The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response

Background: FUS, EWS and TAF15 are structurally similar multifunctional proteins that were first discovered upon characterization of fusion oncogenes in human sarcomas and leukemias. The proteins belong to the FET ( previously TET) family of RNA-binding proteins and are implicated in central cellular processes such as regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. In the present study, we investigated the expression and cellular localization of FET proteins in multiple human tissues and cell types. Results: FUS, EWS and TAF15 were expressed in both distinct and overlapping patterns in human tissues. The three proteins showed almost ubiquitous nuclear expression and FUS and TAF15 were in addition present in the cytoplasm of most cell types. Cytoplasmic EWS was more rarely detected and seen mainly in secretory cell types. Furthermore, FET expression was downregulated in differentiating human embryonic stem cells, during induced differentiation of neuroblastoma cells and absent in terminally differentiated melanocytes and cardiac muscle cells. The FET proteins were targeted to stress granules induced by heat shock and oxidative stress and FUS required its RNA-binding domain for this translocation. Furthermore, FUS and TAF15 were detected in spreading initiation centers of adhering cells. Conclusion: Our results point to cell-specific expression patterns and functions of the FET proteins rather than the housekeeping roles inferred from earlier studies. The localization of FET proteins to stress granules suggests activities in translational regulation during stress conditions. Roles in central processes such as stress response, translational control and adhesion may explain the FET proteins frequent involvement in human cancer

Child Neurodevelopmental and Behavioural Problems are Intercorrelated and Dimensionally Distributed in the General Population

The Autism – Tics, AD/HD, and other Comorbidities inventory (A-TAC) is a comprehensive interview for evaluating problems related to autism spectrum disorders (ASD), tic disorders, attention-deficit/hyperactivity disorder (AD/HD), and common comorbid conditions in children and adolescents. A-TAC telephone interviews were administered to parents of 2,957 children aged nine- or twelve-years, representing one in each twin pair included in the populationbased Child and Adolescent Twin Study in Sweden (CATSS). A total of 16.4% were screen-positive for one or several of the targeted disorder, 1.3% for ASD and 5.6% for AD/HD. All types of problems were more common among boys, with the exception of those related to “eating habits”. They were all dimensionally/continuously distributed, highly inter-correlated, and overlapped across types. They aggregated in three basic factors corresponding to externalizing/disruptiveness, socio-communicative problems, and compulsiveness. Population-based data on problems in children thus challenge current categorical diagnostic definitions, calling for dimensional and complementary models of problem descriptions

Autism Spectrum Disorders in forensic psychiatric investigations–patterns of comorbidity and criminality

BackgroundThere are contradictory research findings regarding whether individuals with Autism Spectrum Disorders (ASDs) are more or less likely to commit crimes. The aims of the current study were to: (1) Describe psychiatric and crime-related characteristics of a large group of offenders with ASD who had undergone a Forensic Psychiatric Investigation (FPI). (2) Identify clinical subgroups among this group of offenders. (3) Investigate associations between the identified clinical subgroups and (a) psychiatric comorbidity (b) types of crimes and (c) criminal responsibility.MethodsThe study cohort consists of all subjects (n = 831) who received an ASD-diagnosis at an FPI between 2002 and 2018 in Sweden. Descriptive and clinical, as well as crime related variables were obtained from the FPIs. Non-parametric (Pearson χ2, Fisher's exact and Mann-Whitney U-test) inferential statistics were used for analyses of between-group differences and effect sizes were reported. A Latent Class Analysis was used to identify homogeneous subgroups (or classes) from categorical characteristics.ResultsThe cohort consisted of 708 men and 123 women, aged 18 to 74 yrs. Two-thirds (66.7%) of the cohort had at least one other psychiatric diagnosis, the most prevalent was substance use disorder (SUD). A severe mental disorder, equivalent to lack of criminal responsibility, was most often reported among offenders with a comorbid diagnosis of schizophrenia spectrum disorder. The most common type of crime was violent crime. Three person-oriented clinical subgroups were identified; (1) ASD with few other diagnoses; (2) ASD and very high levels of SUDs, plus moderate levels of other externalizing disorders and psychotic psychopathology and (3) ASD and moderate to high levels of personality disorders (other than ASPD) and SUDs.ConclusionOur results highlight the importance of all parts of the CJS to be prepared to handle offenders with ASD, often with high levels of additional psychiatric problems. Traditional approaches in treatment or other psychosocial interventions for ASD may need to be adapted to at least three general clinical profiles– one with mainly neurodevelopmental problems, one with a spectrum of externalizing problems and one with complex personality related difficulties

Mental health problems in youths committed to juvenile institutions: prevalences and treatment needs

