Real-life instability in ADHD from young to middle adulthood: a nationwide register-based study of social and occupational problems.

BACKGROUND: Studies using self-reports indicate that individuals with ADHD are at increased risk for functional impairments in social and occupational settings, but evidence around real-life instability remains limited. It is furthermore unclear if these functional impairments in ADHD differ across sex and across the adult lifespan. METHOD: A longitudinal observational cohort design of 3,448,440 individuals was used to study the associations between ADHD and residential moves, relational instability and job shifting using data from Swedish national registers. Data were stratified on sex and age (18-29 years, 30-39 years, and 40-52 years at start of follow up). RESULTS: 31,081 individuals (17,088 males; 13,993 females) in the total cohort had an ADHD-diagnosis. Individuals with ADHD had an increased incidence rate ratio (IRR) of residential moves (IRR 2.35 [95% CI, 2.32-2.37]), relational instability (IRR = 1.07 [95% CI, 1.06-1.08]) and job shifting (IRR = 1.03 [95% CI, 1.02-1.04]). These associations tended to increase with increasing age. The strongest associations were found in the oldest group (40-52 years at start of follow). Women with ADHD in all three age groups had a higher rate of relational instability compared to men with ADHD. CONCLUSION: Both men and women with a diagnosis of ADHD present with an increased risk of real-life instability in different domains and this behavioral pattern was not limited to young adulthood but also existed well into older adulthood. It is therefore important to have a lifespan perspective on ADHD for individuals, relatives, and the health care sector.

Differential modulation of transendothelial electrical resistance by TRPV4 agonists is mediated by apoptosis and/or necrosis.

Transient receptor potential vanilloid 4 (TRPV4) has been implicated in many disease conditions also in the lung. Its activation leads to an increase endothelial permeability in an intracellular calcium-influx dependent manner. We investigated its function in vitro on primary human endothelial cells using two TRPV4 agonists, GSK1016790A and 4α-Phorbol 12,13-didecanoate (4α-PDD) and a selective TRPV4 blocker GSK2193874. Both TRPV4 agonists leaded to a reduction in transendothelial electrical resistance (TER) which was mediated however by differential cytotoxic effects. 4α-PDD induced apoptosis that could not be blocked by TRPV4 inhibition in HUVECs, whereas GSK1016790A selectively activated TRPV4 and reduced TER as a consequence of cellular necrosis. TRPV4 mediated cytotoxicity is poorly described and may provide significant context to the role of TRPV4 in barrier-function.

The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis.

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in the protein huntingtin (htt). Pathogenesis in HD appears to involve the formation of ubiquitinated neuronal intranuclear inclusions containing N-terminal mutated htt, abnormal protein interactions, and the aggregate sequestration of a variety of proteins (noticeably, transcription factors). To identify novel htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted WW domain protein (ZK1127.9) that interacts with N-terminal fragments of htt in two-hybrid tests. A human homologue of ZK1127.9 is CA150, a transcriptional coactivator with a N-terminal insertion that contains an imperfect (Gln-Ala)(38) tract encoded by a polymorphic repeat DNA. CA150 interacted in vitro with full-length htt from lymphoblastoid cells. The expression of CA150, measured immunohistochemically, was markedly increased in human HD brain tissue compared with normal age-matched human brain tissue, and CA150 showed aggregate formation with partial colocalization to ubiquitin-positive aggregates. In 432 HD patients, the CA150 repeat length explains a small, but statistically significant, amount of the variability in the onset age. Our data suggest that abnormal expression of CA150, mediated by interaction with polyglutamine-expanded htt, may alter transcription and have a role in HD pathogenesis.