Intragenic recombination between pseudogenes as a source of new disease specificity at a simple resistance locus

BACKGROUND: Pooling of multi-site MRI data is often necessary when a large cohort is desired. However, different scanning platforms can introduce systematic differences which confound true effects of interest. One may reduce multi-site bias by calibrating pivotal scanning parameters, or include them as covariates to improve the data integrity. NEW METHOD: In the present study we use a source-based morphometry (SBM) model to explore scanning effects in multi-site sMRI studies and develop a data-driven correction. Specifically, independent components are extracted from the data and investigated for associations with scanning parameters to assess the influence. The identified scanning-related components can be eliminated from the original data for correction. RESULTS: A small set of SBM components captured most of the variance associated with the scanning differences. In a dataset of 1460 healthy subjects, pronounced and independent scanning effects were observed in brainstem and thalamus, associated with magnetic field strength-inversion time and RF-receiving coil. A second study with 110 schizophrenia patients and 124 healthy controls demonstrated that scanning effects can be effectively corrected with the SBM approach. COMPARISON WITH EXISTING METHOD(S): Both SBM and GLM correction appeared to effectively eliminate the scanning effects. Meanwhile, the SBM-corrected data yielded a more significant patient versus control group difference and less questionable findings. CONCLUSIONS: It is important to calibrate scanning settings and completely examine individual parameters for the control of confounding effects in multi-site sMRI studies. Both GLM and SBM correction can reduce scanning effects, though SBM's data-driven nature provides additional flexibility and is better able to handle collinear effects

Genome-wide association study of regional brain volume suggests involvement of known psychiatry candidate genes, identified new candidates for psychiatric disorders and points to potential modes of their action

Though most psychiatric disorders are highly heritable, it has been hard to identify genetic risk factors involved, which are most likely of small individual effect size. A possible way to aid identification of risk genes is the use of intermediate phenotypes. These are supposed to be closer to the biological substrate(s) of the disorder than psychiatric diagnoses, and therefore less genetically complex. Intermediate phenotypes can be defined e. g. at the level of brain function and of regional brain structure. Both are highly heritable, and regional brain structure is linked to brain function. Within the Brain Imaging Genetics (BIG) study at the Radboud University Nijmegen (Medical Centre) we performed a genome-wide association study (GWAS) in 1000 of the currently 1400 healthy study participants. For all BIG participants, structural MRI brain images were available. Gray and white matter volumes were determined by brain segmentation using SPM software. FSL-FIRST was used to assess volumes of specific brain structures. Genotyping was performed on Affymetrix 6.0 arrays. Results implicate known candidates from earlier GWAS and candidate gene studies in mental disorders in the regulation of regional brain structure. E. g. polymorphisms in CDH13, featuring among the top-findings of GWAS in disorders including ADHD, addiction and schizophrenia, were found associated with amygdala volume. The ADHD candidate gene SNAP25 was found associated with total brain volume. In conclusion, the use of intermediate phenotypes based on (subcortical) brain volumes may shed more light on pathways from genes to diseases, but can also be expected to facilitate gene identification in psychiatric disorders

A Portable Microwave Scanner for Brain Stroke Monitoring: Design, Implementation and Experimental Validation

This paper presents the design, the realization, and the experimental assessment of a novel portable microwave scanner prototype for brain stroke monitoring. The device employs a 22-antenna-array, placed conformal to the upper head part, composed of compact, flexible, and custom-made antennas working at around 1 GHz. The validation includes the monitoring of an experimentally emulated evolving hemorrhagic stroke. The progression of the medical condition is emulated via a non-static phantom (custom-shape balloon), derived from medical images, and a single-cavity 3-D anthropomorphic head phantom. The phantoms are filled with liquids mimicking the dielectric properties of the hemorrhage and the average brain tissues, respectively. The imaging-based follow-up is approached using a differential scheme that receives the scattering matrices, taken at two different instants, and exploits the distorted Born approximation to form the image in real-time. The kernel of the imaging algorithm is computed through accurate numerical models. The results verify the capabilities of the system to assess the continuous evolution of the stroke

