In Search for the Genetic Basis of Quality of Life in Healthy Swedish Women—A GWAS Study Using the iCOGS Custom Genotyping Array

Background

Quality of life (QoL) is increasingly measured in both research and clinical practice. QoL-assessments are built on a long, empirically-based, and stringent approach. There is ample evidence that QoL is, in part, heritable. We therefore performed a GWAS relating genetic variation to QoL in healthy females.

Methods

In 5,142 healthy females, background characteristics (e.g. demographic, clinical, lifestyle and psychological factors) and QoL by means of the EORTC QLQ-C30 were measured. Moreover, women were genotyped using a custom array including ~210,000 single nucleotide polymorphisms (SNPs). Initially, SNPs were related to each QoL-domain, by means of partially adjusted (controlling for age and population stratification) and fully adjusted (controlling for age, population stratification, and background characteristics) regression analyses. Additionally, gene-based analyses were performed relating the combined effect of SNPs within each gene to QoL using the statistical software package VEGAS.

Results

None of the associations between QoL and genetic variation (i.e. individual SNPs and genes) reached the bonferroni corrected significance level.

Conclusion

Reasons for a lack of association between genetic markers and QoL could be low variation in QoL-scores; selecting genetic markers not tagging QoL; or that the genetic effect that impacts one’s QoL is mediated through biological pathways rather than the effect of single SNPs or genes. Therefore, we opt for a pathway-based or system biology approach as a complementary and powerful approach to analyze the combined effect of genes and their biological implications in future studies focusing on QoL-issues.     

Supported employment: cost-effectiveness across six European sites

A high proportion of people with severe mental health problems are unemployed but would like to work. Individual Placement and Support (IPS) offers a promising approach to establishing people in paid employment. In a randomized controlled trial across six European countries, we investigated the economic case for IPS for people with severe mental health problems compared to standard vocational rehabilitation. Individuals (n=312) were randomized to receive either IPS or standard vocational services and followed for 18 months. Service use and outcome data were collected. Cost‐effectiveness analysis was conducted with two primary outcomes: additional days worked in competitive settings and additional percentage of individuals who worked at least 1 day. Analyses distinguished country effects. A partial cost‐benefit analysis was also conducted. IPS produced better outcomes than alternative vocational services at lower cost overall to the health and social care systems. This pattern also held in disaggregated analyses for five of the six European sites. The inclusion of imputed values for missing cost data supported these findings. IPS would be viewed as more cost‐effective than standard vocational services. Further analysis demonstrated cost‐benefit arguments for IPS. Compared to standard vocational rehabilitation services, IPS is, therefore, probably cost‐saving and almost certainly more cost‐effective as a way to help people with severe mental health problems into competitive employment.     

Evidence That Transition from Health to Psychotic Disorder Can Be Traced to Semi-Ubiquitous Environmental Effects Operating against Background Genetic Risk

Background

In order to assess the importance of environmental and genetic risk on transition from health to psychotic disorder, a prospective study of individuals at average (n = 462) and high genetic risk (n = 810) was conducted.

Method

A three-year cohort study examined the rate of transition to psychotic disorder. Binary measures indexing environmental exposure (combining urban birth, cannabis use, ethnicity and childhood trauma) and proxy genetic risk (high-risk sibling status) were used to model transition.

Results

The majority of high-risk siblings (68%) and healthy comparison subjects (60%) had been exposed to one or more environmental risks. The risk of transition in siblings (n = 9, 1.1%) was higher than the risk in healthy comparison subjects (n = 2, 0.4%; OR_adj  = 2.2,95%CI:5–10.3). All transitions (100%) were associated with environmental exposure, compared to 65% of non-transitions (p = 0.014), with the greatest effects for childhood trauma (OR_adj  = 34.4,95%CI:4.4–267.4), cannabis use (OR = 4.1,95%CI:1.1, 15.4), minority ethnic group (OR = 3.8,95%CI:1.2,12.8) and urban birth (OR = 3.7,95%CI:0.9,15.4). The proportion of transitions in the population attributable to environmental and genetic risk ranged from 28% for minority ethnic group, 45% for urban birth, 57% for cannabis use, 86% for childhood trauma, and 50% for high-risk sibling status. Nine out of 11 transitions (82%) were exposed to both genetic and environmental risk, compared to only 43% of non-transitions (p = 0.03).

Conclusion

Environmental risk associated with transition to psychotic disorder is semi-ubiquitous regardless of genetic high risk status. Careful prospective documentation suggests most transitions can be attributed to powerful environmental effects that become detectable when analysed against elevated background genetic risk, indicating gene-environment interaction.     

