Bioaccumulation and behavioral effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in perinatally exposed mice

Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants that have become pervasive environmental contaminants and may contribute to adverse health outcomes. We evaluated in mice the developmental neurotoxicity of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), one of the most abundant PBDE congeners detected in animal and human tissues. Female C57BL/6J mice were exposed to daily doses of 0, 0.03, 0.1 or 1 mg/kg beginning 4 weeks prior to conception, continuing through gestation and lactation, and ending at weaning on postnatal day (PND) 21. Levels of BDE-47 in blood, brain, liver and adipose tissues of dams were markedly increased after 4 weeks of exposure, around the time of mating, and continued to increase through the time of parturition. Blood levels of BDE-47 in the dosed dams were within the range reported in humans. BDE-47 tissue levels in the dams decreased between parturition and weaning, possibly reflecting mobilization during lactation. Brain BDE-47 levels in the offspring at PND 1 approached those of the dams at parturition. Perinatal exposure to BDE-47 resulted in significant dose dependent growth retardation, slower motor performance in several behavioral tests, and mice exposed to 1 mg/kg/day BDE-47 showed altered performance in the Morris water maze. There were no differences between groups in the numbers of pyramidal neurons in hippocampus CA1. These results document accumulation of BDE-47 in several organ systems following exposure to low-levels of BDE-47, and provide evidence that such exposure is associated with early behavioral deficits in exposed neonates.     

Early adolescent executive functioning, intrauterine exposures and own drug use

Individual differences in adolescents' executive functioning are often attributed either to intrauterine substance exposure or to adolescents' own substance use, but both predictors typically have not been evaluated simultaneously in the same study. This prospective study evaluated whether intrauterine drug exposures, the adolescents' own substance use, and/or their potential interactions are related to poorer executive functioning after controlling for important contextual variables. Analyses were based on data collected on a sample of 137 predominantly African-American/African Caribbean adolescents from low-income urban backgrounds who were followed since their term birth. Intrauterine substance exposures (cocaine, marijuana, alcohol, and cigarettes) and adolescents' substance use were documented using a combination of biological assays and maternal and adolescent self-report. At 12-14 years of age, examiners masked to intrauterine exposures and current substance use assessed the adolescents using the Delis-Kaplan Executive Function System (D-KEFS), an age-referenced instrument evaluating multiple dimensions of executive functioning (EF).Results of covariate-controlled analyses in this study suggest that when intrauterine substance exposures and young adolescents' substance use variables were in the same analysis models, subtle differences in specific EF outcomes were identifiable in this non-referred sample. While further study with larger samples is indicated, these findings suggest that 1) research on adolescent substance use and intrauterine exposure research should evaluate both predictors simultaneously, 2) subtle neurocognitive effects associated with specific intrauterine drug exposures can be identified during early adolescence, and 3) intrauterine substance exposure effects may differ from those associated with adolescents' own drug use.     

Caregiver and self-report of mental health symptoms in 9-year old children with prenatal cocaine exposure

Objective

To assess the effect of prenatal cocaine exposure on mental health symptoms in 9-year old children controlling for potential confounders.

Methods

332 children (170 prenatally cocaine-exposed (PCE), 162 non cocaine-exposed (NCE) were assessed using self (Dominic Interactive; DI) and caregiver report (Child Behavior Checklist; CBCL).

Results

Higher levels of PCE were associated with caregiver report of clinically elevated aggressive and delinquent behavior. With each increased unit of PCE, children were 1.3 times more likely to be rated as aggressive (OR = 1.30, 95% CI: 1.02-1.67, p < 0.04). For each increased unit of PCE, girls were 2 times more likely to be rated as having delinquent behavior (OR = 2.08, 95% CI: 1.46-2.96, p < 0.0001). PCE status was also associated with increased odds of delinquent behavior (OR = 2.41; 95% CI: 1.16-4.97, p = 0.02), primarily due to the increased risk among girls with PCE. While girls with PCE status were 7 times more likely than NCE girls to have delinquent behaviors (OR = 7.42; 95% CI: 2.03-27.11, p < 0.002) boys with PCE did not demonstrate increased risk (OR = 0.98; 95% CI: 0.36-2.65, p > 0.97). Foster or adoptive parents were more likely to rate their PCE children as having more thought problems, inattention, delinquent behavior, aggression, externalizing and overall problems (p < 0.05) than biologic mothers or relative caregivers. Higher 2nd trimester tobacco exposure was associated with increased odds of caregiver reported anxiety (OR = 1.73; 95% CI 1.06-2.81, p < 0.03) and marijuana exposure increased the odds of thought problems (OR = 1.68; 95% CI 1.01-2.79, p < 0.05). Children with PCE self-reported fewer symptoms of oppositional defiant disorder (ODD) compared to NCE children (OR = 0.44, 95% CI: 0.21-0.92, p < 0.03). Greater tobacco exposure was associated with increased odds of child reported ODD (OR = 1.24; 95% CI 1.03-1.78, p < 0.03).

