimulus hybrids has pleiotropic effects on corolla and pistil traits.

The mechanisms underlying genetic associations have important consequences for evolutionary outcomes, but distinguishing linkage from pleiotropy is often difficult. Here, we use a fine mapping approach to determine the genetic basis of association between cytonuclear male sterility and other floral traits in Mimulus hybrids. Previous work has shown that male sterility in hybrids between Mimulus guttatus and Mimulus nasutus is due to interactions between a mitochondrial gene from M. guttatus and two tightly linked nuclear restorer alleles on Linkage Group 7, and that male sterility is associated with reduced corolla size. In the present study, we generated a set of nearly isogenic lines segregating for the restorer region and male sterility, but with unique flanking introgressions. Male-sterile flowers had significantly smaller corollas, longer styles and greater stigmatic exsertion than fertile flowers. Because these effects were significant regardless of the genotypic composition of introgressions flanking the restorer region, they suggest that these floral differences are a direct byproduct of the genetic incompatibility causing anther abortion. In addition, we found a non-significant but intriguing trend for male-sterile plants to produce more seeds per flower than fertile siblings after supplemental pollination. Such pleiotropic effects may underlie the corolla dimorphism frequently observed in gynodioecious taxa and may affect selection on cytoplasmic male sterility genes when they initially arise.

The mode of delivery in women taken to theatre at full dilatation: does consultant presence make a difference?

The objective to this study was to assess whether consultant presence made a difference to the outcome of the mode of delivery when a woman was taken to theatre at full dilatation. During March to September 2009, the chance of a woman having a vaginal delivery if the consultant was present when they were taken to theatre at full dilatation was 70% (7/10), however in their absence, the chance of vaginal delivery was only 30% (12/40) (p < 0.05). Caesareans at full dilatation were associated with a higher rate of postpartum haemorrhage and longer hospital stay. This study shows that an increased consultant presence on labour ward, as advocated by the RCOG, could lead to a decrease in caesarean section at full dilatation.

Ultrasound Probe Pose Classification for Task Recognition in Central Venous Catheterization.

Central Line Tutor is a system that facilitates real-time feedback during training for central venous catheterization. One limitation of Central Line Tutor is its reliance on expensive, cumbersome electromagnetic tracking to facilitate various training aids, including ultrasound task identification and segmentation of neck vasculature. The purpose of this study is to validate deep learning methods for vessel segmentation and ultrasound pose classification in order to mitigate the system's reliance on electromagnetic tracking. A large dataset of segmented and classified ultrasound images was generated from participant data captured using Central Line Tutor. A U-Net architecture was used to perform vessel segmentation, while a shallow Convolutional Neural Network (CNN) architecture was designed to classify the pose of the ultrasound probe. A second classifier architecture was also tested that used the U-Net output as the CNN input. The mean testing set Intersect over Union score for U-Net cross-validation was 0.746 ± 0.052. The mean test set classification accuracy for the CNN was 92.0% ± 3.0, while the U-Net + CNN achieved 92.7% ± 2.1%. This study highlights the potential for deep learning on ultrasound images to replace the current electromagnetic tracking-based methods for vessel segmentation and ultrasound pose classification, and represents an important step towards removing the electromagnetic tracker altogether. Removing the need for an external tracking system would significantly reduce the cost of Central Line Tutor and make it far more accessible to the medical trainees that would benefit from it most.

Energy balancing in Nitella cells treated with dinitrophenol.

The toxic action of 2,4-dinitrophenol on the large cells of the alga, Nitella clavata, was evaluated, with the rate of protoplasmic streaming and the survival time at three light intensities used as criteria. At a sufficiently high intensity the cells survived several weeks, an indication that the energy-uncoupling action of dinitrophenol could be counterbalanced to some extent by an increased energy input. In the treated cells chloroplasts moved from the outer gel-type cytoplasm into the inner, streaming cytoplasm.

Mutation screen and association analysis of the glucocorticoid receptor gene (NR3C1) in childhood-onset mood disorders (COMD).

