Susceptibility to ankylosing spondylitis in twins: The role of genes, HLA, and the environment

Objective To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis (AS). Methods Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database. Clinical and radiographic examinations were performed to establish diagnoses, and disease severity was assessed using a combination of validated scoring systems. HLA typing for HLA-B27, HLA-B60, and HLA-DR1 was performed by polymerase chain reaction with sequence- specific primers, and zygosity was assessed using microsatellite markers. Genetic and environmental variance components were assessed with the program Mx, using data from this and previous studies of twins with AS. Results Six of 8 monozygotic (MZ) twin pairs were disease concordant, compared with 4 of 15 B27-positive dizygotic (DZ) twin pairs (27%) and 4 of 32 DZ twin pairs overall (12.5%). Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease-concordant MZ twins compared with concordant DZ twins. HLA-B27 and B60 were associated with the disease in probands, and the rate of disease concordance was significantly increased among DZ twin pairs in which the co- twin was positive for both B27 and DR1. Additive genetic effects were estimated to contribute 97% of the population variance. Conclusion Susceptibility to AS is largely genetically determined, and the environmental trigger for the disease is probably ubiquitous. HLA-B27 accounts for a minority of the overall genetic susceptibility to AS.

Ratcheting and wear behavior of Australian rail steel: Experimental investigation of material properties and sampling method

To The ratcheting behavior of high-strength rail steel (Australian Standard AS1085.1) is studied in this work for the purpose of predicting wear and damage to the rail surface. Historically, researchers have used circular test coupons obtained from the rail head to conduct cyclic load tests, but according to hardness profile data, considerable variation exists across the rail head section. For example, the induction-hardened rail (AS1085.1) shows high hardness (400-430 HV100) up to four-millimeters into the rail head’s surface, but then drops considerably beyond that. Given that cyclic test coupons five millimeters in diameter at the gauge area are usually taken from the rail sample, there is a high probability that the original surface properties of the rail do not apply across the entire test coupon and, therefore, data representing only average material properties are obtained. In the literature, disks (47 mm in diameter) for a twin-disk rolling contact test machine have been obtained directly from the rail sample and used to validate rolling contact fatigue wear models. The question arises: How accurate are such predictions? In this research paper, the effect of rail sampling position on the ratcheting behavior of AS1085.1 rail steel was investigated using rectangular shaped specimens. Uniaxial stress-controlled tests were conducted with samples obtained at four different depths to observe the ratcheting behaviour of each. Micro-hardness measurements of the test coupons were carried out to obtain a constitutive relationship to predict the effect of depth on the ratcheting behaviour of the rail material. This work ultimately assists the selection of valid material parameters for constitutive models in the study of rail surface ratcheting.

Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors

Introduction: Ankylosing spondylitis (AS) is unique in its pathology where inflammation commences at the entheses before progressing to an osteoproliferative phenotype generating excessive bone formation that can result in joint fusion. The underlying mechanisms of this progression are poorly understood. Recent work has suggested that changes in Wnt signalling, a key bone regulatory pathway, may contribute to joint ankylosis in AS. Using the proteoglycan-induced spondylitis (PGISp) mouse model which displays spondylitis and eventual joint fusion following an initial inflammatory stimulus, we have characterised the structural and molecular changes that underlie disease progression. Methods: PGISp mice were characterised 12 weeks after initiation of inflammation using histology, immunohistochemistry (IHC) and expression profiling. Results: Inflammation initiated at the periphery of the intervertebral discs progressing to disc destruction followed by massively excessive cartilage and bone matrix formation, as demonstrated by toluidine blue staining and IHC for collagen type I and osteocalcin, leading to syndesmophyte formation. Expression levels of DKK1 and SOST, Wnt signalling inhibitors highly expressed in joints, were reduced by 49% and 63% respectively in the spine PGISp compared with control mice (P < 0.05) with SOST inhibition confirmed by IHC. Microarray profiling showed genes involved in inflammation and immune-regulation were altered. Further, a number of genes specifically involved in bone regulation including other members of the Wnt pathway were also dysregulated. Conclusions: This study implicates the Wnt pathway as a likely mediator of the mechanism by which inflammation induces bony ankylosis in spondyloarthritis, raising the potential that therapies targeting this pathway may be effective in preventing this process.

