Genome-wide gene pathway analysis of psychotic illness symptom dimensions based on a new schizophrenia-specific model of the OPCRIT

Empirically derived phenotypic measurements have the potential to enhance gene-finding efforts in schizophrenia. Previous research based on factor analyses of symptoms has typically included schizoaffective cases. Deriving factor loadings from analysis of only narrowly defined schizophrenia cases could yield more sensitive factor scores for gene pathway and gene ontology analyses. Using an Irish family sample, this study 1) factor analyzed clinician-rated Operational Criteria Checklist items in cases with schizophrenia only, 2) scored the full sample based on these factor loadings, and 3) implemented genome-wide association, gene-based, and gene-pathway analysis of these SCZ-based symptom factors (final N= 507). Three factors emerged from the analysis of the schizophrenia cases: a manic, a depressive, and a positive symptom factor. In gene-based analyses of these factors, multiple genes had q<. 0.01. Of particular interest are findings for PTPRG and WBP1L, both of which were previously implicated by the Psychiatric Genomics Consortium study of SCZ; results from this study suggest that variants in these genes might also act as modifiers of SCZ symptoms. Gene pathway analyses of the first factor indicated over-representation of glutamatergic transmission, GABA-A receptor, and cyclic GMP pathways. Results suggest that these pathways may have differential influence on affective symptom presentation in schizophrenia.

Exposure to the “Troubles” in Northern Ireland influences the clinical presentation of schizophrenia

Introduction: This study investigates the effect of exposure to "The Troubles" (the period of civil unrest from 1968 onwards) in Northern Ireland on symptomatology in people with schizophrenia.

Method: Eighty-two participants were assessed on a number of psychiatric rating scales and on measures of trauma, including an instrument designed to assess exposure to "Troubles"-related trauma.

Results: People with schizophrenia and a history of exposure to "The Troubles" had significantly higher levels of anxiety, depression, dissociative symptoms and number of admissions compared to those patients with no such exposure.

Discussion: "Troubles"-related trauma has a direct effect on the presentation of schizophrenia in Northern Ireland. Specific therapeutic intervention may be required in order to help patients come to terms with their experiences. © 2008 Elsevier B.V. All rights reserved.

Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women

Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin ( RELN) gene (p = 2.9 x 10(-5) in women), with a significant gene-sex effect (p = 1.8 x 10(-4)). We studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p = 2.1 x 10(-3) in women; p = 4.2 x 10(-3) for gene-sex interaction). Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p = 8.8 x 10(-7); p = 1.6 x 10(-5) for gene-sex interaction). The female-specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease.

Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia

The purpose of this study was to determine whether a haplotype in the dystrobrevin binding protein 1 (DTNBP1) gene previously associated with schizophrenia not only increases the susceptibility to psychotic illness but also to a more or less clinically specific form of psychotic illness.

Utilisation of a novel ProteaseTag™ activity immunoassay for the specific measurement of neutrophil elastase in BAL from children with cystic fibrosis

Introduction: Neutrophil elastase (NE) is a serine protease implicated in the pathogenesis of several respiratory diseases including cystic fibrosis (CF). The presence of free NE in BAL is a predictor of subsequent bronchiectasis in children with CF (Sly et al, 2013, NEJM 368: 1963-1970). Furthermore, children with higher levels of sputum NE activity (NEa) tend to experience a more rapid decline in FEV1 over time even after adjusting for age, gender and baseline FEV1 (Sagel et al, 2012, AJRCCM 186: 857-865). Its detection and quantification in biological samples is however confounded by a lack of robust methodologies. Standard assays using chromogenic or fluorogenic substrates are not specific when added to complex samples containing multiple proteolytic and hydrolytic enzymes. ELISA systems measure total protein levels which can be a mixture of latent, active and protease-inhibitor complexes. We have therefore developed a novel assay (ProteaseTag™ Active NE Immunoassay), which couples an activity dependent NE-Tag with a specific antibody step, resulting in an assay which is both selective and specific for NEa. Aims: To clinically validate ProteaseTag™ Active NE for the detection of free NEa in BAL from children with CF. Methods: A total of 95 paediatric BAL samples [CF (n=76; 44M, 32F) non-CF (n=19; 12M, 7F)] collected through the Study of Host Immunity and Early Lung Disease in CF (SHIELD CF) were analysed for NEa using ProteaseTag™ Active NE (ProAxsis Ltd) and a fluorogenic substrate-based assay utilising Suc-AAPV-AMC (Sigma). IL-8 was measured by ELISA (R&D Systems). Results were analysed to show comparisons in free NEa between CF and non-CF samples alongside correlations with a range of clinical parameters. Results: NEa measured by ProteaseTag™ Active NE correlated significantly with age (r=0.3, p=0.01) and highly significantly with both IL-8 (r=0.4, p=<0.0001) and the absolute neutrophil count (ANC) (r=0.4, p=<0.0001). These correlations were not observed when NEa was measured by the substrate assay even though a significant correlation was found between the two assays (r=0.8, p<0.0001). A trend towards significance was found between NEa in the CF and non-CF groups when measured by ProteaseTag™ Active NE (p=0.07). Highly significant differences were found with the other inflammatory parameters between the 2 groups (IL-8: p=0.0002 and ANC: p=0.006). Conclusion: NEa as a primary efficacy endpoint in clinical trials or as a marker of inflammation within the clinic has been hampered by the lack of a robust and simple to use assay. ProteaseTag™ Active NE has been shown to be a specific and superior tool in the measurement of NEa in paediatric CF BAL samples (supporting data from previous studies using adult CF expectorated samples). The technology is currently being transferred to a lateral flow device for use at Point of Care. Acknowledgements: This work was supported by the National Children’s Research Centre, Dublin (SHIELD CF) and grants from the Medical Research Council and Cystic Fibrosis Foundation Therapeutics.

