An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12

Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci. An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical α = 1×10−5) ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92×10−4), whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65×10−4). Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women’s Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05). Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63×10−5) is located within the 5′UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.

Longitudinal Evidence on Educational and Occupational Outcomes Amongst South Sudanese Men from Refugee Backgrounds Living in Urban and Regional Southeast Queensland

Australia has continued to benefit from the human, social and economic capital contributed by immigrant resettlement over many years. Humanitarian entrants have also made significant economic, social and civic contributions to the Australian society. Since 2000, approximately 160,000 people have entered Australia under the refugee and humanitarian resettlement program; around 15% have come from South Sudan and one third of these are adult males. In response to the 2003 evaluation of the Integrated Humanitarian Settlement Strategy (IHSS), which recommended to seek further opportunities to settle humanitarian entrants in regional Australia, the Department of Immigration and Citizenship (DIAC) has since encouraged regional settlement to “address the demand for less skilled labour in regional economies and to assist humanitarian entrants to achieve early employment”. There is evidence, however, of the many challenges faced by humanitarian arrivals living in regional areas. This chapter focuses on the educational and occupational outcomes among 117 South Sudanese adult men from refugee backgrounds. In particular, the chapter uses both cross-sectional (at first interview) and longitudinal data (four interviews with each participant at six-month intervals) to compares outcomes between men living in Brisbane and those living in the Toowoomba–Gatton region in Southeast Queensland.

Are employment effects of gender discrimination important? Some evidence from Great Britain

Interpreting the unexplained component of the gender wage gap as indicative of discrimination, the empirical literature to date has tended to ignore the potential impact wage discrimination may have on employment. Employment effects may arise if discrimination lowers the female offered wage and the labour supply curve is upward sloping. The empirical analysis employs the British Household Panel Study and finds evidence of both wage and associated employment effects.

The hazards of starting and quitting smoking: Some Australian evidence

The empirical analysis employs individual level data from the Australian Health Survey combined with retrospective data on tobacco price matched to the age at which the individual started and quit smoking. Split-population hazard models are estimated for both starting and quitting smoking. The analysis suggests price plays a significant role in the decision to start smoking but not in the decision to quit. Further sensitivity analysis of different age groups and an alternative data source, questions the robustness of the significant role of price in the smoking initiation decision. From a policy perspective, the results indicate that increases in tobacco taxation can be an important instrument in reducing the incidence of smoking, but should be combined with other mechanisms such as mandating smoke-free environments and antismoking education. Our results strongly support the targeting of antismoking campaigns towards teenagers.

Genetics of menstrual migraine : the molecular evidence

Migraine is considered to be a multifactorial disorder in which genetic, environmental, and, in the case of menstrual and menstrually related migraine, hormonal events influence the phenotype. Certainly, the role of female sex hormones in migraine has been well established, yet the mechanism behind this well-known relationship remains unclear. This review focuses on the potential role of hormonally related genes in migraine, summarizes results of candidate gene studies to date, and discusses challenges and issues involved in interpreting hormone-related gene results. In light of the molecular evidence presented, we discuss future approaches for analysis with the view to elucidate the complex genetic architecture that underlies the disorder.

A genome-wide scan provides evidence for loci influencing a severe heritable form of common migraine

Migraine is a prevalent neurovascular disease with a significant genetic component. Linkage studies have so far identified migraine susceptibility loci on chromosomes 1, 4, 6, 11, 14, 19 and X. We performed a genome-wide scan of 92 Australian pedigrees phenotyped for migraine with and without aura and for a more heritable form of “severe” migraine. Multipoint non-parametric linkage analysis revealed suggestive linkage on chromosome 18p11 for the severe migraine phenotype (LOD*=2.32, P=0.0006) and chromosome 3q (LOD*=2.28, P=0.0006). Excess allele sharing was also observed at multiple different chromosomal regions, some of which overlap with, or are directly adjacent to, previously implicated migraine susceptibility regions. We have provided evidence for two loci involved in severe migraine susceptibility and conclude that dissection of the “migraine” phenotype may be helpful for identifying susceptibility genes that influence the more heritable clinical (symptom) profiles in affected pedigrees. Also, we concluded that the genetic aetiology of the common (International Headache Society) forms of the disease is probably comprised of a number of low to moderate effect susceptibility genes, perhaps acting synergistically, and this effect is not easily detected by traditional single-locus linkage analyses of large samples of affected pedigrees.

