Thyroid disrupting effects of low-dose dibenzothiophene and cadmium in single or concurrent exposure: New evidence from a translational zebrafish model.

Thyroid hormones (THs) are major regulators of biological processes essential for correct development and energy homeostasis. Although thyroid disruptors can deeply affect human health, the impact of exogenous chemicals and in particular mixture of chemicals on different aspects of thyroid development and metabolism is not yet fully understood. In this study we have used the highly versatile zebrafish model to assess the thyroid axis disrupting effects of cadmium (Cd) and dibenzothiophene (DBT), two environmental endocrine disruptors found to be significantly correlated in epidemiological co-exposure studies. Zebrafish embryos (5hpf) were exposed to low concentrations of Cd (from 0.05 to 2 µM) and DBT (from 0.05 to 1 µM) and to mixtures of them. A multilevel assessment of the pollutant effects has been obtained by combining in vivo morphological analyses allowed by the use of transgenic fluorescent lines with liquid chromatography mass spectrometry determination of TH levels and quantification of the expression levels of key genes involved in the Hypothalamic-Pituitary-Thyroid Axis (HPTA) and TH metabolism. Our results underscore for the first time an important synergistic toxic effect of these pollutants on embryonic development and thyroid morphology highlighting differences in the mechanisms through which they can adversely impact on multiple physiological processes of the HPTA and TH disposal influencing also heart geometry and function.

Long-term validity of the At Risk Mental State (ARMS) for predicting psychotic and non-psychotic mental disorders.

BACKGROUND: The long-term clinical validity of the At Risk Mental State (ARMS) for the prediction of non-psychotic mental disorders is unknown. METHODS: Clinical register-based cohort study including all non-psychotic individuals assessed by the Outreach And Support in South London (OASIS) service (2002-2015). The primary outcome was risk of developing any mental disorder (psychotic or non-psychotic). Analyses included Cox proportional hazard models, Kaplan-Meier survival/failure function and C statistics. RESULTS: A total of 710 subjects were included. A total of 411 subjects were at risk (ARMS+) and 299 not at risk (ARMS-). Relative to ARMS-, the ARMS+ was associated with an increased risk (HR=4.825) of developing psychotic disorders, and a reduced risk (HR=0.545) of developing non-psychotic disorders (mainly personality disorders). At 6-year, the ARMS designation retained high sensitivity (0.873) but only modest specificity (0.456) for the prediction of psychosis onset (AUC 0.68). The brief and limited intermittent psychotic symptoms (BLIPS) subgroup had a higher risk of developing psychosis, and a lower risk of developing non-psychotic disorders as compared to the attenuated psychotic symptoms (APS) subgroup (P<0.001). CONCLUSIONS: In the long-term, the ARMS specifically predicts the onset of psychotic disorders, with modest accuracy, but not of non-psychotic disorders. Individuals meeting BLIPS criteria have distinct clinical outcomes. SIGNIFICANT OUTCOMES: In the long-term, the ARMS designation is still significantly associated with an increased risk of developing psychotic disorders but its prognostic accuracy is only modest. There is no evidence that the ARMS is associated with an increased risk of developing non-psychotic mental disorders. The BLIPS subgroup at lower risk of developing non-psychotic disorders compared to the APS subgroup. LIMITATIONS: While incident diagnoses employed in this study are high in ecological validity they have not been subjected to formal validation with research-based criteria.

Towards a Standard Psychometric Diagnostic Interview for Subjects at Ultra High Risk of Psychosis: CAARMS versus SIPS.

Background. Several psychometric instruments are available for the diagnostic interview of subjects at ultra high risk (UHR) of psychosis. Their diagnostic comparability is unknown. Methods. All referrals to the OASIS (London) or CAMEO (Cambridgeshire) UHR services from May 13 to Dec 14 were interviewed for a UHR state using both the CAARMS 12/2006 and the SIPS 5.0. Percent overall agreement, kappa, the McNemar-Bowker χ (2) test, equipercentile methods, and residual analyses were used to investigate diagnostic outcomes and symptoms severity or frequency. A conversion algorithm (CONVERT) was validated in an independent UHR sample from the Seoul Youth Clinic (Seoul). Results. There was overall substantial CAARMS-versus-SIPS agreement in the identification of UHR subjects (n = 212, percent overall agreement = 86%; kappa = 0.781, 95% CI from 0.684 to 0.878; McNemar-Bowker test = 0.069), with the exception of the brief limited intermittent psychotic symptoms (BLIPS) subgroup. Equipercentile-linking table linked symptoms severity and frequency across the CAARMS and SIPS. The conversion algorithm was validated in 93 UHR subjects, showing excellent diagnostic accuracy (CAARMS to SIPS: ROC area 0.929; SIPS to CAARMS: ROC area 0.903). Conclusions. This study provides initial comparability data between CAARMS and SIPS and will inform ongoing multicentre studies and clinical guidelines for the UHR psychometric diagnostic interview.

Neurobiological Models of Self-Disorders in Early Schizophrenia.

Self-disorders (SDs) (from the German Ichstörungen) are alterations of the first-person perspective, long associated with schizophrenia, particularly in early phases. Although psychopathological features of SDs continue to be studied, their neurobiological underpinnings are unknown. This makes it difficult to integrate SDs into contemporary models of psychosis. The present review aims to address this issue, starting from an historical excursus revealing an interconnection between neuroscientific models and the origin of the psychopathological concept of SDs. Subsequently, the more recent neurobiological models related to SDs are discussed, particularly with respect to the onset of schizophrenia.

The bioavailability of orphenadrine hydrochloride after intramuscular and oral administration.

The bioavailability of orphenadrine hydrochloride after a single intramuscular injection was compared to that after a single oral dose by following serial plasma concentration estimations of the unchanged drug. Eight subjects received 40 mg orphenadrine HCl intramuscularly and 50 mg orally on separate occasions 1 week apart. The bioavailability of orphenadrine from the intramuscular dosage form proved to be equal to or even greater than that from the tablet. The first hour plasma concentrations after intramuscular doses were significantly higher than those after oral doses, supporting the clinical use of the intramuscular route in those indications where rapid effects of the drug are required.