Substitution of pseudokinase domain residue Val-617 by large non-polar amino acids causes activation of JAK2

Explaining the uniqueness of the acquired somatic JAK2 V617F mutation, which is present in more than 95% of polycythemia vera patients, has been a challenge. The V617F mutation in the pseudokinase domain of JAK2 renders the unmutated kinase domain constitutively active. We have performed random mutagenesis at position 617 of JAK2 and tested each of the 20 possible amino acids for ability to induce constitutive signaling in Ba/F3 cells expressing the erythropoietin receptor. Four JAK2 mutants, V617W, V617M, V617I, and V617L, were able to induce cytokine independence and constitutive downstream signaling. Only V617W induced a level of constitutive activation comparable with V617F. Also, only V617W stabilized tyrosine-phosphorylated suppressor of cytokine signaling 3 ( SOCS3), a mechanism by which JAK2 V617F overcomes inhibition by SOCS3. The V617W mutant induced a myeloproliferative disease in mice, mainly characterized by erythrocytosis and megakaryocytic proliferation. Although JAK2 V617W would predictably be pathogenic in humans, the substitution of the Val codon, GTC, by TTG, the codon for Trp, would require three base pair changes, and thus it is unlikely to occur. We discuss how the predicted conformations of the activated JAK2 mutants can lead to better screening assays for novel small molecule inhibitors.

Response variability in Attention Deficit Hyperactivity Disorder: Evidence for neuropsychological heterogeneity

Response time (RT) variability is a common finding in ADHD research. RT variability may reflect frontal cortex function and may be related to deficits in sustained attention. The existence of a sustained attention deficit in ADHD has been debated, largely because of inconsistent evidence of time-on-task effects. A fixed-sequence Sustained Attention to Response Task (SART) was given to 29 control, 39 unimpaired and 24 impaired-ADHD children (impairment defined by the number of commission errors). The response time data were analysed using the Fast Fourier Transform, to define the fast-frequency and slow-frequency contributions to overall response variability. The impaired-ADHD group progressively slowed in RT over the course of the 5.5 min task, as reflected in this group's greater slow-frequency variability. The fast-frequency trial-to-trial variability was also significantly greater, but did not differentially worsen over the course of the task. The higher error rates of the impaired-ADHD group did not become differentially greater over the length of the task. The progressive slowing in mean RT over the course of the task may relate to a deficit in arousal in the impaired-ADHD group. The consistently poor performance in fast-frequency variability and error rates may be due to difficulties in sustained attention that fluctuate on a trial-to-trial basis. (c) 2006 Elsevier Ltd. All rights reserved.

Movement-related potentials in high-functioning autism and Asperger's disorder

Autism and Asperger's disorder (AD) are neurodevelopmental conditions that affect cognitive and social-communicative function. Using a movement-related potential (MRP) paradigm, we investigated the clinical and neurobiological issue of 'disorder separateness' versus 'disorder variance' in autism and AD. This paradigm has been used to assess basal ganglia/supplementary motor functioning in Parkinson's disease. Three groups (high functioning autism [HFA]: 16 males, 1 female; mean age 12y 5mo [SD 4y 4mo]; AD: 11 males, 2 females; mean age 13y 5mo [SD 3y 8mo]; comparison group: 13 males, 8 females; mean age 13y 10mo, [SD 3y 11 mo]) completed a cued motor task during electroencephalogram recording of MRPs. The HFA group showed reduced peak amplitude at Cz, indicating less activity over the supplementary motor area during movement preparation. Although an overall significant between-group effect was found for early slope and peak amplitude, subanalysis revealed that the group with AD did not differ significantly from either group. However, it is suggested that autism and AD may be dissociated on the basis of brain-behaviour correlations of IQ with specific neurobiological measures. The overlap between MRP traces for autism and Parkinson's disease suggests that the neurobiological wiring of motor functioning in autism may bypass the supplementary motor area/primary motor cortex pathway.

Patterns of neurocognitive impairment in first-episode bipolar disorder and schizophrenia.

BACKGROUND:
Researching psychotic disorders in unison rather than as separate diagnostic groups is widely advocated, but the viability of such an approach requires careful consideration from a neurocognitive perspective.
AIMS:
To describe cognition in people with bipolar disorder and schizophrenia and to examine how known causes of variability in individual's performance contribute to any observed diagnostic differences.
METHOD:
Neurocognitive functioning in people with bipolar disorder (n = 32), schizophrenia (n = 46) and healthy controls (n = 67) was compared using analysis of covariance on data from the Northern Ireland First Episode Psychosis Study.
RESULTS:
The bipolar disorder and schizophrenia groups were most impaired on tests of memory, executive functioning and language. The bipolar group performed significantly better on tests of response inhibition, verbal fluency and callosal functioning. Between-group differences could be explained by the greater proclivity of individuals with schizophrenia to experience global cognitive impairment and negative symptoms.
CONCLUSIONS:
Particular impairments are common to people with psychosis and may prove useful as endophenotypic markers. Considering the degree of individuals' global cognitive impairment is critical when attempting to understand patterns of selective impairment both within and between these diagnostic groups.

Polar, non-coordinating ionic liquids as solvents for the alternating copolymerization of styrene and CO catalyzed by cationic palladium catalysts

The palladium-catalyzed copolymerization of styrene and CO in an ionic liquid solvent, 1-hexylpyridinium bis(trifluoromethanesulfonyl) imide, gave improved yields and increased molecular weights compared to polymerizations run in methanol.

Auditory hallucinations in dissociative identity disorder and schizophrenia with and without a childhood trauma history: Similarities and differences.

Little is known about similarities and differences in voice hearing in schizophrenia and dissociative identity disorder (DID) and the role of child maltreatment and dissociation. This study examined various aspects of voice hearing, along with childhood maltreatment and pathological dissociation in 3 samples: schizophrenia without child maltreatment (n = 18), schizophrenia with child maltreatment (n = 16), and DID (n = 29). Compared with the schizophrenia groups, the DID sample was more likely to have voices starting before 18, hear more than 2 voices, have both child and adult voices and experience tactile and visual hallucinations. The 3 groups were similar in that voice content was incongruent with mood and the location was more likely internal than external. Pathological dissociation predicted several aspects of voice hearing and appears an important variable in voice hearing, at least where maltreatment is present.

Experiences of parents during diagnosis and forward planning for children with Autism Spectrum Disorder.

Background For families of children diagnosed with autism spectrum disorder (ASD) getting a diagnosis is a traumatic experience on which future care and education plans for the child depend. In this paper parental experiences of diagnosis and forward planning for children with ASD are reported. Method This paper is part of a large cross-sectional study conducted in Northern Ireland and the Republic of Ireland that assessed the needs and experiences of parents of children diagnosed with ASD. Questionnaires were designed and completed by 95 parents, reporting on 100 children, as well as 67 multi-disciplinary professionals. Results Findings confirm that diagnostic and planning processes are extremely stressful for parents, that statutory diagnosis takes a long time, that care and education plans do not include full parental participation, and that reviews of plans do not consistently include intervention data. Conclusion Policy and practice implications of these findings are important for future revisions of diagnostic tools and manuals.