The findings provide additional support for the hypothesis that obsessive-compulsive symptoms are related to basal ganglia dysfunction.

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genomic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study (N = 891 individuals at baseline), an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. To provide an initial characterization of the PsyCourse study sample, we compare two broad diagnostic groups defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) classification system, that is, predominantly affective (n = 367 individuals) versus predominantly psychotic disorders (n = 524 individuals). Depressive, manic, and psychotic symptoms as well as global functioning over time were contrasted using linear mixed models. Furthermore, we explored the effects of polygenic risk scores for schizophrenia on diagnostic group membership and addressed their effects on nonparticipation in follow-up visits. While phenotypic results confirmed expected differences in current psychotic symptoms and global functioning, both manic and depressive symptoms did not vary between both groups after correction for multiple testing. Polygenic risk scores for schizophrenia significantly explained part of the variability of diagnostic group. The PsyCourse study presents a unique resource to research the complex relationships of psychopathology and biology in severe mental disorders not confined to traditional diagnostic boundaries and is open for collaborations.

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Identifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle illness trajectories, and investigate genetic associations. OBJECTIVE To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement. DESIGN, SETTING, AND PARTICIPANTS This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites.

Various parameters which may be useful in quantification of drug transit from blood into CSF and vice versa after a short duration infusion are compared here by recalculating previously published data from our group. Due to the slower entry into and elimination from the CSF compartment as compared to the central compartment, the ratio of drug concentrations in CSF and serum sampled at the same time increase with time after an infusion. Therefore, concentration quotients of simultaneously drawn blood and CSF are inadequate to characterise CSF penetration. The ratio of the areas under the concentration-time curves in a body fluid and serum (AUCbody fluid/AUCs) is an established measure to quantify overall penetration from the central into a peripheral compartment. AUCCSF/AUCs is closely correlated with the quotient of the maximum CSF and serum concentrations (CmaxCSF/CmaxS) (rs = 0.87, n = 42, P < 0.001) and with the rate constant of distribution in CSF (CLin/VCSF) (rs = 0.80, n = 42, P < 0.001). Since CmaxCSF/CmaxS depends on the mode of drug administration, it is suggested that AUCCSF/AUCs be used to quantify overall drug transit into CSF. CLin/VCSF is of use when CSF can only be sampled once, or when the velocity of the transit of a drug into CSF is to be described. The CSF exit rate constant (CLout/VCSF) characterises elimination from CSF independent of the elimination from serum and may be applied to estimate the formation rate of CSF; in the present study it averaged 20 ml/h.

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 ± 23.7 μg/ml. A CSF maximum (C maxCSF) of 0.63 ± 0.50 μg/ml (mean ± standard deviation) was observed 4.1 ± 2.6 h after the end of the infusion. CmaxCSF and the area under the curve for CSF (AUCCSF) depended on the AUC for serum (AUCS), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at β phase [t 1/2β] of 7.36 ± 2.89 h in CSF versus t 1/2βof 1.69 ± 0.60 h in serum). The AUCCSF/AUCS ratio for meropenem, as a measure of overall CSF penetration, was 0.047 ± 0.022. The AUCCSF/AUCS ratio for meropenem was similar to that for other β-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.

The paper complements work on the re-scaling of resource governance by developing a theoretical understanding based on the distributional theory of institutional change, and by examining the case of water governance in Portugal. Different from the reactions of other European Member States to the Water Framework Directive, the central water authority and multi-sectoral deconcentrated administrations lost competencies in favour of new water administrations. The level of water governance shifted from administrative districts to hydrographic regions. Significant players in this process were the central state and the Minister of the Environment. Our explanation considers time preferences, mental models, credibility and transaction and transition costs of governance, which affected the timing and content of the reform, and the paper compares the situation to the rest of Europe.re-scaling, water governance, Portugal, institutional change,