Many international studies show that adolescents in coercive institutional care display high prevalences of mental disorders, especially in the form of disruptive behavior disorders [including attention-deficit/hyperactivity disorder (AD/HD), oppositional defiant disorder, and conduct disorder], anxiety disorders, and mood disorders. High degrees of overlap across mental disorders have also been reported. In addition, institutionalized adolescents are often traumatized. Despite this well-documented psychiatric morbidity, the mental health care needs of detained adolescents are often overlooked. The main objective of this study is to assess prevalences of psychiatric disorders, results of intelligence tests, and previous contacts with child and adolescent psychiatric services among adolescents in institutional care. DSM-IV diagnoses, mental health contacts, substance abuse, neurocognitive abilities, and school performance were registered in 100 adolescents (92 boys, 8 girls) aged 12–19 years (mean age 16.0; SD ± 1.5) consecutively committed to Swedish juvenile institutions between 2004 and 2007. At least one psychiatric disorder was diagnosed in 73% of the subjects: 48% met DSM-IV diagnostic criteria for AD/HD, 17% for an autism spectrum disorder, and 10% for a mental retardation. The collapsed prevalence for psychiatric disorders requiring specialist attention was 63%. Our data indicate that systematic diagnostic procedures are crucial in the treatment planning for institutionalized adolescents. Adequate treatment strategies need to be designed and implemented to meet the extensive mental health care needs of this vulnerable population

Variations of the Candidate SEZ6L2 Gene on Chromosome 16p11.2 in Patients with Autism Spectrum Disorders and in Human Populations

Background: Autism spectrum disorders (ASD) are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate. Methodology/Principal Findings: We further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP), complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls. Conclusions/Significance: Our results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD

ARCH 14 - International Conference on Research on Health Care Architecture - November 19-21, 2014, Espoo, Finland - Conference Proceedings

Healthcare Architecture has grown rapidly in recent years. However, there are still many questions remaining. The commission, therefore, is to share the existing research knowledge and latest results and to carry out research projects focusing more specifically on the health care situation in a variety of contexts. The ARCH14 conference was the third conference in the series of ARCH conferences on Research on Health Care Architecture initiated by Chalmers University. It was realized in collaboration with the Nordic Research Network for Healthcare Architecture .It was a joint event between Aalto University, Finnish Institute of Occupational Health (FIOH) and National Institute of Health and Welfare (THL International).The conference gathered together more than 70 researchers and practitioners from across disciplines and countries to discuss the current themes

The Autism - Tics, AD/HD and other Comorbidities inventory (A-TAC): further validation of a telephone interview for epidemiological research

<p>Abstract</p> <p>Background</p> <p>Reliable, valid, and easy-to-administer instruments to identify possible caseness and to provide proxies for clinical diagnoses are needed in epidemiological research on child and adolescent mental health.</p> <p>The aim of this study is to provide further validity data for a parent telephone interview focused on Autism - Tics, Attention-deficit/hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC), for which reliability and preliminary validation data have been previously reported.</p> <p>Methods</p> <p>Parents of 91 children clinically diagnosed at a specialized Child Neuropsychiatric Clinic, 366 control children and 319 children for whom clinical diagnoses had been previously assigned were interviewed by the A-TAC over the phone. Interviewers were blind to clinical information. Different scores from the A-TAC were compared to the diagnostic outcome.</p> <p>Results</p> <p>Areas under ROC curves for interview scores as predictors of clinical diagnoses were around 0.95 for most disorders, including autism spectrum disorders (ASDs), attention deficit/hyperactivity disorder (AD/HD), tic disorders, developmental coordination disorders (DCD) and learning disorders, indicating excellent screening properties. Screening cut-off scores with sensitivities above 0.90 (0.95 for ASD and AD/HD) were established for most conditions, as well as cut-off scores to identify proxies to clinical diagnoses with specificities above 0.90 (0.95 for ASD and AD/HD).</p> <p>Conclusions</p> <p>The previously reported validity of the A-TAC was supported by this larger replication study using broader scales from the A-TAC-items and a larger number of diagnostic categories. Short versions of algorithms worked as well as larger. Different cut-off levels for screening versus identifying proxies for clinical diagnoses are warranted. Data on the validity for mood problems and oppositional defiant/conduct problems are still lacking. Although the A-TAC is principally intended for epidemiological research and general investigations, the instrument may be useful as a tool to collect information in clinical practice as well.</p

Psychiatric and psychosocial problems in adults with normal-intelligence autism spectrum disorders

<p>Abstract</p> <p>Background</p> <p>Individuals with autism spectrum disorders (ASDs) often display symptoms from other diagnostic categories. Studies of clinical and psychosocial outcome in adult patients with ASDs without concomitant intellectual disability are few. The objective of this paper is to describe the clinical psychiatric presentation and important outcome measures of a large group of normal-intelligence adult patients with ASDs.</p> <p>Methods</p> <p>Autistic symptomatology according to the DSM-IV-criteria and the Gillberg & Gillberg research criteria, patterns of comorbid psychopathology and psychosocial outcome were assessed in 122 consecutively referred adults with normal intelligence ASDs. The subjects consisted of 5 patients with autistic disorder (AD), 67 with Asperger's disorder (AS) and 50 with pervasive developmental disorder not otherwise specified (PDD NOS). This study group consists of subjects pooled from two studies with highly similar protocols, all seen on an outpatient basis by one of three clinicians.</p> <p>Results</p> <p>Core autistic symptoms were highly prevalent in all ASD subgroups. Though AD subjects had the most pervasive problems, restrictions in non-verbal communication were common across all three subgroups and, contrary to current DSM criteria, so were verbal communication deficits. Lifetime psychiatric axis I comorbidity was very common, most notably mood and anxiety disorders, but also ADHD and psychotic disorders. The frequency of these diagnoses did not differ between the ASD subgroups or between males and females. Antisocial personality disorder and substance abuse were more common in the PDD NOS group. Of all subjects, few led an independent life and very few had ever had a long-term relationship. Female subjects more often reported having been bullied at school than male subjects.</p> <p>Conclusion</p> <p>ASDs are clinical syndromes characterized by impaired social interaction and non-verbal communication in adulthood as well as in childhood. They also carry a high risk for co-existing mental health problems from a broad spectrum of disorders and for unfavourable psychosocial life circumstances. For the next revision of DSM, our findings especially stress the importance of careful examination of the exclusion criterion for adult patients with ASDs.</p

