Adverse childhood experiences, childhood relationships and associated substance use and mental health in young Europeans

Background: Adverse childhood experiences (ACEs) can increase risks of health-harming behaviours and poor health throughout life. While increases in risk may be affected by resilience resources such as supportive childhood relationships, to date few studies have explored these effects. Methods: We combined data from cross-sectional ACE studies among young adults (n = 14 661) in educational institutions in 10 European countries. Nine ACE types, childhood relationships and six health outcomes (early alcohol initiation, problem alcohol use, smoking, drug use, therapy, suicide attempt) were explored. Multivariate modelling estimated relationships between ACE counts, supportive childhood relationships and health outcomes. Results: Almost half (46.2%) of participants reported ≥1 ACE and 5.6% reported ≥4 ACEs. Risks of all outcomes increased with ACE count. In individuals with ≥4 ACEs (vs. 0 ACEs), adjusted odds ratios ranged from 2.01 (95% CIs: 1.70-2.38) for smoking to 17.68 (95% CIs: 12.93-24.17) for suicide attempt. Supportive childhood relationships were independently associated with moderating risks of smoking, problem alcohol use, therapy and suicide attempt. In those with ≥4 ACEs, adjusted proportions reporting suicide attempt reduced from 23% with low supportive childhood relationships to 13% with higher support. Equivalent reductions were 25% to 20% for therapy, 23% to 17% for problem drinking and 34% to 32% for smoking. Conclusions: ACEs are strongly associated with substance use and mental illness. Harmful relationships are moderated by resilience factors such as supportive childhood relationships. Whilst ACEs continue to affect many children, better prevention measures and interventions that enhance resilience to the life-long impacts of toxic childhood stress are required

Mechanisms of illegal aggressive behavior of women suffering from schizophrenia

Aim. To establish comparative clinical and psychopathological and social factors leading to realization of intrafamilial and extrafamilial aggressive actions of females suffering from schizophrenia when comparing the mechanisms of illegal actions. Methods. The article presents the results of the study of 91 female patients diagnosed with schizophrenia according to the International Classification of Diseases, 10th revision, (F20.0) of continuous and episodic with progressive deficit type of course, who committed aggressive socially dangerous acts and are admitted for involuntary treatment to Kazan psychiatric hospital of specialized type with intensive supervision. Two groups were identified: group 1 included 57 patients committed aggressive criminal acts in the family, and group 2 included 34 patients committed criminal acts against persons outside the family. A comparison was performed between two basic scientific concepts regarding the reasons and conditions of illegal acts committed by mentally ill persons. Statistical significance of the differences between the compared data was determined (using Fisher's angular transformation criterion and Mann-Whitney test). Results. Comparative study of the analysis concepts of illegal behavior in females suffering from schizophrenia demonstrated that the results turned out to be more detailed when using the concept of psychopathological mechanisms. So, in the productive psychotic mechanism imperative hallucinations and automatisms were noted predominantly in women from group 1 - in 59.5% (p

Association of the Epithelial-to-Mesenchymal Transition (EMT) Phenotype with Responsiveness to the p21-Activated Kinase Inhibitor, PF-3758309, in Colon Cancer Models

The p21-activated kinase (PAK) family of serine/threonine kinases, which are overexpressed in several cancer types, are critical mediators of cell survival, motility, mitosis, transcription, and translation. In the study presented here we utilized a panel of CRC cell lines to identify potential biomarkers of sensitivity or resistance that may be used to individualize therapy to the PAK inhibitor PF-03758309. We observed a wide range of proliferative responses in the CRC cell lines exposed to PF-03758309, this response was recapitulated in other phenotypic assays such as anchorage-independent growth, three dimensional tumor spheroid formation, and migration. Interestingly, we observed that cells most sensitive to PF-03758309 exhibited up regulation of genes associated with a mesenchymal phenotype (CALD1, VIM, ZEB1) and cells more resistant had an up regulation of genes associated with an epithelial phenotype (CLDN2, CDH1, CLDN3, CDH17) allowing us to derive an epithelial-to-mesenchymal transition (EMT) gene signature for this agent. We assessed the functional role of EMT-associated genes in mediating responsiveness to PF-3758309, by targeting known genes and transcriptional regulators of EMT. We observed that suppression of genes associated with the mesenchymal phenotype conferred resistance to PF-3758309, in vitro and in vivo. These results indicate that PAK inhibition is associated with a unique response phenotype in CRC and that further studies should be conducted to facilitate both patient selection and rational combination strategies with these agents