MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Changing primary care requesting practices for MRI knee: A quality improvement project.

OBJECTIVES: The objectives of this work were first to examine referral practices from primary care for MRI knee in patients ≥45 years old and then to develop a new referral pathway to reduce the number of inappropriate MRI knee referrals. Following this, the aim was to re-assess the effect of the intervention and identify further areas for improvement. METHODS: A baseline retrospective analysis of knee MRIs requested from primary care in symptomatic patients ≥45years over a two-month period was undertaken. A new referral pathway was implemented in consensus with orthopaedic specialists and the clinical commissioning group (CCG), via the CCG resource webpage and local education. Following implementation, a repeat data analysis was undertaken. RESULTS: The number of MRI knees acquired from primary care referrals reduced by 42% after the new pathway was implemented. 67% (46/69) were compliant with the new guidelines. The number of patients having an MRI knee without a prior plain radiograph was 14/69 (20%) compared to 55/118 (47%) prior the pathway changes. CONCLUSION: The new referral pathway reduced the number of knee MRI acquisitions in primary care patients ≥45 years by 42%. Changing the pathway has decreased the number of patients undergoing MRI knee without a prior radiograph from 47% to 20%. These outcomes bring our standards towards the evidence-based recommendations of the Royal College of Radiology and have reduced our outpatient waiting list for MRI knee. IMPLICATIONS FOR PRACTICE: Implementing a new referral pathway with the local CCG can successfully reduce the number of inappropriate MRI knee acquisitions from primary care referrals in older symptomatic patients.

Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa.

In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from - 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN.

Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10-6), and rs7700147, an intergenic variant (P=2.93 × 10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium.

OBJECTIVE: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. METHOD: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. RESULTS: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: ßstd = -0.052; P = 0.021; right: ßstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. CONCLUSION: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent developmental disorder, associated with a range of long-term impairments. Variation in DNA methylation, an epigenetic mechanism, is implicated in both neurobiological functioning and psychiatric health. However, the potential role of DNA methylation in ADHD symptoms is currently unclear. In this study, we examined data from the Avon Longitudinal Study of Parents and Children (ALSPAC)-specifically the subsample forming the Accessible Resource for Integrated Epigenomics Studies (ARIES)-that includes (1) peripheral measures of DNA methylation (Illumina 450k) at birth (n=817, 49% male) and age 7 (n=892, 50% male) and (2) trajectories of ADHD symptoms (7-15 years). We first employed a genome-wide analysis to test whether DNA methylation at birth associates with later ADHD trajectories; and then followed up at age 7 to investigate the stability of associations across early childhood. We found that DNA methylation at birth differentiated ADHD trajectories across multiple genomic locations, including probes annotated to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes that play a key role in the maturation and stability of cortical circuits.

DNA methylation and substance-use risk: a prospective, genome-wide study spanning gestation to adolescence.

Epigenetic processes have been implicated in addiction; yet, it remains unclear whether these represent a risk factor and/or a consequence of substance use. Here, we believe we conducted the first genome-wide, longitudinal study to investigate whether DNA methylation patterns in early life prospectively associate with substance use in adolescence. The sample comprised of 244 youth (51% female) from the Avon Longitudinal Study of Parents and Children (ALSPAC), with repeated assessments of DNA methylation (Illumina 450k array; cord blood at birth, whole blood at age 7) and substance use (tobacco, alcohol and cannabis use; age 14-18). We found that, at birth, epigenetic variation across a tightly interconnected genetic network (n=65 loci; q<0.05) associated with greater levels of substance use during adolescence, as well as an earlier age of onset amongst users. Associations were specific to the neonatal period and not observed at age 7. Key annotated genes included PACSIN1, NEUROD4 and NTRK2, implicated in neurodevelopmental processes. Several of the identified loci were associated with known methylation quantitative trait loci, and consequently likely to be under significant genetic control. Collectively, these 65 loci were also found to partially mediate the effect of prenatal maternal tobacco smoking on adolescent substance use. Together, findings lend novel insights into epigenetic correlates of substance use, highlight birth as a potentially sensitive window of biological vulnerability and provide preliminary evidence of an indirect epigenetic pathway linking prenatal tobacco exposure and adolescent substance use.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

The associations between socio-economic status and major depressive disorder among Blacks, Latinos, Asians and non-Hispanic Whites: findings from the Collaborative Psychiatric Epidemiology Studies.

BACKGROUND: This study examined whether there were associations between individual measures of socio-economic status (SES) and the 12-month prevalence of major depressive disorder (MDD) in representative samples of Blacks, Latinos, Asians and Whites in the USA. METHOD: The data used were from the Collaborative Psychiatric Epidemiology Studies (CPES). RESULTS: There was an association between household income and MDD among Whites. However, the association was not statistically significant. Statistically significant associations were present between educational attainment and MDD among Whites. Among both Whites and Latinos, being out of the labor force was significantly associated with MDD. In analyses by nativity, being out of the labor force was significantly associated with MDD among US-born and foreign-born Latinos. CONCLUSIONS: Significant associations between various measures of SES and MDD were consistently observed among White and, in some cases, Latino populations. Future studies should continue to examine sociopsychological factors related to SES that increase the risk of MDD among people from racial-ethnic communities.

