Obsessive-compulsive symptoms in psychotic disorders: longitudinal associations of symptom clusters on between- and within-subject levels

Obsessive-compulsive symptoms (OCS) are frequently reported in patients with schizophrenia and have been associated with subjective distress and higher impairment. Recent studies suggest fluctuation in co-occurring OCS and associations with the course of psychotic symptoms. Current evidence is limited by few studies with long assessments intervals and a sole focus on between-subject comparisons. The aim of this study was to specifically investigate co-variation of symptom domains over time within individuals. Patients with a psychotic disorder (n = 56) and un-affected siblings (n = 49) completed monthly assessments of clinical and subclinical symptoms over 6 months. Mixed-model multilevel analyses examined the variability and relationship between OCS and positive, negative, and depressive symptoms on the between- and within-subject level. Symptom domains were associated across subjects and assessment times, in patients and siblings, with the strongest association between OCS and (subclinical) positive symptoms. Within-subjects, substantial variability and co-variation of all symptom domains was found. Particularly, between-subject differences in positive symptoms and within-subject change in depressive symptoms predicted subsequent OCS in patients 1 months later. This is the first prospective study disaggregating between and within-subject associations between co-occurring OCS and symptom cluster of psychosis. Differences on these two levels suggest different underlying mechanisms. The association between depressive symptoms and subsequent increase/decrease of OCS within patients may have important treatment implications.status: publishe

Obsessive-compulsive symptoms in psychotic disorders: longitudinal associations of symptom clusters on between- and within-subject levels

Obsessive–compulsive symptoms (OCS) are frequently reported in patients with schizophrenia and have been associated with subjective distress and higher impairment. Recent studies suggest fluctuation in co-occurring OCS and associations with the course of psychotic symptoms. Current evidence is limited by few studies with long assessments intervals and a sole focus on between-subject comparisons. The aim of this study was to specifically investigate co-variation of symptom domains over time within individuals. Patients with a psychotic disorder (n = 56) and un-affected siblings (n = 49) completed monthly assessments of clinical and subclinical symptoms over 6 months. Mixed-model multilevel analyses examined the variability and relationship between OCS and positive, negative, and depressive symptoms on the between- and within-subject level. Symptom domains were associated across subjects and assessment times, in patients and siblings, with the strongest association between OCS and (subclinical) positive symptoms. Within-subjects, substantial variability and co-variation of all symptom domains was found. Particularly, between-subject differences in positive symptoms and within-subject change in depressive symptoms predicted subsequent OCS in patients 1 months later. This is the first prospective study disaggregating between and within-subject associations between co-occurring OCS and symptom cluster of psychosis. Differences on these two levels suggest different underlying mechanisms. The association between depressive symptoms and subsequent increase/decrease of OCS within patients may have important treatment implications

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers*

Iron- and 2-oxoglutarate-dependent dioxygenases are a diverse family of non-heme iron enzymes that catalyze various important oxidations in cells. A key structural motif of these dioxygenases is a facial triad of 2-histidines-1-carboxylate that coordinates the Fe(II) at the catalytic site. Using histone demethylase JMJD1A and DNA repair enzyme ABH2 as examples, we show that this family of dioxygenases is highly sensitive to inhibition by carcinogenic nickel ions. We find that, with iron, the 50% inhibitory concentrations of nickel (IC50 [Ni(II)]) are 25 μm for JMJD1A and 7.5 μm for ABH2. Without iron, JMJD1A is 10 times more sensitive to nickel inhibition with an IC50 [Ni(II)] of 2.5 μm, and approximately one molecule of Ni(II) inhibits one molecule of JMJD1A, suggesting that nickel causes inhibition by replacing the iron. Furthermore, nickel-bound JMJD1A is not reactivated by excessive iron even up to a 2 mm concentration. Using x-ray absorption spectroscopy, we demonstrate that nickel binds to the same site in ABH2 as iron, and replacement of the iron by nickel does not prevent the binding of the cofactor 2-oxoglutarate. Finally, we show that nickel ions target and inhibit JMJD1A in intact cells, and disruption of the iron-binding site decreases binding of nickel ions to ABH2 in intact cells. Together, our results reveal that the members of this dioxygenase family are specific targets for nickel ions in cells. Inhibition of these dioxygenases by nickel is likely to have widespread impacts on cells (e.g. impaired epigenetic programs and DNA repair) and may eventually lead to cancer development