Asylum seeker’s ‘brain death’ shows failure of care and of democracy

The news that Hamid Kehazaei, a 24-year-old Iranian asylum seeker detained on Manus Island, has been diagnosed as brain dead following his transfer to the Mater Hospital in Brisbane is a tragedy. That it is a tragedy for this young man and his family is unquestionable – but the extent of this tragedy may be much more pervasive than we realise. If the emerging details of his case are correct, Kehazaei developed septicaemia as a complication of cellulitis (skin and soft-tissue infection) arising from a cut in his foot. This, in itself, is disturbing. Severe infection can result in brain death – either from infection of the brain itself (meningitis, encephalitis or brain abscess), or from brain injury due to a lack of oxygen resulting from cardiac arrest (as appears to be the case here), or from reduced blood supply to the brain. Yet it is very uncommon, especially in a young, previously healthy man. Such a case could occur in Australia and has been described in 2012 in young Indigenous adults in Central Australia. Nevertheless, severe sepsis resulting from a foot infection is preventable. And a case like this occurring in an Australian national would raise serious questions about the appropriateness of the antibiotics used and the timeliness of care. Most cases of brain death result from traumatic brain injury, stroke or lack of oxygen to the brain following asphyxia, near-drowning, or prolonged cardiopulmonary resuscitation. What happened to Hamid Kehazaei raises concerns about the adequacy of care provided to him during initial treatment, including wound care and antibiotics, and how soon he was transferred to expert medical care, first to Port Moresby and subsequently to Brisbane. If this young man became ill and had his brain die while seeking asylum in Australia and while in our care, then we must examine the details of his case and ask ourselves not only whether it was preventable but whether our policies and processes actually contributed to his death

Participant music listening behaviours in interactive multimedia music instruction

While emerging technologies such as interactive multimedia are increasingly being employed in computerised music instruction, understanding of participant music listening behaviours in interactive multimedia music instruction is currently very limited. With the aim of elucidating music listening behaviour, the central concern of this work is to identify and explain participant interactions with the audio components of interactive multimedia music instruction. The investigation employs a novel documentation procedure, which extends the application of digital audio recording technology, to provide a finely calibrated analysis of the audio activity of a sample of 20 undergraduate music education majors during individual sessions with two commercially-available interactive multimedia music instruction programs. Graphically-based Sound Activity Profiles, which the researcher developed specifically for the current investigation, characterise and summarise participant interactions with audio components, while an analysis of questionnaire responses and follow-up interview transcripts provides supplementary information that further explains participants' music listening behaviours. The results of the investigation show that music listening behaviours during the study sessions were highly variable. While extensive participant interaction with music examples occasionally reflected attentive music listening behaviours, many study sessions were characterised by brief, fragmentary music excerpts and lengthy periods of silence. Participants spent as little as five percent of their session time listening to music and as much as 88 percent of the session time in silence. A substantial number of the study cohort frequently interrupted the music examples they had activated. Participants' perceptions of the extent of their interaction with music examples were frequently inaccurate, as subjects often substantially overestimated the amount of session time they had spent listening to music. The study findings suggest that many interactive multimedia music instruction participants would benefit from interventions that elicit more extensive and prolonged interaction with music examples. Accordingly, recommendations include a call for research to develop and test software designs that incorporate automated monitoring of session audio activity so that dynamic on-screen information about music listening behaviour can be provided to interactive multimedia music instruction participants. Such information may encourage participants to modify inappropriate music listening behaviours

Diet quality, stress and common mental health problems: A cohort study of 121,008 adults

Background & aims Overall diet quality may partially mediate the detrimental effects of stress and neuroticism on common mental health problems: stressed and/or neurotic individuals may be more prone to unhealthy dietary habits, which in turn may contribute to depression and anxiety. Lifestyle interventions for depressed, anxious or at-risk individuals hinge on this idea, but evidence to support such pathway is missing. Here, we aim to prospectively evaluate the role of overall diet quality in common pathways to developing depression and anxiety. Methods At baseline, N = 121,008 individuals from the general population (age 18–93) completed an extensive food frequency questionnaire, based on which overall diet quality was estimated. Participants also reported on two established risk factors for mental health problems, i.e. past-year stress exposure (long-term difficulties, stressful life-events) and four neuroticism traits (anger-hostility, self-consciousness, impulsivity, vulnerability). Depression and anxiety were assessed at baseline and follow-up (n = 65,342, +3.6 years). Overall diet quality was modeled as a mediator in logistic regression models predicting the development of depression and anxiety from common risk factors. Results High stress and high neuroticism scores were - albeit weakly - associated with poorer diet quality. Poor diet quality, in turn, did not predict mental health problems. Overall diet quality did not mediate the relationship between stress/neuroticism and common mental health problems: effects of stress, neuroticism and stress-by-neuroticism interactions on mental health problems at follow-up consisted entirely of direct effects (98.6%–100%). Conclusions Diet quality plays no mediating role in two established pathways to common mental health problems. As overall diet quality was reduced in stressed and neurotic individuals, these groups may benefit from dietary interventions. However, such interventions are unlikely to prevent the onset or recurrence of depression and anxiety.publishedVersio

Gene-Environment Interactions in Attention-Deficit/Hyperactivity Disorder Symptom Dimensions:The Role of Unhealthy Food Habits

