Metabonomic Investigation of Liver Profiles of Nonpolar Metabolites Obtained from Alcohol-Dosed Rats and Mice Using High Mass Accuracy MSn Analysis

Alcoholism is a complex disorder that, in man, appears to be genetically influenced, although the underlying genes and molecular pathways are not completely known. Here the intragastric alcohol feeding model in rodents was used together with high mass accuracy LC/MS(n) analysis to assess the metabonomic changes in nonpolar metabolite profiles for livers from control and alcohol treated rats and mice. Ion signals with a peak area variance of less than 30% (based on repeat analysis of a pooled quality control sample analysed throughout the batch) were submitted to multivariate statistical analysis (using principal components analysis, PCA). PCA revealed robust differences between profiles from control and alcohol-treated animals from both species. The major metabolites seen to differ between control and alcohol-treated animals were identified using high accuracy MS(n) data and verified using external search engines (http://www.lipidmaps.org; http://www.hmdb.ca; http://www.genome.jp/kegg/) and authentic standards. The main metabolite classes to show major changes in the alcoholic liver-derived samples were fatty acyls, fatty acid ethyl esters, glycerolipids and phosphatidylethanol homologues. Significant metabolites that were up-regulated by alcohol treatment in both rat and mouse livers included fatty acyls, metabolites such as octadecatrienoic acid and eicosapentaenoic acid, a number of fatty acid ethyl esters such as ethyl arachidonate, ethyl docosahexaenoic acid, ethyl linoleate and ethyl oleate and phosphatidylethanol (PEth) homologues (predominantly PEth 18:0/18:2 and PEth 16:0/18:2; PEth homologues are currently considered as potential biomarkers for harmful and prolonged alcohol consumption in man). A number of glycerophospholipids resulted in both up-regulation (m/z 903.7436 [M+H](+) corresponding to a triglyceride) and down-regulation (m/z 667.5296 [M+H](+) corresponding to a diglyceride). Metabolite profiles were broadly similar in both mouse and rat models. However, there were a number of significant differences in the alcohol-treated group particularly in the marked down-regulation of retinol and free cholesterol in the mouse compared to the rat. Unique markers for alcohol treatment included ethyl docosahexaenoic acid. Metabolites were identified with high confidence using predominantly negative ion MS(n) data for the fatty acyl components to match to www.lipidmaps.org MS and MS/MS databases; interpreting positive ion data needed to take into account possible adduct ions which may confound the identification of other lipid classes. The observed changes in lipid profiles were consistent with alcohol induced liver injury in humans

Development and validation of the schedule for the assessment of insight in eating disorders (SAI-ED)

This study examined the reliability, validity and internal structure of the newly developed, interview-based Schedule for the Assessment of Insight in Eating Disorders (SAI-ED) and the relationships of insight with demographic and clinical characteristics in EDs. Ninety-four female patients – 44 with anorexia nervosa (AN) and 50 with bulimia nervosa (BN) – were assessed with SAI-ED. The Brown Assessment of Beliefs Scale was used to evaluate convergent validity of SAI-ED. Hierarchical cluster analysis and multidimensional scaling were used to identify insight components and assess their inter-relationships. The final 8-item SAI-ED demonstrated good psychometric properties. Inter-rater and test-retest reliabilities were high. Three subscales of SAI-ED were identified which measure major insight components: awareness of illness, awareness of symptoms, and treatment engagement. Patients with AN had significant lower score on SAI-ED than patients with BN. Impaired insight was associated with: (a) lower current and lowest lifetime BMI and more severe dietary restrain in AN, (b) illness duration, severity of overall ED symptoms, body-related concerns and obsessionality in BN. Insight is a multidimensional construct in EDs associated with different clinical aspects in AN and BN. The SAI-ED is a valid and reliable tool for the assessment of insight in EDs patients

Levels of State and Trait Anxiety in Patients Referred to Ophthalmology by Primary Care Clinicians: A Cross Sectional Study