Depressive disorders are highly heterogeneous psychiatric disorders involving deficits to cognitive, psychomotor, and emotional processing. Considerable evidence links disruption to the hypothalamic-pituitary-adrenal (HPA) axis to the etiology of depression, with specific deficits reported in glucocorticoid receptor (GR)-mediated negative feedback. Given the role of GR-mediated negative feedback in mediating response to stress, and the clear link between stress and depression, it is plausible that polymorphisms in the GR gene (NR3C1) act to increase susceptibility. Maternal behavior in rats epigenetically alters a NGF1-A transcription factor binding-site in the promoter region of the GR gene, providing a mechanism by which environmental cues can regulate GR expression and thus response to stress. The analogous region of the human GR gene (NR3C1) has not been studied, but it is possible that polymorphisms in this region may alter the binding of transcription factors known to regulate GR expression. In this study, we have performed bioinformatic analyses on the promoter region of NR3C1 to identify conserved promoter sequences and predicted transcription factor binding sites. These regions were screened with denaturing high-performance liquid chromatography (DHPLC) and direct re-sequencing, and several novel polymorphic variants were identified. We genotyped nine polymorphisms across NR3C1 in a large sample of Hungarian nuclear families ascertained through affected probands with a diagnosis of childhood-onset mood disorders (COMD). Single-marker analysis provided little evidence for an association of this gene with COMD, but multi-marker analysis across a region of high linkage disequilibrium revealed modest evidence for the biased transmission of several haplotypes.

Holocene El Niño-Southern Oscillation variability reflected in subtropical Australian precipitation.

The La Niña and El Niño phases of the El Niño-Southern Oscillation (ENSO) have major impacts on regional rainfall patterns around the globe, with substantial environmental, societal and economic implications. Long-term perspectives on ENSO behaviour, under changing background conditions, are essential to anticipating how ENSO phases may respond under future climate scenarios. Here, we derive a 7700-year, quantitative precipitation record using carbon isotope ratios from a single species of leaf preserved in lake sediments from subtropical eastern Australia. We find a generally wet (more La Niña-like) mid-Holocene that shifted towards drier and more variable climates after 3200 cal. yr BP, primarily driven by increasing frequency and strength of the El Niño phase. Climate model simulations implicate a progressive orbitally-driven weakening of the Pacific Walker Circulation as contributing to this change. At centennial scales, high rainfall characterised the Little Ice Age (~1450-1850 CE) in subtropical eastern Australia, contrasting with oceanic proxies that suggest El Niño-like conditions prevail during this period. Our data provide a new western Pacific perspective on Holocene ENSO variability and highlight the need to address ENSO reconstruction with a geographically diverse network of sites to characterise how both ENSO, and its impacts, vary in a changing climate.

Electrostatic subframing and compressive-sensing video in transmission electron microscopy.

We present kilohertz-scale video capture rates in a transmission electron microscope, using a camera normally limited to hertz-scale acquisition. An electrostatic deflector rasters a discrete array of images over a large camera, decoupling the acquisition time per subframe from the camera readout time. Total-variation regularization allows features in overlapping subframes to be correctly placed in each frame. Moreover, the system can be operated in a compressive-sensing video mode, whereby the deflections are performed in a known pseudorandom sequence. Compressive sensing in effect performs data compression before the readout, such that the video resulting from the reconstruction can have substantially more total pixels than that were read from the camera. This allows, for example, 100 frames of video to be encoded and reconstructed using only 15 captured subframes in a single camera exposure. We demonstrate experimental tests including laser-driven melting/dewetting, sintering, and grain coarsening of nanostructured gold, with reconstructed video rates up to 10 kHz. The results exemplify the power of the technique by showing that it can be used to study the fundamentally different temporal behavior for the three different physical processes. Both sintering and coarsening exhibited self-limiting behavior, whereby the process essentially stopped even while the heating laser continued to strike the material. We attribute this to changes in laser absorption and to processes inherent to thin-film coarsening. In contrast, the dewetting proceeded at a relatively uniform rate after an initial incubation time consistent with the establishment of a steady-state temperature profile.

Impact of compliance and persistence with bisphosphonate therapy on health care costs and utilization.