Background: Dietary habits were investigated as environmental risk factors for Attention-Deficit/Hyperactivity Disorder (ADHD). However, no previous studies explored the effects of dietary factors on modifying the role of genetic factors on ADHD. Methods: Based on a Swedish population-based twin study with 1518 twin pairs aged 20-47 years, we tested whether the importance of genetic and environmental effects on ADHD varied as a function of dietary habits. Self-reported dietary habits and ADHD symptoms were collected. Twin methods were used to test the degree to which high-sugar and unhealthy food intake moderated the genetic and environmental influences on ADHD symptoms. Results: In middle-aged adults, genetic influences on inattention symptoms were statistically significantly higher among individuals with higher levels of high-sugar (45%, 95%CI: 25-54%) and unhealthy food intake (51%, 95%CI: 31-60%), compared with those with lower levels of consumption of high-sugar (36%, 95%CI: 25-47%) and unhealthy foods (30%, 95%CI: 20-41%). Similar patterns were also found for the associations between hyperactivity/impulsivity and high-sugar/unhealthy food intake, even though the moderation effects were not statistically significant. Conclusion The present study suggests that genetic factors play a more prominent role in individual differences of ADHD symptoms in the presence of the high consumption of sugar and unhealthy foods. Future longitudinal studies with multiple assessments of ADHD and dietary habits are needed to replicate our findings.</p

Low-grade inflammation as mediator between diet and behavioral disinhibition:A UK Biobank study

BACKGROUND: Dietary patterns have been associated with variations in behavior. However, evidence has been limited and mixed, and the underlying mechanism remains unclear. OBJECTIVE: Extend a previous study reporting significant associations between food patterns and behavioral disinhibition and explore whether low-grade inflammation is linked to behaviors and mediates the association between diet and behavioral disinhibition. DESIGN: Among participants of the UK Biobank (UKB) we extracted a single behavioral disinhibition principal component using the UKB touchscreen questionnaire, Mental Health Questionnaire (MHQ), and registered diagnoses. We identified four dietary patterns (prudent diet, elimination of wheat/dairy/eggs, meat-based diet, full-cream dairy consumption) by using the Food Frequency Questionnaire (FFQ). Immune biomarkers and an aggregated inflammation score (INFLA-score) were used to characterize low-grade inflammation. Associations between dietary patterns and immune biomarkers, between immune biomarkers and disinhibition were assessed, with adjustment for demographics, lifestyle factors, and somatic health conditions. Next, mediation analyses were run to examine whether the association between dietary patterns and disinhibition was partially explained by inflammatory levels. We also conducted subgroup analyses to explore whether associations and the mediation effect differed by sex, age, ethnicity/race, body-mass-index (BMI), and socioeconomic status (SES). RESULTS: The prudent diet was negatively, and the meat-based diet was positively associated with several pro-inflammatory biomarkers. Most immune biomarkers were positively associated with disinhibition (numbers of lymphocytes (βstandardized = 0.082, p < 0.001), monocytes (βstandardized = 0.043, p < 0.001), neutrophils (βstandardized = 0.071, p < 0.001), platelets (βstandardized = 0.022, p < 0.001), leukocytes (βstandardized = 0.093, p < 0.001), C-reactive protein (βstandardized = 0.051, p < 0.001), and for INFLA-score (βstandardized = 0.074, p < 0.001). In the mediation model, the INFLA-score mediated the association between prudent diet and meat-based diet and disinhibition score, with a significant indirect effect of low-grade inflammation for the prudent diet-disinhibition association (βstandardized = -0.007, p < 0.001) and for meat-disinhibition association (βstandardized = 0.001, p < 0.001)). Although all effects were small, covariates and interaction term adjustments did not attenuate the effects, and neither did most subgroup-only analyses. CONCLUSIONS: The prudent diet was associated with a lower disinhibition score and this effect was partially mediated by the lower inflammation. Reversely, the meat-based diet was linked to more inflammation, which was associated with more disinhibition. Our findings suggest mediating effects of immune function in the relationship between diet and behavioral disinhibition. However further alternative designs such as interventional trials are needed to establish causal effects

Structural brain alterations and their association with cognitive function and symptoms in Attention-deficit/Hyperactivity Disorder families

Gray matter disruptions have been found consistently in Attention-deficit/Hyperactivity Disorder (ADHD). The organization of these alterations into brain structural networks remains largely unexplored. We investigated 508 participants (281 males) with ADHD (N = 210), their unaffected siblings (N = 108), individuals with subthreshold ADHD (N = 49), and unrelated healthy controls (N = 141) with an age range from 7 to 18 years old from 336 families in the Dutch NeuroIMAGE project. Source based morphometry was used to examine structural brain network alterations and their association with symptoms and cognitive performance. Two networks showed significant reductions in individuals with ADHD compared to unrelated healthy controls after False Discovery Rate correction. Component A, mainly located in bilateral Crus I, showed a ADHD/typically developing difference with subthreshold cases being intermediate between ADHD and typically developing controls. The unaffected siblings were similar to controls. After correcting for IQ and medication status, component A showed a negative correlation with inattention symptoms across the entire sample. Component B included a maximum cluster in the bilateral insula, where unaffected siblings, similar to individuals with ADHD, showed significantly reduced loadings compared to controls; but no relationship with individual symptoms or cognitive measures was found for component B. This multivariate approach suggests that areas reflecting genetic liability within ADHD are partly separate from those areas modulating symptom severity