Evidence for an X-linked genetic component in familial typical migraine

Migraine is a common complex disorder that shows strong familial aggregation. There is a general increased prevalence of migraine in females compared with males, with recent studies indicating that migraine affects 18% of females compared with 6% of males. This preponderance of females among migraine sufferers coupled with evidence of an increased risk of migraine in first degree relatives of male probands but not in relatives of female probands suggests the possibility of an X-linked dominant gene. We report here the localization of a typical migraine susceptibility locus to the X chromosome. Of three large multigenerational migraine pedigrees two families showed significant excess allele sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from all three pedigrees gave significant evidence in support of linkage and heterogeneity (HLOD = 3.1). These findings provide conclusive evidence that familial typical migraine is a heterogeneous disorder. We suggest that the localization of a migraine susceptibility locus to the X chromosome could in part explain the increased risk of migraine in relatives of male probands and may be involved in the increased female prevalence of this disorder.

Phenotypic changes in artemisinin-resistant plasmodium falciparum lines in vitro: evidence for decreased sensitivity to dormancy and growth inhibition

The appearance of Plasmodium falciparum parasites with decreased in vivo sensitivity but no measurable in vitro resistance to artemisinin has raised the urgent need to characterize the artemisinin resistance phenotype. Changes in the temporary growth arrest (dormancy) profile of parasites may be one aspect of this phenotype. In this study, we investigated the link between dormancy and resistance, using artelinic acid (AL)-resistant parasites. Our results demonstrate that the AL resistance phenotype has (i) decreased sensitivity of mature-stage parasites, (ii) decreased sensitivity of the ring stage to the induction of dormancy, and (iii) a faster recovery from dormancy.

Heterogeneity evidence and linkage studies on Charcot-Marie-Tooth disease

Charcot-Marie-Tooth neuropathy type 1 (CMT1) is an autosomal dominant disorder originally localized to chromosome 1 by linkage to the Duffy blood group. Studies have since shown that the disorder may be heterogeneous, as not all families show this linkage. We tested genetic heterogeneity by the HOMOG computer program in 15 CMT1 pedigrees informative for Duffy. We detected no evidence for heterogeneity in this sample, but when we combined results with previously published lod scores, heterogeneity was statistically significant. Twelve of the 15 families studied did not show linkage to Duffy. We found six of these families to be informative for a chromosome 19 marker, apolipoprotein CII(ApoC2). Despite a previous report showing probable linkage of a non-Duffy-linked CMT1 pedigree to two chromosome 19 markers, we did not detect significant linkage of ApoC2 to CMT1 in these families.

School libraries and teacher-librarians : evidence of their contribution to student literacy and learning

International research provides compelling evidence that school libraries and teacher-librarians make a significant contribution to student literacy and learning outcomes. After summarising previous research, this article presents recent research focused on Gold Coast schools. These new Australian findings present an evidenced based snapshot of school libraries and teacher-librarians, from the principals’ perspective. They indicate that school NAPLAN scores for reading and writing were generally higher when student-to-library staff ratios were lower (i.e. better) and when the school employed a teacher-librarian. In light of the National Plan for School Improvement, the findings are of potential interest to education authorities, policy makers, school leadership teams, teacher-librarians, teachers, parents and researchers. They offer evidence to inform policy development and strategic planning for school libraries and professional staffing.

Familial typical migraine: Linkage to chromosome 19p13 and evidence for genetic heterogeneity

Migraine is a frequent familial disorder that, in common with most multifactorial disorders, has an unknown etiology. The authors identified several families with multiple individuals affected by typical migraine using a single set of diagnostic criteria and studied these families for cosegregation between the disorder and markers on chromosome 19, the location of a mutation that causes a rare form of familial hemiplegic migraine (FHM). One large tested family showed both cosegregation and significant allele sharing for markers situated within or adjacent to the FHM locus. Multipoint GENEHUNTER results indicated significant excess allele sharing across a 12.6- cM region containing the FHM Ca2+ channel gene, CACNL1A4 (maximum nonparametric linkage Z score = 6.64, p = 0.0026), with a maximum parametric lod score of 1.92 obtained for a (CAG)(n) triplet repeat polymorphism situated in exon 47 of this gene. The CAG expansion did not, however, appear to be the cause of migraine in this pedigree. Other tested families showed neither cosegregation nor excess allele sharing to chromosome 19 markers. HOMOG analysis indicated heterogeneity, generating a maximum HLOD score of 3.6. It was concluded that Chr19 mutations either in the CACNL1A4 gene or a closely linked gene are implicated in some pedigrees with familial typical migraine, and that the disorder is genetically heterogeneous.

Evidence for allelic association of the dopamine β-hydroxylase gene (DBH) with susceptibility to typical migraine

Migraine is a debilitating neurological disorder characterized by recurrent attacks of severe headache. The disorder is highly prevalent, affecting approximately 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. However, the calcium channel gene, CACNA1A, on chromosome 19 contains mutations responsible for familial hemiplegic migraine, a rare and severe subtype of migraine. There is also evidence to suggest that serotonin- and dopamine-related genes may be involved in the pathogenesis of migraine. This study employed a linkage and association approach to investigate neurotransmitter-related migraine candidate genes. Polymorphisms within the dopamine beta-hydroxylase (DBH) gene, serotonin transporter gene (SERT), and dopamine receptor gene (DRD2) were tested in 177 unrelated Caucasian migraineurs and 182 control individuals. In addition, an independent sample of 82 families affected with migraine was examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (L2=16.53, P=0.019). Furthermore, the transmission/disequilibrium test, which was implemented on the family data, also indicated distortion of allele transmission for the same DBH marker (L2=4.44, P=0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's combined P value=0.006) and indicate that further research into the role of the DBH gene in the etiology of migraine is warranted.

