Psychiatric genetics and the structure of psychopathology

For over a century, psychiatric disorders have been defined by expert opinion and clinical observation. The modern DSM has relied on a consensus of experts to define categorical syndromes based on clusters of symptoms and signs, and, to some extent, external validators, such as longitudinal course and response to treatment. In the absence of an established etiology, psychiatry has struggled to validate these descriptive syndromes, and to define the boundaries between disorders and between normal and pathologic variation. Recent advances in genomic research, coupled with large-scale collaborative efforts like the Psychiatric Genomics Consortium, have identified hundreds of common and rare genetic variations that contribute to a range of neuropsychiatric disorders. At the same time, they have begun to address deeper questions about the structure and classification of mental disorders: To what extent do genetic findings support or challenge our clinical nosology? Are there genetic boundaries between psychiatric and neurologic illness? Do the data support a boundary between disorder and normal variation? Is it possible to envision a nosology based on genetically informed disease mechanisms? This review provides an overview of conceptual issues and genetic findings that bear on the relationships among and boundaries between psychiatric disorders and other conditions. We highlight implications for the evolving classification of psychopathology and the challenges for clinical translation

Global Existence and Regularity for the 3D Stochastic Primitive Equations of the Ocean and Atmosphere with Multiplicative White Noise

The Primitive Equations are a basic model in the study of large scale Oceanic and Atmospheric dynamics. These systems form the analytical core of the most advanced General Circulation Models. For this reason and due to their challenging nonlinear and anisotropic structure the Primitive Equations have recently received considerable attention from the mathematical community. In view of the complex multi-scale nature of the earth's climate system, many uncertainties appear that should be accounted for in the basic dynamical models of atmospheric and oceanic processes. In the climate community stochastic methods have come into extensive use in this connection. For this reason there has appeared a need to further develop the foundations of nonlinear stochastic partial differential equations in connection with the Primitive Equations and more generally. In this work we study a stochastic version of the Primitive Equations. We establish the global existence of strong, pathwise solutions for these equations in dimension 3 for the case of a nonlinear multiplicative noise. The proof makes use of anisotropic estimates, $L^{p}_{t}L^{q}_{x}$ estimates on the pressure and stopping time arguments.Comment: To appear in Nonlinearit

Reverse dynamisation: a modern perspective on Stephan Perren’s strain theory

The present review acknowledges the tremendous impact of Stephan Perren’s strain theory, considered with respect to the earlier contributions of Roux and Pauwels. Then, it provides further insight by examining how the concept of reverse dynamisation extended Perren’s theory within a modern context. A key factor of this more contemporary theory is that it introduces variable mechanical conditions at different time points during bone healing, opening the possibility of manipulating biology through mechanics to achieve the desired clinical outcome. The discussion focusses on the current state of the art and the most recent advances made towards optimising and accelerating bone regeneration, by actively controlling the mechanical environment as healing progresses. Reverse dynamisation utilises a very specific mechanical manipulation regimen, with conditions initially flexible to encourage and expedite early callus formation. Once callus has formed, the mechanical conditions are intentionally modified to create a rigid environment under which the soft callus is quickly converted to hard callus, bridging the fracture site and leading to a more rapid union. The relevant literature, principally animal studies, was surveyed to provide ample evidence in support of the effectiveness of reverse dynamisation. By providing a modern perspective on Stephan Perren’s strain theory, reverse dynamisation perhaps holds the key to tipping the balance in favour of a more rapid and reliable union when treating acute fractures, osteotomies, non-unions and other circumstances where it is necessary to regenerate bone

Efficacy of atomoxetine in adult attention-Deficit/Hyperactivity Disorder: a drug-placebo response curve analysis

