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Psychotic patients with a lifetime history of cannabis use generally show better cognitive functioning than other psychotic patients. Some authors suggest that cannabis-using patients may have been less cognitively impaired and less socially withdrawn in their premorbid life. Using a dataset comprising 948 patients with first-episode psychosis (FEP) and 1313 population controls across 6 countries, we examined the extent to which IQ and both early academic (Academic Factor [AF]) and social adjustment (Social Factor [SF]) are related to the lifetime frequency of cannabis use in both patients and controls. We expected a higher IQ and a better premorbid social adjustment in psychotic patients who had ever used cannabis compared to patients without any history of use. We did not expect such differences in controls. In both patients and controls, IQ was 3 points higher among occasional-users than in never-users (mean difference [Mdiff] = 2.9, 95% CI = [1.2, 4.7]). Both cases and control daily-users had lower AF compared to occasional (Mdiff = −0.3, 95% CI = [−0.5; −0.2]) and never-users (Mdiff = −0.4, 95% CI = [−0.6; −0.2]). Finally, patient occasional (Mdiff = 0.3, 95% CI = [0.1; 0.5]) and daily-users (Mdiff = 0.4, 95% CI = [0.2; 0.6]) had better SF than their never-using counterparts. This difference was not present in controls (Fgroup*frequency(2, 2205) = 4.995, P = .007). Our findings suggest that the better premorbid social functioning of FEP with a history of cannabis use may have contributed to their likelihood to begin using cannabis, exposing them to its reported risk-increasing effects for Psychotic Disorders.

BACKGROUND: Evidence has accumulated that implicates childhood trauma in the aetiology of psychosis, but our understanding of the putative psychological processes and mechanisms through which childhood trauma impacts on individuals and contributes to the development of psychosis remains limited. We aimed to investigate whether stress sensitivity and threat anticipation underlie the association between childhood abuse and psychosis. METHOD: We used the Experience Sampling Method to measure stress, threat anticipation, negative affect, and psychotic experiences in 50 first-episode psychosis (FEP) patients, 44 At-Risk Mental State (ARMS) participants, and 52 controls. Childhood abuse was assessed using the Childhood Trauma Questionnaire. RESULTS: Associations of minor socio-environmental stress in daily life with negative affect and psychotic experiences were modified by sexual abuse and group (all p FWE < 0.05). While there was strong evidence that these associations were greater in FEP exposed to high levels of sexual abuse, and some evidence of greater associations in ARMS exposed to high levels of sexual abuse, controls exposed to high levels of sexual abuse were more resilient and reported less intense negative emotional reactions to socio-environmental stress. A similar pattern was evident for threat anticipation. CONCLUSIONS: Elevated sensitivity and lack of resilience to socio-environmental stress and enhanced threat anticipation in daily life may be important psychological processes underlying the association between childhood sexual abuse and psychosis. ispartof: Psychological Medicine vol:46 issue:13 pages:2799-2813 ispartof: location:England status: published

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype. © 2014 The Author.

Topotecan is a substrate of the ATP-binding cassette transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). To define the role of these transporters in topotecan penetration into the ventricular cerebrospinal fluid (vCSF) and brain parenchymal extracellular fluid (ECF) compartments, we performed intracerebral microdialysis on transporter-deficient mice after an intravenous dose of topotecan (4 mg/kg). vCSF penetration of unbound topotecan lactone was measured as the ratio of vCSF-to-plasma area under the concentration-time curves. The mean +/- SD ratios for wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice were 3.07 +/- 0.09, 2.57 +/- 0.17, 1.63 +/- 0.12, and 0.86 +/- 0.05, respectively. In contrast, the ECF-to-plasma ratios for wild-type, Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice were 0.36 +/- 0.06, 0.42 +/- 0.06, and 0.88 +/- 0.07. Topotecan lactone was below detectable limits in the ECF of Mdr1a/b(-/-) mice. When gefitinib (200 mg/kg) was preadministered to inhibit Bcrp1 and P-gp, the vCSF-to-plasma ratio decreased to 1.29 +/- 0.09 in wild-type mice and increased to 1.13 +/- 0.13 in Mdr1a/b(-/-)Bcrp1(-/-) mice, whereas the ECF-to-plasma ratio increased to 0.74 +/- 0.14 in wild-type and 1.07 +/- 0.03 in Mdr1a/b(-/-)Bcrp1(-/-) mice. Preferential active transport of topotecan lactone over topotecan carboxylate was shown in vivo by vCSF lactone-to-carboxylate area under the curve ratios for wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice of 5.69 +/- 0.83, 3.85 +/- 0.64, 3.61 +/- 0.46, and 0.78 +/- 0.19, respectively. Our results suggest that Bcrp1 and P-gp transport topotecan into vCSF and out of brain parenchyma through the blood-brain barrier. These findings may help to improve pharmacologic strategies to treat brain tumors.

A monoclonal antibody specific for thymine glycol (TG) in irradiated or OsO4-treated DNA was obtained by immunizing with thymidine glycol monophosphate (TMP-glycol) conjugated to bovine serum albumin by a carbodiimide procedure. Screening by dot-immunobinding and enzyme-linked immunosorbant assay (ELISA) procedures gave eight clones that bound OsO4- treated DNA. One of them, 2.6F.6B.6C, an IgG2a kappa, was characterized further. Hapten inhibition studies with OsO4-treated DNA showed that the antibody was specific for TMP-glycol. Among the various inhibitors tested, inhibition was in the order TMP-glycol greater than 5,6-dihydrothymidine phosphate greater than TMP greater than thymidine glycol greater than TG. Inhibition by 5,6-dihydrothymidine, thymidine, thymine, AMP, and CMP was negligible. In OsO4-treated DNA, as few as 0.5 TG per 10,000 bp were detectable by direct ELISA. Inhibition assays could detect as few as 1.5 TG per 10,000 bp. The antibody was equally reactive with native or denatured DNA containing TG. Among the X-irradiated homopolymers dC, dA, dG, and dT, only dT reacted with the antibody. Using an ELISA, the antibody could detect damage in irradiated DNA at the level of 20 Gy. Thus the antibody is of potential use in assays for DNA damage caused by X rays or other agents that damage DNA by free radical interactions.