Non-major-histocompatibility-complex genetics of ankylosing spondylitis

There is strong evidence from twin and family studies indicating that a substantial proportion of the heritability of susceptibility to ankylosing spondylitis (AS) and its clinical manifestations is encoded by non-major-histocompatibility-complex genes. Efforts to identify these genes have included genomewide linkage studies and candidate gene association studies. One region, the interleukin (IL)-1 gene complex on chromosome 2, has been repeatedly associated with AS in both Caucasians and Asians. It is likely that more than one gene in this complex is involved in AS, with the strongest evidence to date implicating IL-1A. Identifying the genes underlying other linkage regions has been difficult due to the lack of obvious candidates and the low power of most studies to date to identify genes of the small to moderate magnitude that are likely to be involved. The field is moving towards genomewide association analysis, involving much larger datasets of unrelated cases and controls. Early successes using this approach in other diseases indicates that it is likely to identify genes in common diseases like AS, but there remains the risk that the common-variant, common-disease hypothesis will not hold true in AS. Nonetheless, it is appropriate for the field to be cautiously optimistic that the next few years will bring great advances in our understanding of the genetics of this condition.

Genetic susceptibility to ankylosing spondylitis

Ankylosing spondylitis is a highly heritable, common rheumatic condition, primarily affecting the axial skeleton. The association with HLA-B27 has been demonstrated worldwide, and evidence for a role of HLA-B27 in disease comes from linkage and association studies in humans, and transgenic animal models. However, twin studies indicate that HLA-B27 contributes only 16% of the total genetic risk for disease. Furthermore, there is compelling evidence that non-B27 genes, both within and outwith the major histocompatability complex, are involved in disease aetiology. In this post-genomic era we have the tools to help elicit the genetic basis of disease. This review describes methods for genetic investigation of ankylosing spondylitis, and summarises the status of current research in this exciting area.

Genetic aspects of susceptibility, severity, and clinical expression in ankylosing spondylitis

While twin studies have previously demonstrated high heritability of susceptibility to ankylosing spondylitis (AS), it is only recently that the involvement of genetic factors in determining the severity of the disease has been demonstrated. The genes involved in determining the rate of ankylosis in AS are likely to be different from those involved in the underlying immunologic events, and represent important potential targets for treatment of AS. This article will describe the progress that has been made in the genetic epidemiology of AS, and in identifying the genes involved.

The correlation between reading and mathematics ability at age twelve has a substantial genetic component

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve.

Genetic control of bone density and turnover: Role of the collagen 1α1, estrogen receptor, and vitamin D receptor genes

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1α1 (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Implementation mechanism: Protection against harassment of women at workplace

Pakistan is widely known and appreciated in the world for its history, Islamic culture and norms. Since the creation of Pakistan, it inherited poverty in its roots. There are many reasons for poverty but one lies on the shoulder of women who are 50% of the total population of Pakistan. On the apex of it, women do not take part in the development of Pakistan because when they step out of their homes, they suffer a lot of problems. These problems are a hurdle in their active participation in development .Government has tried to create an environment for those women, who suffer different problems. Harassment of women at work place is one of those problems which discourage women in taking active part in economic and social development of society. Women Activists, from the last decade, were working for the protection of woman’s right at workplace and they succeeded in formulation of Harassment Act 2010. Since law is ineffective without its proper mechanism of implementation, steps should be taken for its proper implementation mechanism. This article aims to provide information about the provisions of law, related to the harassment of women at workplace with an attempt to explore the effectiveness of its implementation. The study was conducted in twin cities of Pakistan, Islamabad and Rawalpindi. Interviews were conducted with the employees and employers of organizations, educational institutions, women activists, NGOs workers, lawyers, judges and some law enforcement officers. Group discussions were also held with teachers, students of Human rights and religious personalities. This report focuses on the implementation mechanism of new legislation in Pakistan. It also highlights some important facts related to its enforcement.