Injury patterns at US and Canadian overnight summer camps: first year of the Healthy Camp study.

OBJECTIVE: To describe injury patterns at overnight summer camps in 2006, and identify risk factors for more significant injury. DESIGN: Surveillance data obtained from Healthy Camp Study from 2006 were analyzed from 71 overnight camps, representing 437,541 camper-days and 206,031 staff-days. RESULTS: Injuries were reported in 218 campers and 81 staff. 51.8% of injured campers were male versus 34.6% of staff. Among campers, 60.1% were evaluated off-site; 2.3% required hospital admission. 43.9% of injuries required >24 h activity restriction (deemed "significant injury"). Among campers, significant injury was associated with camp sessions > or =14 days (RR 1.48); among staff, with male sex (RR 1.85) and camper-to-staff ratio (RR 0.67). There were no associations with age, time of day, setting, or level of supervision. CONCLUSIONS: Significant injuries are uncommon at overnight summer camps. Rates appear similar to those in comparable activities. Targeted interventions may further reduce injury risk.

Shedding of Mycobacterium bovis in the nasal mucus of cattle infected experimentally with tuberculosis by the intranasal and intratracheal routes.

Four groups of six calves were infected experimentally with either a low dose of approximately 10(4) colony-forming units (cfu) or a high dose of approximately 10(6) cfu of Mycobacterium bovis. Each dose was delivered by the intranasal and intratracheal routes. More severe disease was observed in the groups inoculated with the high dose. Visible lesions were identified in 21 of the 24 animals, all of which also gave positive skin tests and interferon-gamma (IFN-gamma) responses. Nasal shedding was detected in 15 of the 24 animals and the frequency of shedding was influenced by both the route and the dose of infection; no shedding was observed in the group infected intratracheally with the low dose. Two of the 15 confirmed shedders had no visible lesions at postmortem examination; both of these calves gave IFN-gamma responses but only one was skin test positive.

Breaking up and getting together: evolution of symbiosis and cloning by fission in sea anemones (Genus Anthopleura).

Clonal growth and symbiosis with photosynthetic zooxanthellae typify many genera of marine organisms, suggesting that these traits are usually conserved. However, some, such as Anthopleura, a genus of sea anemones, contain members lacking one or both of these traits. The evolutionary origins of these traits in 13 species of Anthopleura were inferred from a molecular phylogeny derived from 395 bp of the mitochondrial 16S rRNA gene and 410 bp of the mitochondrial cytochrome oxidase subunit III gene. Sequences from these genes were combined and analyzed by maximum-parsimony, maximum-likelihood, and neighbor-joining methods. Best trees from each method indicated a minimum of four changes in growth mode and that symbiosis with zooxanthellae has arisen independently in eastern and western Pacific species. Alternative trees in which species sharing growth modes or the symbiotic condition were constrained to be monophyletic were significantly worse than best trees. Although clade composition was mostly consistent with geographic sympatry, A. artemisia from California was included in the western Pacific clade. Likewise, A. midori from Japan was not placed in a clade containing only other Asian congeners. The history of Anthopleura includes repeated shifts between clonality and solitariness, repeated attainment of symbiosis with zooxanthellae, and intercontinental dispersal.

S-alk(en)yl-L-cysteine sulfoxides, alliinase and aroma in Leucocoryne.

Levels of S-alk(en)yl-L-cysteine sulfoxides, alliinase and enzymatically generated pyruvic acid were determined in the bulb, leaf and scape of five species and a natural hybrid of Leucocoryne (Liliaceae), a genus of ornamental geophytes indigenous to Chile. (+)-S-Methyl-L-cysteine sulfoxide (MCSO) was present in all plant parts of all species at levels between 0.09 and 1.41 mg g(-1) fr. wt. Trans-(+)-S-(1-propenyl)-L-cysteine sulfoxide (PRENCSO) was present in plant parts of three species only (L. angustipetala, L. oadorata and L. purpurea) at levels between 0.12 and 1.82 mg g(-1) fr. wt. No other S-alk(en)yl-L-cysteine sulfoxides were detected. Alliinase (EC 4.4.1.4) was detected in the leaf, bulb and scape of L. angustipetala and L. purpurea, only in the leaves of L. coquimbensis and L. purpurea x L. coquimbensis, and only in the bulb of L. odorata. Enzymatically generated pyruvic acid was detected in all plant parts of all species at levels between trace amounts and 5.33 micromol g(-1) fr. wt. As PRENCSO is produced only in Leucocoryne species exhibiting a strong and unpleasant onion-like aroma, it is probable that the enzymatic degradation of PRENCSO is the main cause of that aroma. Consequently, Leucocoryne cultivars should be selected in species and hybrids that lack the ability to synthesise PRENCSO.

