Intracerebral hemorrhage after external ventricular drain placement: an evaluation of risk factors for post-procedural hemorrhagic complications

Abstract Background The objective of this study was to evaluate and identify the risk factors for developing a new or enlarged intracranial hemorrhage (ICH) after the placement of an external ventricular drain. Methods A single center, nested case-control study of individuals who received an external ventricular drain from June 1, 2011 to June 30, 2014 was conducted at a large academic medical center. A bivariate analysis was conducted to compare those individuals who experienced a post-procedural intracranial hemorrhage to those who did not experience a new bleed. The variables identified as having a p-value less than 0.15 in the bivariate analysis were then evaluated using a multivariate logistic regression model. Results Twenty-seven of the eighty-one study participants experienced a new or enlarged intracranial hemorrhage after the placement of an external ventricular drain. Of these twenty-seven patients, 6 individuals received an antiplatelet within ninety-six hours of external ventricular drain placement (p = 0.024). The multivariate logistic regression model identified antiplatelet use within 96 h of external ventricular drain insertion as an independent risk factor for post-EVD ICH (OR 13.1; 95% CI 1.95–88.6; p = 0.008). Conclusion Compared to those study participants who did not receive an antiplatelet within 96 h of external ventricular drain placement, those participants who did receive an antiplatelet were 13.1 times more likely to exhibit a new or enlarged intracranial hemorrhage

Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy

Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [3H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [3H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of \u3e100-fold over other PDE subtypes tested. Specific [3H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident

Prefrontal cortical dysfunction during visual perspective-taking in schizophrenia

Schizophrenia is characterized by marked impairments in a broad and diverse array of social-cognitive domains. Fundamental deficits in the ability to visualize and shift to the perspectives of others and the neural networks that support this ability may contribute to many of these impairments. This study sought to investigate deficits in prefrontal brain function and connectivity in patients with schizophrenia during visual perspective-taking, and the degree to which such deficits contribute to higher-order impairments in social cognition. A total of 20 outpatients with schizophrenia and 20 age- and gender-matched healthy volunteers completed a basic, visual perspective-taking task during functional magnetic resonance imaging, along with a behavioral assessment of theory of mind after neuroimaging. Results revealed hypoactivity in the medial prefrontal (anterior cingulate) and orbitofrontal cortices during perspective-taking trials compared to control trials in schizophrenia patients relative to healthy controls. In addition, patients demonstrated significant deficits in negative connectivity between medial prefrontal and medial-temporal regions during perspective-taking, which fully mediated behavioral impairments observed in theory of mind. These findings suggest that disruptions are present in the most fundamental aspects of perspective-taking in schizophrenia, and that these disruptions impact higher-order social information processing

Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

Polθ has been recently identified as a therapeutic target in cancer but specific inhibitors are currently unavailable. Here, the authors identify small molecule inhibitors of Polθ’s polymerase activity which elicit BRCA1/2 synthetic lethality, enhance the effect of PARP inhibitors and target PARP inhibitor resistance caused by 53BP1/Shieldin pathway defects