Echoes: World music from Queensland

Research background: Echoes-World Music in Queensland is a full-length album produced in collaboration with the Brisbane Multicultural Arts Centre (BEMAC). The project involved the recording and production of 13 different artists’ original compositions and arrangements of traditional works, drawing on hybrid digital-analog production techniques. The recording of the album was informed by prior scholarly work by Taylor, Feld, Wong and others. These existing studies have discussed the complexities of intercultural collaboration, and the types of cultural politics that are involved in the recording and distribution of what has been known by the term ‘World Music.’ Aspects of applied ethnomusicology have informed the creative work, as a means of interpreting the implicit and explicit complexities that arise through the recording and dissemination of intercultural creative practice. The project asked the research question, in what ways is intercultural music making effected by collaborative practices in the recording studio? Research contribution: This project has identified that the recording and production of intercultural music making involves a complex amalgam of aspects of live or ‘authentic’ performance practices, alongside highly mediated production practices that are influenced by new forms of digital recording technology. Research significance: The compact disc was launched at a live performance showcase as part of the 2014 Big Sound music industry conference, and was added to feature album rotation for all Virgin Australia flights in February-March 2015. The album has received airplay on Radio National, Edge Radio (Hobart) and Radio Adelaide, and was a Feature Album on PBS FM (Melbourne), 2SER (Sydney), and ArtsoundFM Canberrra. The research context of the work is detailed in Gavin Carfoot (in press), ‘Musical discovery, colonialism and the possibilities of intercultural communication through music’ in Popular Communication.

Mrs Curly and the Norwegian Smoking Pipe

Research background: Mrs Curly and the Norwegian Smoking Pipe is a full-length album and book release, produced in collaboration with renowned multi-instrumentalist Linsey Pollak. The project involved the recording and production of Pollak’s original compositions and arrangements of traditional works, drawing on hybrid digital-analog production techniques. The recording of the album was informed by prior scholarly work by Taylor, Feld, Wong and others. These existing studies have discussed the complexities of intercultural collaboration, and the types of cultural politics that are involved in the recording and distribution of what has been known by the term ‘World Music.’ Aspects of applied ethnomusicology have informed the creative work, as a means of interpreting the implicit and explicit complexities that arise through the recording and dissemination of intercultural creative practice. The project asked the research question, in what ways is intercultural music making effected by collaborative practices in the recording studio? Research contribution: This project has identified that the recording and production of intercultural music making involves a complex amalgam of aspects of live or ‘authentic’ performance practices, alongside highly mediated production practices that are influenced by new forms of digital recording technology. Research significance: The compact disc and book was released and promoted on the Marata Music label. The song ‘Plačam za’ was nominated in the World category of the 2015 Queensland Music Awards. The research context of the work is detailed in Gavin Carfoot, 2015 (in press), ‘Musical discovery, colonialism and the possibilities of intercultural communication through music’ in Popular Communication.

Partial intervertebral fusion secures successful outcomes after thoracoscopic anterior scoliosis correction: A low-dose computed tomography study

Study Design Retrospective review of prospectively collected data. Objectives To analyze intervertebral (IV) fusion after thoracoscopic anterior spinal fusion (TASF) and explore the relationship between fusion scores and key clinical variables. Summary of Background Information TASF provides comparable correction with some advantages over posterior approaches but reported mechanical complications, and their relationship to non-union and graft material is unclear. Similarly, the optimal combination of graft type and implant stiffness for effecting successful radiologic union remains undetermined. Methods A subset of patients from a large single-center series who had TASF for progressive scoliosis underwent low-dose computed tomographic scans 2 years after surgery. The IV fusion mass in the disc space was assessed using the 4-point Sucato scale, where 1 indicates <50% and 4 indicates 100% bony fusion of the disc space. The effects of rod diameter, rod material, graft type, fusion level, and mechanical complications on fusion scores were assessed. Results Forty-three patients with right thoracic major curves (mean age 14.9 years) participated in the study. Mean fusion scores for patient subgroups ranged from 1.0 (IV levels with rod fractures) to 2.2 (4.5-mm rod with allograft), with scores tending to decrease with increasing rod size and stiffness. Graft type (autograft vs. allograft) did not affect fusion scores. Fusion scores were highest in the middle levels of the rod construct (mean 2.52), dropping off by 20% to 30% toward the upper and lower extremities of the rod. IV levels where a rod fractured had lower overall mean fusion scores compared to levels without a fracture. Mean total Scoliosis Research Society (SRS) questionnaire scores were 98.9 from a possible total of 120, indicating a good level of patient satisfaction. Conclusions Results suggest that 100% radiologic fusion of the entire disc space is not necessary for successful clinical outcomes following thoracoscopic anterior selective thoracic fusion.