Purpose There is a high level of over-referral from primary eye care leading to significant numbers of people without ocular pathology (false positives) being referred to secondary eye care. The present study used a psychometric instrument to determine whether there is a psychological burden on patients due to referral to secondary eye care, and used Rasch analysis to convert the data from an ordinal to an interval scale. Design Cross sectional study. Participants and Controls 322 participants and 80 control participants. Methods State (i.e. current) and trait (i.e. propensity to) anxiety were measured in a group of patients referred to a hospital eye department in the UK and in a control group who have had a sight test but were not referred. Response category analysis plus infit and outfit Rasch statistics and person separation indices were used to determine the usefulness of individual items and the response categories. Principal components analysis was used to determine dimensionality. Main Outcome Measure Levels of state and trait anxiety measured using the State-Trait Anxiety Inventory. Results State anxiety scores were significantly higher in the patients referred to secondary eye care than the controls (p0.1). Rasch analysis highlighted that the questionnaire results needed to be split into “anxiety-absent” and “anxiety-present” items for both state and trait anxiety, but both subscales showed the same profile of results between patients and controls. Conclusions State anxiety was shown to be higher in patients referred to secondary eye care than the controls, and at similar levels to people with moderate to high perceived susceptibility to breast cancer. This suggests that referral from primary to secondary eye care can result in a significant psychological burden on some patients

U-Shaped Relation between Plasma Oxytocin Levels and Behavior in the Trust Game

10.1371/journal.pone.0051095PLoS ONE712

Association of ATP6V1B2 rs1106634 with lifetime risk of depression and hippocampal neurocognitive deficits: possible novel mechanisms in the etiopathology of depression

Current understanding and treatment of depression is limited to the monoaminergic theory with little knowledge of the involvement of other cellular processes. Genome-wide association studies, however, implicate several novel single-nucleotide polymorphisms with weak but replicable effects and unclarified mechanisms. We investigated the effect of rs1106634 of the ATPV1B2 gene encoding the vacuolar H+ATPase on lifetime and current depression and the possible mediating role of neuroticism by logistic and linear regression in a white European general sample of 2226 subjects. Association of rs1106634 with performance on frontal (Stockings of Cambridge (SOC)) and hippocampal-dependent (paired associates learning (PAL)) cognitive tasks was investigated in multivariate general linear models in a smaller subsample. The ATP6V1B2 rs1106634 A allele had a significant effect on lifetime but not on current depression. The effect of the A allele on lifetime depression was not mediated by neuroticism. The A allele influenced performance on the PAL but not on the SOC test. We conclude that the effects of variation in the vacuolar ATPase may point to a new molecular mechanism that influences the long-term development of depression. This mechanism may involve dysfunction specifically in hippocampal circuitry and cognitive impairment that characterizes recurrent and chronic depression

Staging of schizophrenia with the use of PANSS: an international multi-center study

Introduction: A specific clinically relevant staging model for schizophrenia has not yet been developed. The aim of the current study was to evaluate the factor structure of the PANSS and develop such a staging method. Methods: Twenty-nine centers from 25 countries contributed 2358 patients aged 37.21 ± 11.87 years with schizophrenia. Analysis of covariance, Exploratory Factor Analysis, Discriminant Function Analysis, and inspection of resultant plots were performed. Results: Exploratory Factor Analysis returned 5 factors explaining 59% of the variance (positive, negative, excitement/hostility, depression/anxiety, and neurocognition). The staging model included 4 main stages with substages that were predominantly characterized by a single domain of symptoms (stage 1: positive; stages 2a and 2b: excitement/hostility; stage 3a and 3b: depression/anxiety; stage 4a and 4b: neurocognition). There were no differences between sexes. The Discriminant Function Analysis developed an algorithm that correctly classified >85% of patients. Discussion: This study elaborates a 5-factor solution and a clinical staging method for patients with schizophrenia. It is the largest study to address these issues among patients who are more likely to remain affiliated with mental health services for prolonged periods of time