The Irish hospitals sweepstake in the United States of America, 1930-1939

The Irish hospitals sweepstake was established by statute in the Irish Free State in 1930 to fund the state’s hospital service. The vast majority of tickets were sold outside Ireland, particularly in countries where such gambling was illegal at the time. Initially the largest market was in the United Kingdom, but following the introduction of restrictive legislation there in 1934, the promoters of the sweepstake turned their attentions to North America and after 1936 the United States became the largest source of contributions to the Irish sweep. This article examines a number of factors concerning the relationship of the Irish sweep with the USA, including: an effort to estimate the amount of money contributed to the sweep by Americans; the role of the Irish diaspora and of prominent republicans, including Joseph McGarrity and Connie Neenan, in the illegal ticket distribution network; the efforts of American Federal agencies and government departments to disrupt the sweepstake organisation in America; how the sweep was used by those who sought to legalise gambling in the USA; the attitudes of both the Irish and American governments to the sweep’s activities in America; and how the legalisation of gambling in America brought about the demise of the Irish sweep.

Radiative lifetimes of metastable states of negative ions

We present a technique for measuring the radiative lifetimes of metastable states of negative ions that involves the use of a heavy-ion storage ring. The method has been applied to investigate the radiative decay of the np3 2P1/2 levels of Te–(n=5) and Se–(n=4) and the 3p3 2D state of Si– for which the J=3/2 and 5/2 levels were unresolved. All of these states are metastable and decay primarily by emission of E2 and M1 radiation. Multi Configuration Dirac-Hartree-Fock calculations of rates for the transitions in Te– and Se– yielded lifetimes of 0.45 s and 4.7 s, respectively. The measured values agree well with these predicted values. In the case of the 2D state of Si–, however, our measurement was only able to set a lower limit on the lifetime. The upper limit of the lifetime that can be measured with our apparatus is set by how long the ions can be stored in the ring, a limit determined by the rate of collisional detachment. Our lower limit of 1 min for the lifetime of the 2D state is consistent with both the calculated lifetimes of 162 s for the 2D3/2 level and 27.3 h for the 2D5/2 level reported by O'Malley and Beck and 14.5 h and 12.5 h, respectively, from our Breit-Pauli calculations.

The general and specific effects of educational programmes aimed at promoting awareness of and respect for diversity among young children

This article reports the findings of a mixed-method evaluation of a pilot educational programme undertaken with 6-7 year olds in a sample of primary schools in England with the aim of increasing their awareness of and respect for diversity through theatre, workshops and related teacher-led classroom activities. The qualitative feedback from the teachers involved was extremely positive and encouraging and an analysis of the actual impact of the pilot programme on the children’s attitudes and awareness, using an experimental design, demonstrated some positive effects. In particular, the programme was found to increase the children’s general awareness of diversity and their ability to recognise instances of exclusion. While not a planned objective of the pilot programme, the evaluation also examined whether it had any effects on the children’s attitudes to specific differences, in this particular case racial differences. Interestingly, however, no evidence was found of any change in the children’s racial attitudes. With this in mind the article suggests that there is a need to distinguish between the general and specific effects of such educational programmes. The article considers the implications of this for future work in the area and also stresses the need to undertake more thorough and rigorous evaluations of such initiatives.

Habitat-specific adaptation of immune responses of stickleback (Gasterosteus aculeatus) lake and river ecotypes

Freshwater populations of three-spined sticklebacks (Gasterosteus aculeatus) in northern Germany are found as distinct lake and river ecotypes. Adaptation to habitat-specific parasites might influence immune capabilities of stickleback ecotypes. Here, naive laboratory-bred sticklebacks from lake and river populations were exposed reciprocally to parasite environments in a lake and a river habitat. Sticklebacks exposed to lake conditions were infected with higher numbers of parasite species when compared with the river. River sticklebacks in the lake had higher parasite loads than lake sticklebacks in the same habitat. Respiratory burst, granulocyte counts and lymphocyte proliferation of head kidney leucocytes were increased in river sticklebacks exposed to lake when compared with river conditions. Although river sticklebacks exposed to lake conditions showed elevated activation of their immune system, parasites could not be diminished as effectively as by lake sticklebacks in their native habitat. River sticklebacks seem to have reduced their immune-competence potential due to lower parasite diversity in rivers