An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity

Recent evidence indicates that the estrogen receptor-a-negative, androgen receptor (AR)- positive molecular apocrine subtype of breast cancer is driven by AR signaling. The MDA-MB-453 cell line is the prototypical model of this breast cancer subtype; its proliferation is stimulated by androgens such as 5a-dihydrotestosterone (DHT) but inhibited by the progestin medroxyprogesterone acetate (MPA) via AR-mediated mechanisms. We report here that the AR gene in MDAMB- 453 cells contains a G-T transversion in exon 7, resulting in a receptor variant with a glutamine to histidine substitution at amino acid 865 (Q865H) in the ligand binding domain. Compared with wild-type AR, the Q865H variant exhibited reduced sensitivity to DHT and MPA in transactivation assays in MDA-MB-453 and PC-3 cells but did not respond to non-androgenic ligands or receptor antagonists. Ligand binding, molecular modeling, mammalian two-hybrid and immunoblot assays revealed effects of the Q865H mutation on ligand dissociation, AR intramolecular interactions, and receptor stability. Microarray expression profiling demonstrated that DHT and MPA regulate distinct transcriptional programs in MDA-MB-453 cells. Gene Set Enrichment Analysis revealed that DHT- but not MPA-regulated genes were associated with estrogen-responsive transcriptomes from MCF-7 cells and the Wnt signaling pathway. These findings suggest that the divergent proliferative responses of MDA-MB-453 cells to DHT and MPA result from the different genetic programs elicited by these two ligands through the AR-Q865H variant. This work highlights the necessity to characterize additional models of molecular apocrine breast cancer to determine the precise role of AR signaling in this breast cancer subtype. Endocrine-Related Cancer (2012) 19 599–613

The experience of being an advanced practice nurse within Australian acute care settings : a systematic review of qualitative evidence

Background There is a vast amount of international literature which, although agreeing on the need for advanced practice nurse roles, simultaneously debates and discusses the difficulties with nomenclature, definition and subsequent implementation of such roles. Due to this ambiguity it is difficult to equally compare evidence in this field across different countries. A context-specific systematic review on the qualitative evidence of the experience of being an advanced practice nurse in Australia has not been undertaken previously, however it is imperative for nursing managers and leaders to understand the complexities of advanced nursing roles in order to effectively utilise and retain these experienced and valuable nurses. With the creation of a national nursing regulating authority in 2010, it is timely to explore in-depth the experience of being an advanced practice nurse from a national perspective. Objective To identify the experience of being an advanced practice nurse working in Australian acute care settings. Inclusion criteria -Types of participants Registered nurses working in advanced practice roles in acute care settings throughout Australia. -Phenomena of interest The experience of being an advanced practice registered nurse working in an Australian acute care setting, as reported by the nurses themselves. -Types of studies Interpretive qualitative studies including designs such as phenomenology, grounded theory and ethnography. -Search strategy A three step search strategy was used to identify published and unpublished studies. The search process was conducted from August to October 2011 and considered published and unpublished studies from 1990 to October 2011. -Methodological quality Studies were appraised for methodological quality by two independent reviewers using the Joanna Briggs Qualitative Assessment and Review Instrument. -Data extraction Data was extracted from the papers included in the review using the standardised Joanna Briggs Institute Qualitative Assessment and Review Instrument data extraction tool. -Data synthesis Research findings were pooled using the Joanna Briggs Institute Qualitative Data and Review Instrument. Results Three published studies and one unpublished dissertation were included in the review. From these four studies, 216 findings were extracted, forming 18 categories which were then analysed to create six synthesised findings. Six meta-syntheses under the headings of expert knowledge, confidence, education, relationships, negative experiences and patient centred experience were formed from the findings. Conclusions The synthesised findings confirm that the experience of advanced practice nurses in Australian acute care settings is complex and greatly influenced personally and professionally by the organisation as well as the unpredictable nature of working with people.

Asset allocation policy, returns and expenses of superannuation funds : recent evidence based on default options

We examine the asset allocation, returns, and expenses of superannuation funds whose assets are mainly invested in default investment options between 2004 and 2012. A majority of these funds fail to earn returns commensurate with their strategic asset allocation policy. It appears that much of the variation of returns between the funds might be a result of their engaging in significant active management of assets. Our results indicate that returns from active management are negatively related to expenses. We also find strong evidence of economies of scale existing in these superannuation funds across different size categories.