Identification of Pathway-Biased and Deleterious Melatonin Receptor Mutants in Autism Spectrum Disorders and in the General Population

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration of the melatonin pathway has been reported in circadian disorders, diabetes and autism spectrum disorders (ASD). However, very little is known about the genetic variability of melatonin receptors in humans. Here, we sequenced the melatonin receptor MTNR1A and MTNR1B, genes coding for MT1 and MT2 receptors, respectively, in a large panel of 941 individuals including 295 patients with ASD, 362 controls and 284 individuals from different ethnic backgrounds. We also sequenced GPR50, coding for the orphan melatonin-related receptor GPR50 in patients and controls. We identified six non-synonymous mutations for MTNR1A and ten for MTNR1B. The majority of these variations altered receptor function. Particularly interesting mutants are MT1-I49N, which is devoid of any melatonin binding and cell surface expression, and MT1-G166E and MT1-I212T, which showed severely impaired cell surface expression. Of note, several mutants possessed pathway-selective signaling properties, some preferentially inhibiting the adenylyl cyclase pathway, others preferentially activating the MAPK pathway. The prevalence of these deleterious mutations in cases and controls indicates that they do not represent major risk factor for ASD (MTNR1A case 3.6% vs controls 4.4%; MTNR1B case 4.7% vs 3% controls). Concerning GPR50, we detected a significant association between ASD and two variations, Δ502–505 and T532A, in affected males, but it did not hold up after Bonferonni correction for multiple testing. Our results represent the first functional ascertainment of melatonin receptors in humans and constitute a basis for future structure-function studies and for interpreting genetic data on the melatonin pathway in patients

Comorbidity across childhood-onset neuropsychiatric disorders

Background: Attention-Deficit/Hyperactivity Disorder (ADHD), and Autism Spectrum Disorders (ASDs) are clinically found to be comorbid with each other and with other psychiatric conditions to a greater extent than what is previously assumed. It is, however, difficult to capture this complexity using current diagnostic systems, where exclusion criteria prevent simultaneous diagnosis. Thus, in order to describe this complexity and its consequences for the individual, it is important to describe actual comorbidity in different clinical contexts. Aims: The overall purpose of this thesis was to describe the prevalence and comorbidity between ASD and ADHD, and other psychiatric conditions. Specific aims were to: describe comorbidity in a group of adult out-patients with ADHD and/or ASDs (Paper I); investigate the prevalence of personality disorders and describe the personality profiles of the same group (Paper II); describe psychiatric symptoms associated with aggressive behaviors in adult psychiatric patients (Paper III); describe comorbidity in a group of adolescents placed in special youth institutions (Paper IV); and to investigate whether comorbid ADHD and substance abuse is associated with a more negative outcome, that is, more criminal recidivism, health care needs, and untimely death (Paper V). Methods and results: Paper I-II are based on diagnostic and demographic cross-sectional data showing that ADHD and ASD overlap greatly with each other, and that there is a significant overlap between ADHD and bipolar disorder and ASDs and psychosis. Personality disorder diagnoses are also common in these diagnostic groups, showing specific personality profiles associated with ADHD, ASD, and those with comorbid ADHD and ASD. In Paper III aggressive behaviors in a group of policlinic psychiatric patients have been compared with a group of forensic psychiatric patients, and both groups reported similar high levels of aggressive scores. Paper IV is based on cross-sectional data on institutionalized adolescents, which in Paper V has been combined with longitudinal follow-up data. Psychiatric diagnoses in general, and specifically the occurrence of ADHD and ASD, is high. Criminal recidivism and health care use was overall very high, while there were small differences between the groups with comorbid ADHD and SUD, SUD only, and, finally, no SUD in respect to criminal recidivism, health care needs and untimely death. Conclusion: Comorbidity between ADHD and ASD and other psychiatric diagnoses are common among psychiatric patients, and in many cases associated with character immaturity, aggression and personality disorders. It also seems as the outcome over time tends to worsening with increasing comorbidity, especially in cases with comorbid substance abuse and neuropsychiatric disorders. These complex states constitute diagnostic and treatment challenges for psychiatry and its classic divisions between child and adolescent versus adult psychiatry, mental illness versus personality disorders, and psychological versus medical interventions