Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical ...and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.
In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families ...linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.
Attention-deficit/hyperactivity disorder (ADHD MIM
143465) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that ...genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at
D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at
D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at
D11S1998; multipoint nonparametric linkage NPL −log
P value = 5.49 at ∼128 cM), and 17p11 (multipoint NPL −log
P value >12 at ∼12 cM; multipoint maximum location score 2.48 α = 0.10 at ∼12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at
D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL−log
P value >3.0 at
D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes.
Accretion disks around compact objects are expected to enter an unstable phase at high luminosity
. One instability may occur when the radiation pressure generated by accretion modifies the disk ...viscosity, resulting in the cyclic depletion and refilling of the inner disk on short timescales
. Such a scenario, however, has only been quantitatively verified for a single stellar-mass black hole
. Although there are hints of these cycles in a few isolated cases
, their apparent absence in the variable emission of most bright accreting neutron stars and black holes has been a continuing puzzle
. Here we report the presence of the same multiwavelength instability around an accreting neutron star. Moreover, we show that the variability across the electromagnetic spectrum-from radio to X-ray-of both black holes and neutron stars at high accretion rates can be explained consistently if the accretion disks are unstable, producing relativistic ejections during transitions that deplete or refill the inner disk. Such a new association allows us to identify the main physical components responsible for the fast multiwavelength variability of highly accreting compact objects.
ABSTRACT
V341 Ara was recently recognized as one of the closest (d ≃ 150 pc) and brightest (V ≃ 10) nova-like cataclysmic variables. This unique system is surrounded by a bright emission nebula, ...likely to be the remnant of a recent nova eruption. Embedded within this nebula is a prominent bow shock, where the system’s accretion disc wind runs into its own nova shell. In order to establish its fundamental properties, we present the first comprehensive multiwavelength study of the system. Long-term photometry reveals quasi-periodic, super-orbital variations with a characteristic time-scale of 10–16 d and typical amplitude of ≃1 mag. High-cadence photometry from theTransiting Exoplanet Survey Satellite (TESS) reveals for the first time both the orbital period and a ‘negative superhump’ period. The latter is usually interpreted as the signature of a tilted accretion disc. We propose a recently developed disc instability model as a plausible explanation for the photometric behaviour. In our spectroscopic data, we clearly detect antiphased absorption and emission-line components. Their radial velocities suggest a high mass ratio, which in turn implies an unusually low white-dwarf mass. We also constrain the wind mass-loss rate of the system from the spatially resolved O iii emission produced in the bow shock; this can be used to test and calibrate accretion disc wind models. We suggest a possible association between V341 Ara and a ‘guest star’ mentioned in Chinese historical records in AD 1240. If this marks the date of the system’s nova eruption, V341 Ara would be the oldest recovered nova of its class and an excellent laboratory for testing nova theory.
Littman MP. State-of-the-art-review: Lyme nephritis. Guidelines for treatment of leishmaniasis in dogs. Variation of proteinuria in dogs with leishmaniasis treated with meglumine antimoniate and ...allopurinol: retrospective study.
Summary
Background
Despite a rising incidence of inflammatory bowel disease (IBD) in Hispanics in the United States, there are no studies examining the relationship between immigrant generation and ...IBD onset among Hispanics.
Aims
To determine whether age of IBD diagnosis, time from immigration to IBD diagnosis and IBD phenotype, differed across immigration periods in South Florida Cuban immigrants.
Methods
This was a cohort of consecutively identified Cuban‐born adults who developed IBD in the United States and were followed in gastroenterology (GI) clinic. We divided time cohorts of immigration by historical relevance: before 1980, 1980‐1994 and 1995‐to‐present. We examined differences across time cohorts in diagnosis age, time from immigration to IBD diagnosis, and IBD phenotype (ie, IBD type, disease location).
Results
A total of 130 Cuban patients with IBD were included. Age of IBD diagnosis was older in Cubans arriving before 1980 than in those arriving between 1980‐1994 or after 1995 (44.7 vs 33.79 and 33.71, respectively, P<.0001). Time between immigration and diagnosis was shorter in patients arriving to the US after 1980 (31.77 years, Standard deviation (SD) 12.83 (<1980) vs 17.13 years, SD 8.55 (1980‐1994) and 8.30 years, SD 4.72 (1995‐to‐present). IBD phenotype, including type of IBD, disease location and surgeries, did not differ significantly across time cohorts.
Conclusions
Our study describes changing patterns of IBD onset following immigration in Cubans, suggesting that environmental changes either in the United States, Cuba or both are resulting in faster IBD onset in younger immigrant generations. These studies can inform the search for environmental triggers that may result in IBD.
Linked Content
This article is linked to Kuenzig and Benchimol, and Damas et al, Actis and Pelicano, and Damas and Abreu, papers. To view these articles visit https://doi.org/10.1111/apt.14168, https://doi.org/10.1111/apt.14200, https://doi.org/10.1111/apt.14249 and https://doi.org/10.1111/apt.14278.
Summary Objective Recent developments on high resolution micro computed tomography (μCT) allow imaging of soft tissues in small animal joints. Nevertheless, μCT images cannot distinguish soft tissues ...from synovial fluid due to their similar mass density, limiting the 3D assessment of soft tissues volume and thickness. This study aimed to evaluate a lead chromate contrast agent for μCΤ arthrography of rat knee joints ex vivo. Design Intact tibiofemoral rat joints were injected with the contrast agent at different concentrations and imaged using a μCT at 2.7 μm isotropic voxel size. Cartilage thickness was measured using an automated procedure, validated against histological measurements, and analyzed as a function of μCT image resolution. Changes in hard and soft tissues were also analyzed in tibiofemoral joints 4 weeks after surgical destabilization of the medial meniscus (DMM). Results The contrast agent diffused well throughout the whole knee cavity without penetrating the tissues, therefore providing high contrast at the boundaries between soft tissues and synovial fluid space. Thickness analysis of cartilage demonstrated a high similarity between histology and μ-arthrography approaches ( R2 = 0.90). Four weeks after surgical DMM, the development of osteophytes (Oph) and cartilage ulcerations was recognizable with μCT, as well as a slight increase in trabecular bone porosity, and decrease in trabecular thickness. Conclusions A lead chromate-based contrast agent allowed discriminating the synovial fluid from soft tissues of intact knee joints, and thus made possible both qualitative and quantitative assessment of hard and soft tissues in both intact and DMM tibiofemoral joints using high resolution μCT.
Summary
Background
Recent years have seen the level of blood donation at a world level come to a standstill or even decline. This situation requires blood donation services to make efforts to ...increase donor recruitment and retention, as well as to increase the frequency of donations among current donors. In order to obtain good results, it is essential to understand the factors that affect intention to donate.
Objectives
To determine the explanatory power of a set of factors on intention to donate blood, as well as evaluating the ability of current donors to motivate others.
Methods/Materials
A questionnaire was administered to a sample of 1015 Spanish individuals.
Results
Results indicate that (i) motivations and hindering factors have the greatest explanatory power on intention to donate, (ii) experience as a donor is the most explanatory factor on future intention and (iii) there are significant behavioural and sociodemographic differences between donors and non‐donors.
Conclusion
These findings suggest that it is necessary (i) to enhance the donor retention for maintaining the donation system using a personal and frequent communication with donors not only to remind them to schedule their next donation, but also to attract more donors; (ii) to recapture temporarily deferred donors, as they are less reluctant towards donation; (iii) to describe in detail how donation affects donors and clarify the importance of donation for society and (iv) to develop member get member programs in which current donors act as motivators amongst friends, coworkers and family.
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