BACKGROUND: The objective of this study was to evaluate the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) among adults by using drug-placebo response curve methods. METHODS: We analyzed data from two double-blind, placebo-controlled, parallel design studies of adult patients (Study I, N = 280; Study II, N = 256) with DSM-IV-defined ADHD who were recruited by referral and advertising. Subjects were randomized to 10 weeks of treatment with atomoxetine or placebo, and were assessed with the Conners Adult ADHD Rating Scales and the Clinical Global Impression of ADHD Severity scale before and after treatment. RESULTS: Those treated with atomoxetine were more likely to show a reduction in ADHD symptoms than those receiving placebo. Across all measures, the likelihood that an atomoxetine-treated subject improved to a greater extent than a placebo-treated subject was approximately 0.60. Furthermore, atomoxetine prevented worsening of most symptom classes. CONCLUSION: From these findings, we conclude that atomoxetine is an effective treatment for ADHD among adults when evaluated using several criteria

Efficacy of Atomoxetine in Adult Attention-Deficit/Hyperactivity Disorder: A Drug-placebo Response Curve Analysis

Background: The objective of this study was to evaluate the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) among adults by using drug-placebo response curve methods. Methods: We analyzed data from two double-blind, placebo-controlled, parallel design studies of adult patients (Study I, N = 280; Study II, N = 256) with DSM-IV-defined ADHD who were recruited by referral and advertising. Subjects were randomized to 10 weeks of treatment with atomoxetine or placebo, and were assessed with the Conners Adult ADHD Rating Scales and the Clinical Global Impression of ADHD Severity scale before and after treatment. Results: Those treated with atomoxetine were more likely to show a reduction in ADHD symptoms than those receiving placebo. Across all measures, the likelihood that an atomoxetine-treated subject improved to a greater extent than a placebo-treated subject was approximately 0.60. Furthermore, atomoxetine prevented worsening of most symptom classes. Conclusion: From these findings, we conclude that atomoxetine is an effective treatment for ADHD among adults when evaluated using several criteria

STEP: the VST survey of the SMC and the Magellanic Bridge - I : Overview and first results

STEP (the SMC in Time: Evolution of a Prototype interacting late-type dwarf galaxy) is a Guaranteed Time Observation survey being performed at the VST (the ESO VLT Survey Telescope). STEP will image an area of 74 sq. deg. covering the main body of the Small Magellanic Cloud (32 sq. deg.), the Bridge that connects it to the Large Magellanic Cloud (30 sq. deg.) and a small part of the Magellanic Stream (2 sq. deg.). Our g, r, i, Hα photometry is able to resolve individual stars down to magnitudes well below the main-sequence turn-off of the oldest populations. In this first paper, we describe the observing strategy, the photometric techniques and the upcoming data products of the survey. We also present preliminary results for the first two fields for which data acquisition is completed, including some detailed analysis of the two stellar clusters IC 1624 and NGC 419.Peer reviewedFinal Accepted Versio

An integrated analysis of genes and functional pathways for aggression in human and rodent models

Human genome-wide association studies (GWAS), transcriptome analyses of animal models, and candidate gene studies have advanced our understanding of the genetic architecture of aggressive behaviors. However, each of these methods presents unique limitations. To generate a more confident and comprehensive view of the complex genetics underlying aggression, we undertook an integrated, cross-species approach. We focused on human and rodent models to derive eight gene lists from three main categories of genetic evidence: two sets of genes identified in GWAS studies, four sets implicated by transcriptome-wide studies of rodent models, and two sets of genes with causal evidence from online Mendelian inheritance in man (OMIM) and knockout (KO) mice reports. These gene sets were evaluated for overlap and pathway enrichment to extract their similarities and differences. We identified enriched common pathways such as the G-protein coupled receptor (GPCR) signaling pathway, axon guidance, reelin signaling in neurons, and ERK/MAPK signaling. Also, individual genes were ranked based on their cumulative weights to quantify their importance as risk factors for aggressive behavior, which resulted in 40 top-ranked and highly interconnected genes. The results of our cross-species and integrated approach provide insights into the genetic etiology of aggression