Conclusion

Higher PCE was associated with disruptive behaviors including aggression and delinquent behavior among girls by caregiver report, but not child report. These findings highlight the need for early behavioral assessment using multiple informants in multi-risk children.     

Epistatic interaction of CREB1 and KCNJ6 on rumination and negative emotionality

G protein-activated K+ channel 2 (GIRK2) and cAMP-response element binding protein (CREB1) are involved in synaptic plasticity and their genes have been implicated depression and memory processing. Excessive rumination is a core cognitive feature of depression which is also present in remission. High scores on the Ruminative Response Scale (RRS) questionnaire are predictive of relapse and recurrence. Since rumination involves memory, we tested the hypothesis that variation in the genes encoding GIRK2 (KCNJ6) and CREB1 mechanisms would influence RRS scores. GIRK2 and CREB1 polymorphisms were studied in two independent samples (n = 651 and n = 1174) from the general population. Strongly significant interaction between the TT genotype of rs2070995 (located in KCNJ6) and the GG genotype of rs2253206 (located in CREB1) on RRS were found in both samples. These results were validated in an independent third sample (n = 565; individuals with personality disorders) showing significant main effect of the variants mentioned as well as significant interaction on a categorical diagnosis of Cluster C personality disorder (obsessional-compulsive, avoidant and dependent) in which rumination is a prominent feature. Our results suggest that genetic epistasis in post-receptor signaling pathways in memory systems may have relevance for depression and its treatment.     

Shared changes in gene expression in frontal cortex of four genetically modified mouse models of depression

This study aimed to identify whether genetic manipulation of four systems implicated in the pathogenesis of depression converge on shared molecular processes underpinning depression-like behaviour in mice. Altered 5HT function was modelled using the 5-HT transporter knock out mouse, impaired glucocorticoid receptor (GR) function using an antisense-induced knock down mouse, disrupted glutamate function using a heterozygous KO of the vesicular glutamate transporter 1 gene, and impaired cannabinoid signalling using the cannabinoid 1 receptor KO mouse. All 4 four genetically modified mice were previously shown to show exaggerated helpless behaviour compared to wild-type controls and variable degrees of anxiety and anhedonic behaviour. mRNA was extracted from frontal cortex and hybridised to Illumina microarrays. Combined contrast analysis was used to identify genes showing different patterns of up- and down-regulation across the 4 models. 1823 genes were differentially regulated. They were over-represented in gene ontology categories of metabolism, protein handling and synapse. In each model compared to wild-type mice of the same genetic background, a number of genes showed increased expression changes of > 10%, other genes showed decreases in each model. Most of the genes showed mixed effects. Several previous array findings were replicated. The results point to cellular stress and changes in post-synaptic remodelling as final common mechanisms of depression and resilience.     

The EU paediatric regulation:: Effects on paediatric psychopharmacology in Europe

Child and adolescent psychiatry is a relatively young field and the recognition, classification, and treatment of disorders in children and adolescents lag behind those in adults. In recent years there is an increasing awareness of the differences between children and adults in psychopathology and pharmacology. Related to this new paediatric regulations have been introduced. This article reviews the regulatory and legislative measures that were adopted in the EU in 2007 and the subsequent impact of these measures on the field of paediatric psychopharmacology.The consequences of the paediatric regulation in the EU are reflected in several domains: regulatory, research aimed at drug development and clinical practices. In the regulatory domain, the consequences include: new paediatric indications, inclusion of special (class) warnings, specification of dose regimens, and information on safety specific to children and adolescents, and development of new medicinal formulations.The paediatric regulation leads to timely development of paediatric friendly formulations and better quality of the clinical evidence. In clinical practices, an increased awareness of the uniqueness of paediatric pharmacology is emerging among medical professionals, and subsequent improvement of medical care (i.e. correct doses, appropriate formulation, monitoring for expected adverse events). In addition, clinical guidelines will have to be revised more frequently in order to integrate the recently acquired knowledge.The new regulations stimulate transparency and discussions between academia, pharmaceutical industry, and regulators. The purpose is to optimize clinical research and obtain evidence for paediatric psychopharmacology, thereby providing adequate support for treatment.     

Costs of illness and care in Parkinson's Disease: An evaluation in six countries

We investigated the costs of Parkinson's Disease (PD) in 486 patients based on a survey conducted in six countries. Economic data were collected over a 6-month period and presented from the societal perspective. The total mean costs per patient ranged from EUR 2620 to EUR 9820. Direct costs totalled about 60% to 70% and indirect costs about 30% to 40% of total costs. The proportions of costs components of PD vary notably; variations were due to differences in country-specific health system characteristics, macro economic conditions, as well as frequencies of resource use and price differences. However, inpatient care, long-term care and medication were identified as the major expenditures in the investigated countries.     