UNLABELLED: The impact of persistence and compliance with bisphosphonate therapy on health care costs and utilization was examined in women newly prescribed bisphosphonates. At 3 years, women who were persistent and compliant with bisphosphonate therapy had lower total costs compared with non-persistent and non-compliant women, after controlling for relevant risk factors. INTRODUCTION: The impact of persistence and compliance with bisphosphonate therapy on health care costs and utilization was examined in bisphosphonate-naïve women. METHODS: Two claims databases were used to identify women > or = 45 years of age and who filled a new bisphosphonate prescription during 2000-2002. Persistence and compliance were evaluated over 3 years. Compliance was defined as a medication possession ratio (days of bisphosphonate supply/days of follow-up) > or = 0.80; persistence was defined as no refill gaps > or = 30 days. Multivariate models accounted for potential confounders. RESULTS: This analysis included 32,944 women (mean age, 64 years) who filled a new prescription for daily or weekly alendronate (n = 26,581) or risedronate (n = 6,363). At 3 years, 37% of women were compliant and 21% of women were persistent. Unadjusted total mean health care costs were lower for the compliant vs. non-compliant and persistent vs. non-persistent cohorts. After adjusting for potential confounders, total health care costs were reduced by 8.9% for persistent patients (p < 0.001) and 3.5% for compliant patients (p = 0.014). Persistence decreased the likelihood of inpatient admission by 47%. CONCLUSION: At 3 years, women who were persistent and compliant with bisphosphonate therapy had lower total costs compared with non-persistent and non-compliant women, after controlling for relevant risk factors.

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and childhood-onset mood disorders.

BACKGROUND/AIMS: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. METHODS: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. RESULTS: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. CONCLUSION: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

Association study between Gilles de la Tourette Syndrome and two genes in the Robo-Slit pathway located in the chromosome 11q24 linked/associated region.

Gilles de la Tourette Syndrome (GTS) is an inherited neuropsychiatric disorder characterized by the presence of motor and phonic tics. Previous genetic studies have identified linkage and association between GTS and the 11q24 chromosomal region. We selected for study, within this region, two possible susceptibility genes for GTS, the ROBO3 and ROBO4 genes. These two genes were selected because of the recent identification of SLITRK1 as a potential susceptibility gene for GTS based on a translocation breakpoint and the further finding of two mutations in the SLITRK1 gene in three patients with GTS. While thus far, the SLITRK1 gene appears to account for only a few cases of GTS, these findings, if confirmed, point to other genes in these pathways that may contribute to GTS. Based on this, we examined two genes in the Slit-Robo pathway involved in cell migration, axonal pathfinding, and/or neuronal differentiation because of their location in 11q24, a region previously identified as linked and associated with GTS. We selected six haplotype tagging single nucleotide polymorphisms (SNPs) for ROBO3 and four for ROBO4 and genotyped them in our sample of trios and sibpair families diagnosed with GTS. Based on 155 nuclear families with 255 affected children, we did not find evidence for association between GTS and either the ROBO3 or ROBO4 genes. Thus, these two genes are unlikely to be the susceptibility genes contributing to GTS on 11q24.

The contribution of alternative splicing to genetic risk for psychiatric disorders.

A genetic contribution to psychiatric disorders has clearly been established and genome-wide association studies now provide the location of risk genes and genetic variants associated with risk. However, the mechanism by which these genes and variants contribute to psychiatric disorders is mostly undetermined. This is in part because non-synonymous protein coding changes cannot explain the majority of variants associated with complex genetic traits. Based on this, it is predicted that these variants are causing gene expression changes, including changes to alternative splicing. Genetic changes influencing alternative splicing have been identified as risk factors in Mendelian disorders; however, currently there is a paucity of research on the role of alternative splicing in complex traits. This stems partly from the difficulty of predicting the role of genetic variation in splicing. Alterations to canonical splice site sequences, nucleotides adjacent to splice junctions, and exonic and intronic splicing regulatory sequences can influence splice site choice. Recent studies have identified global changes in alternatively spliced transcripts in brain tissues, some of which correlate with altered levels of splicing trans factors. Disease-associated variants have also been found to affect cis-acting splicing regulatory sequences and alter the ratio of alternatively spliced transcripts. These findings are reviewed here, as well as the current datasets and resources available to study alternative splicing in psychiatric disorders. Identifying and understanding risk variants that cause alternative splicing is critical to understanding the mechanisms of risk as well as to pave the way for new therapeutic options.

Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder.

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.