[Quality control of medical documentation of in-patients at the St. Stephen Municipal Hospital in Budapest]. / A fekvöbetegek orvosi dokumentációjának minöségellenörzö vizsgálata a FB1árosi Szent István Kórházban.

Within the frame of hospital quality control programme, the authors have investigated since 1997 the medical documentation concerning in-patients of St. Stephen Hospital Budapest. An assessment form of 26 items related to main elements of medical documentation has been created for the study. Choosing of both order of departments' succession and cases to be investigated took place at random. Evaluation was performed at a scala of 0-3 points, by a five-membered work-group; all members first carried out the qualifications independently of each other, and then they formed the final opinion together at common sessions. Investigation of 204 "first round" cases proved the feasibility of the applied method. As it turned out from the results, the quality of documentation showed statistically significant differences between departments of the hospital and the average standard of documentation could not be declared as satisfying at the period of basic survey. Deficiencies of documentation especially in respect of case history, disease course, personal data and informed consent have been found. On the other hand, registration of status on admission and final report got a relatively high average score-number. The authors call attention to the importance of ordinary control of medical documentation.

Immature neutrophils in the blood smears of young febrile children.

OBJECTIVE: To determine whether the immature neutrophil (band) count in the peripheral blood smear helps to distinguish young febrile children with bacterial or respiratory viral infections. DESIGN AND SETTING: A prospective cohort study in 3 pediatric emergency departments. PATIENTS: A convenience sample of 100 febrile children aged 2 years or younger with either laboratory-documented bacterial infections (n = 31; 24 with urinary tract infections, 7 with bacteremia) or laboratory-documented respiratory viral infections (n = 69). Each patient received a clinical appearance score using the Yale Observation Scale prior to laboratory evaluation. A complete blood cell count was obtained from all patients and manual differential count of the peripheral blood smear was performed by 1 senior technician masked to clinical information. MAIN OUTCOME MEASURE: Band counts, represented as a percentage of white blood cells in the peripheral blood smear, the absolute band count, and band-neutrophil ratio. Logistic regression analysis was performed to determine whether the band count helps to distinguish bacterial infections from viral infections after adjusting for age, temperature, Yale Observation Scale score, and absolute neutrophil count. RESULTS: Patients with bacterial infections had a higher mean absolute neutrophil count (11.3 vs 5.9 x 10(9)/L; P<.01) than patients with respiratory viral infections. There was no difference, however, in percentage band count (13.5% vs 13.3%; P = .90), absolute band count (2.2 vs 1.9 X 10(9)/L; P= .31), or band-neutrophil ratio (0.24 vs 0.33; P = .08, bacterial vs viral, respectively); the band count did not help to distinguish bacterial and viral infections after adjusting for age, temperature, Yale Observation Scale score, and absolute neutrophil count in the regression analysis. CONCLUSION: The band count in the peripheral blood smear does not routinely help to distinguish bacterial infections from respiratory viral infections in young febrile children.

Stable production of human gastric lipase by chromosomal integration in the fission yeast Schizosaccharomyces pombe.

Strains of the fission yeast Schizosaccharomyces pombe have been constructed containing single or multiple chromosomally integrated copies of an expression cassette for production of human gastric lipase. Integrant strains of S. pombe secrete active lipase and are stable for lipase production over a minimum of 50 generations in non-selective media. Lipase activity levels for integrant strains containing up to three tandem copies of the expression cassette are strongly correlated with copy number of the cassette in both complete and minimal media. Lipase activity is higher in complete medium than in minimal medium. Strains carrying three chromosomally integrated expression cassette copies can be grown without selection in complete medium and are capable of significantly higher lipase activities than strains containing the expression cassette on a multicopy plasmid.

Cryptic invasions of the crab Carcinus detected by molecular phylogeography.

Coastal marine ecosystems world-wide are threatened by invasions of nonindigenous species. The ubiquity of marine sibling species identifiable only by genetic analysis suggests that many invasions are cryptic and therefore undetected, causing an underestimation of the actual number and impacts of invading species. We test this hypothesis with European crabs in the genus Carcinus that have invaded five regions globally. Partial 16S ribosomal RNA gene sequences confirm sibling species status of morphologically similar Atlantic C. maenas and Mediterranean C. aestuarii. Based on 16S rRNA haplotypes, crabs from California, New England and Tasmania were all C. maenas. However, we report the cryptic multiple invasion of both species in Japan and South Africa, where only C. aestuarii and C. maenas, respectively, were previously recognized.