Amisulpride vs. fluoxetine treatment of Chronic Fatigue Syndrome: A pilot study

Different pharmacologic agents have been evaluated in the treatment of Chronic Fatigue Syndrome (CFS), albeit with moderate efficacy. Among the compounds thought to present with potential to be efficacious in CFS patients stands out low-dose amisulpride, a substituted benzamide that has been shown to be an useful treatment for conditions which exhibit some overlap with CFS such as dysthymia and somatoform disorders. We thus recruited forty non-depressed CFS patients that were randomized to receive either amisulpride 25 mg bid, or fluoxetine 20 mg uid; all subjects were un-blinded to the treatment regimen. At the time of enrollment in the study and after twelve weeks of treatment, enrolled subjects completed the Krupp Fatigue Severity Scale, the Hospital Anxiety and Depression Scale and a visual analog scale focused on pain and bodily discomfort. Moreover, all subjects were evaluated by a clinician, blinded to the treatment regimen, using the Clinical Global Impression Severity Scale. Our data revealed a significant improvement both in self-report, and observer-based measures for the amisulpride-treated, but not for the fluoxetine-treated patients. Amisulpride-treated subjects also presented with a significant reduction of somatic complaints, while the amisulpride effect on anxiety and mood levels was not significant. Both drugs were equally well tolerated. Summing up, we showed a positive symptomatic effect of amisulpride, compared to SSRI treatment, in a group of non-depressed CSF patients on self-report and on observer-based measures of fatigue and somatic complaints. If confirmed by larger, blinded studies, amisulpride thus could represent an effective approach to this difficult-to-treat condition.     

Symptoms and behaviors prior to the first major affective episode of bipolar II disorder. An exploratory study

Background

Few studies have investigated the initial prodrome of bipolar disorders, and none has explicitly addressed bipolar II disorder (BD-II). We explored symptoms and behaviors preceding the first major affective episode (FMAE) of BD-II to generate hypotheses concerning possible clinical targets for early intervention.

Methods

In-depth interviews of 15 BD-II patients and 22 family informants were carried out. Clinical diagnoses were reassessed. The textual data of transcribed interviews were analyzed utilizing qualitative methodology supplemented by quantitative analyses.

Results

All patients experienced clinically significant symptoms and behaviors at an average of more than a decade before the FMAE. Anxiety and depression-type symptoms were the most common. Two distinct subgroups were identified based on prominent and enduring personal characteristics prior to the FMAE. The individuals in one of the subgroups were described as very well-functioning, whereas the individuals in the other subgroup were characterized by neurocognitive deficits, relatively low academic and social functioning, and pronounced irritability and aggressiveness. Furthermore, it is possible that these individuals experience earlier prodromal symptom onset, earlier FMAEs, and more symptoms than individuals without these characteristics.

Limitations

This is a retrospective and hypothesis-generating qualitative study. The hypotheses generated need to be tested in future studies.

Conclusions

Prodromal clinical phenomenology is too nonspecific to predict the occurrence of the FMAE of BD-II. However, identifiable subgroups may exist. We hypothesize that neurocognitive deficits together with pronounced irritability and aggressiveness may constitute a vulnerability marker for a subgroup of individuals who subsequently develop BD-II. This subgroup may be of potential interest for early identification.     

Shared genetic contributions to anxiety disorders and pathological gambling in a male population

Background

Pathological gambling (PG) frequently co-occurs with anxiety disorders. However, the extent to which the co-occurrence is related to genetic or environmental factors across PG and anxiety disorders is not known.

Method

Data from the Vietnam Era Twin Registry (n = 7869, male twins) were examined in bivariate models to estimate genetic and shared and unique environmental contributions to PG and generalized anxiety disorder (GAD) and PG and panic disorder (PD).

Results

While both genetic and unique environmental factors contributed individually to PG, GAD, and PD, the best fitting model indicated that the relationship between PG and GAD was attributable predominantly to shared genetic contributions (r_A = 0.53). In contrast, substantial correlations were observed between both the genetic (r_A = 0.34) and unique environmental (r_E = 0.31) contributions to PG and PD.

Limitations

Results may be limited to middle aged males.

Conclusions

The existence of shared genetic contributions between PG and both GAD and PD suggests that specific genes, perhaps those involved in affect regulation or stress responsiveness, contribute to PG and anxiety disorders. Overlapping environmental contributions to the co-occurrence of PG and PD suggest that common life experiences (e.g., early life trauma) contribute to both PG and PD. Conversely, the data suggest that distinct environmental factors contribute to PG and GAD (e.g., early onset of gambling in PG). Future studies should examine the relationship between PG and anxiety disorders amongst other populations (women and adolescents) to identify specific genetic and environmental influences that account for the manifestation of these disorders and their co-occurrences.