Prevalence and developmental course of 'secret language'.

The prevalence and developmental course of supposed ‘secret language’ was examined in a cohort of twins and closely spaced singletons pairs, with systematic assessments at 20 months and again at 36 months. Two forms of apparent ‘secret language’ were examined: (1) shared understanding—speech directed generally but unintelligible to the parent, although apparently clearly understood within the child pair, and (2) private language directed exclusively to the other twin/sibling—not intelligible to the parent, but apparently clearly understood and used only within the child pair. Both occurred in singleton pairs, but the rate was much higher in twins. In most cases it seemed to be a developmental phenomenon occurring in the second year of life with the emergence of immature speech, and decreasing considerably over the next 16 months. A small group of children, primarily male twins, was reported to use a private language at 36 months. This group had poorer cognitive and language functioning, and was characterized by highly dependent relationships. Some aspects of the twins’ home environment were less stimulating and less responsive, most probably reflecting the abilities and relationships of the children. A follow-up of these children when they were ~6 years of age showed that language outcome was poor for the subgroup (n = 4) who did not develop normal language alongside the use of a private language.

Comparison of prevalence of depression in mothers of twins and mothers of singletons

OBJECTIVE To determine whether the apparent additional and exceptional stresses associated with bearing and parenting twins affect the emotional wellbeing of mothers. SETTING--Great Britain, 1970-5. DESIGN Cohort study of 13,135 children born between 4 April and 11 April 1970. Mothers of all children, both singletons and twins, were interviewed by health visitors (providing demographic data) and completed a self report measure of emotional well-being (the Rutter malaise inventory) when the child was 5 years of age. The malaise scores of mothers of twins were compared with those of all mothers of singletons and then with those of mothers categorised by the age spacing of their children (only one child, widely spaced, or closely spaced), taking account of maternal age, social class, and whether the study child had a disability, by using logistic regression. SUBJECTS 139 mothers of twins--122 pairs of twins and 17 twins whose cotwin had died--and 12,573 controls, who were mothers of singletons. RESULTS A significantly higher proportion of mothers of twins at 5 years had malaise scores indicative of depression than mothers of singletons at the same age. Mothers who had borne twins, one of whom had subsequently died, had the highest malaise scores and were three times more likely than mothers of singletons to experience depression. Both mothers of twin pairs and mothers of singletons closely spaced in age were at significantly higher risk of experiencing depression than mothers of children widely spaced in age or mothers of only one child (p less than 0.0001). Odds ratios indicated that the risk of depression in mothers of twins was higher than that in mothers of closely spaced singletons. CONCLUSION Mothers of twins are more likely to experience depression. This suggests a relation between the additional and exceptional stresses that twins present and the mother's emotional wellbeing.

Understanding how axial loads on the spine influence segmental biomechanics for idiopathic scoliosis patients: A magnetic resonance imaging study

Background Segmental biomechanics of the scoliotic spine are important since the overall spinal deformity is comprised of the cumulative coronal and axial rotations of individual joints. This study investigates the coronal plane segmental biomechanics for adolescent idiopathic scoliosis patients in response to physiologically relevant axial compression. Methods Individual spinal joint compliance in the coronal plane was measured for a series of 15 idiopathic scoliosis patients using axially loaded magnetic resonance imaging. Each patient was first imaged in the supine position with no axial load, and then again following application of an axial compressive load. Coronal plane disc wedge angles in the unloaded and loaded configurations were measured. Joint moments exerted by the axial compressive load were used to derive estimates of individual joint compliance. Findings The mean standing major Cobb angle for this patient series was 46°. Mean intra-observer measurement error for endplate inclination was 1.6°. Following loading, initially highly wedged discs demonstrated a smaller change in wedge angle, than less wedged discs for certain spinal levels (+ 2,+1,− 2 relative to the apex, (p < 0.05)). Highly wedged discs were observed near the apex of the curve, which corresponded to lower joint compliance in the apical region. Interpretation While individual patients exhibit substantial variability in disc wedge angles and joint compliance, overall there is a pattern of increased disc wedging near the curve apex, and reduced joint compliance in this region. Approaches such as this can provide valuable biomechanical data on in vivo spinal biomechanics of the scoliotic spine, for analysis of deformity progression and surgical planning.