Glutamatergic signaling by midbrain dopaminergic neurons: recent insights from optogenetic, molecular and behavioral studies

Although the notion that dopaminergic neurons utilize glutamate as a co-transmitter has long been supported by tantalizing molecular, immunocytochemical and electrophysiological evidence it has only been with the recent addition of optogenetic and other approaches that the existence and functional relevance of this mechanism could be unambiguously demonstrated. Here we discuss the possible mechanisms of action of glutamate released from mesoaccumbens dopaminergic neurons based on recently accumulated evidence. Surprisingly, rather then to confirm a role in conventional fast excitatory transmission, the latest evidence suggests that glutamate released from dopaminergic neurons may primarily act through different unconventional presynaptic and postsynaptic mechanisms.     

The therapeutic relationship and adherence to antipsychotic medication in schizophrenia

Objective

Previous research has shown that a better therapeutic relationship (TR) predicts more positive attitudes towards antipsychotic medication, but did not address whether it is also linked with actual adherence. This study investigated whether the TR is associated with adherence to antipsychotics in patients with schizophrenia.

Methods

134 clinicians and 507 of their patients with schizophrenia or a related psychotic disorder participated in a European multi-centre study. A logistic regression model examined how the TR as rated by patients and by clinicians is associated with medication adherence, adjusting for clinician clustering and symptom severity.

Results

Patient and clinician ratings of the TR were weakly inter-correlated (r_s = 0.13, p = 0.004), but each was independently linked with better adherence. After adjusting for patient rated TR and symptom severity, each unit increase in clinician rated TR was associated with an increase of the odds ratio of good compliance by 65.9% (95% CI: 34.6% to 104.5%). After adjusting for clinician rated TR and symptom severity, for each unit increase in patient rated TR the odds ratio of good compliance was increased by 20.8% (95% CI: 4.4% to 39.8%).

Conclusions

A better TR is associated with better adherence to medication among patients with schizophrenia. Patients'' and clinicians'' perspectives of the TR are both important, but may reflect distinct aspects.     

The dentition of a well-preserved specimen of <Emphasis Type="Italic">Camarasaurus</Emphasis> sp.: implications for function,tooth replacement,soft part reconstruction,and food intake

The basal macronarian genus Camarasaurus was the most common sauropod in the Upper Jurassic Morrison Formation of North America and is known from several complete and partial skeletons. The specimen used for this study is Camarasaurus sp. SMA 0002 from the Sauriermuseum Aathal, Switzerland. This specimen was found in the Howe-Stephens Quarry, Bighorn Basin, WY, USA. In this study, the dental morphology, characterized by the spatulate, broad-crowned teeth, the tooth replacement pattern, and the function of the dentition and its implications for food intake is described. Features such as the absence of denticles, the wrinkled pattern of the enamel, and the occurrence of large wear facets on older teeth are characteristic for Camarasaurus sp. A slab of sediment with soft tissue impressions ranging up to the middle part of the crown suggests the presence of a gingival soft tissue structure partially covering the teeth. The wrinkled enamel on the crown of the teeth of Camarasaurus sp. and other sauropods is interpreted as indication of this cover of gingival connective tissue. In addition, there possibly was a keratinous beak, which together with the gingiva held the teeth in the jaw and provided stability for teeth in which the root is almost completely resorbed.     

Electrical stimulation of the posteromedial thalamus modulates breathing in unanesthetized fetal sheep.

Having previously shown that lesions in the posteromedial group of thalamic nuclei abolish hypoxic inhibition of fetal breathing, we devised this study to identify thalamic loci that depress breathing by focal stimulation of specific sectors of the caudal thalamus and adjacent structures. Multipolar electrode arrays consisting of a series of eight stimulation contacts at 1.25-mm intervals were implanted vertically through guide cannulae into the caudal diencephalon of 12 chronically catheterized fetal sheep (>0.8 term), and central neural tissue was stimulated between adjacent contacts. Each site was stimulated repeatedly with increasing current searching for spatial and stimulus strength parameters for a reliable alteration in respiratory rate. Respiratory period increased when stimulation involved areas of the parafascicular nuclear complex (Pf), which more than doubled the mean period compared with the baseline of 0.90 +/- 0.19 s. The change in respiratory period was due to an increase in expiratory time, whereas inspiratory time and breath amplitude were not significantly affected. Breathing period and expiratory time were also increased when the stimulations involved the intralaminar wing surrounding the mediodorsal nucleus, the rostral central gray, zona incerta, and ventral tegmental area. Reductions in respiratory frequency occurred less consistently, with stimulation involving surrounding zones including the sub-Pf, ventromedial nucleus, and ventrobasal nuclear complex. These findings support the hypothesis that a restricted area of the posteromedial thalamus (principally Pf) constitutes part of a neuronal circuitry that modulates respiratory motoneurons.