Disentangling sex differences in PTSD risk factors

Despite extensive research on sex/gender differences in posttraumatic stress disorder (PTSD), underlying mechanisms are still not fully understood. Here we present a systematic overview of three sex/gender-related risk pathways. We assessed 16 risk factors as well as 3 month PTSD severity in a prospective cohort study (n = 2924) of acutely traumatized individuals and investigated potential mediators in the pathway between sex assigned at birth and PTSD severity using multiple mediation analysis with regularization. Six risk factors were more prevalent/severe in women, and none was more pronounced in men. Analyses showed that acute stress disorder, neuroticism, lifetime sexual assault exposure, anxiety sensitivity and pretrauma anxiety symptoms fully mediated and uniquely contributed to the relationship between sex assigned at birth and PTSD severity. Our results demonstrate different risk mechanisms for women and men. Such knowledge can inform targeted interventions. Our systematic approach to differential risk pathways can be transferred to other mental disorders to guide sex- and gender-sensitive mental health research

Prior differences in previous trauma exposure primarily drive the observed racial/ethnic differences in posttrauma depression and anxiety following a recent trauma

BACKGROUND: Racial and ethnic groups in the USA differ in the prevalence of posttraumatic stress disorder (PTSD). Recent research however has not observed consistent racial/ethnic differences in posttraumatic stress in the early aftermath of trauma, suggesting that such differences in chronic PTSD rates may be related to differences in recovery over time. METHODS: As part of the multisite, longitudinal AURORA study, we investigated racial/ethnic differences in PTSD and related outcomes within 3 months after trauma. Participants (n = 930) were recruited from emergency departments across the USA and provided periodic (2 weeks, 8 weeks, and 3 months after trauma) self-report assessments of PTSD, depression, dissociation, anxiety, and resilience. Linear models were completed to investigate racial/ethnic differences in posttraumatic dysfunction with subsequent follow-up models assessing potential effects of prior life stressors. RESULTS: Racial/ethnic groups did not differ in symptoms over time; however, Black participants showed reduced posttraumatic depression and anxiety symptoms overall compared to Hispanic participants and White participants. Racial/ethnic differences were not attenuated after accounting for differences in sociodemographic factors. However, racial/ethnic differences in depression and anxiety were no longer significant after accounting for greater prior trauma exposure and childhood emotional abuse in White participants. CONCLUSIONS: The present findings suggest prior differences in previous trauma exposure partially mediate the observed racial/ethnic differences in posttraumatic depression and anxiety symptoms following a recent trauma. Our findings further demonstrate that racial/ethnic groups show similar rates of symptom recovery over time. Future work utilizing longer time-scale data is needed to elucidate potential racial/ethnic differences in long-term symptom trajectories

Response time variability and response inhibition predict affective problems in adolescent girls, not in boys: the TRAILS study

The present study examines the relationship between neurocognitive functioning and affective problems through adolescence, in a cross-sectional and longitudinal perspective. Baseline response speed, response speed variability, response inhibition, attentional flexibility and working memory were assessed in a cohort of 2,179 adolescents (age 10–12 years) from the TRacking Adolescents’ Individual Lives Survey (TRAILS). Affective problems were measured with the DSM-oriented Affective Problems scale of the Youth Self Report at wave 1 (baseline assessment), wave 2 (after 2.5 years) and wave 3 (after 5 years). Cross-sectionally, baseline response speed, response time variability, response inhibition and working memory were associated with baseline affective problems in girls, but not in boys. Longitudinally, enhanced response time variability predicted affective problems after 2.5 and 5 years in girls, but not in boys. Decreased response inhibition predicted affective problems after 5 years follow-up in girls, and again not in boys. The results are discussed in light of recent insights in gender differences in adolescence and state–trait issues in depression