Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis

Objectives - It has long been suspected that susceptibility to ankylosing spondylitis (AS) is influenced by genes lying distant to the major histocompatibility complex. This study compares genetic models of AS to assess the most likely mode of inheritance, using recurrence risk ratios in relatives of affected subjects. Methods - Recurrence risk ratios in different degrees of relatives were determined using published data from studies specifically designed to address the question. The methods of Risch were used to determine the expected recurrence risk ratios in different degrees of relatives, assuming equal first degree relative recurrence risk between models. Goodness of fit was determined by χ2 comparison of the expected number of affected subjects with the observed number, given equal numbers of each type of relative studied. Results - The recurrence risks in different degrees of relatives were: monozygotic (MZ) twins 63% (17/27), first degree relatives 8.2% (441/5390), second degree relatives 1.0% (8/834), and third degree relatives 0.7% (7/997). Parent-child recurrence risk (7.9%, 37/466) was not significantly different from the sibling recurrence risk (8.2%, 404/4924), excluding a significant dominance genetic component to susceptibility. Poor fitting models included single gene, genetic heterogeneity, additive, two locus multiplicative, and one locus and residual polygenes (χ2 > 32 (two degrees of freedom), p < 10-6 for all models). The best fitting model studied was a five locus model with multiplicative interaction between loci (χ2 = 1.4 (two degrees of freedom), p = 0.5). Oligogenic multiplicative models were the best fitting over a range of population prevalences and first degree recurrence risk rates. Conclusions - This study suggests that of the genetic models tested, the most likely model operating in AS is an oligogenic model with predominantly multiplicative interaction between loci.

An immunodiagnostic assay for quantitation of specific ige to the major pollen allergen component, pas n 1, of the subtropical bahia grass

Background Pollens of the Panicoideae subfamily of grasses including Bahia (Paspalum notatum) are important allergen sources in subtropical regions of the world. An assay for specific IgE to the major molecular allergenic component, Pas n 1, of Bahia grass pollen (BaGP) would have immunodiagnostic utility for patients with pollen allergy in these regions. Methods Biotinylated Pas n 1 purified from BaGP was coated onto streptavidin ImmunoCAPs. Subjects were assessed by clinical history of allergic rhinitis and skin prick test (SPT) to aeroallergens. Serum total, BaGP-specific and Pas n 1-specific IgE were measured. Results: Pas n 1 IgE concentrations were highly correlated with BaGP SPT (r = 0.795, p < 0.0001) and BaGP IgE (r = 0.915, p < 0.0001). At 0.23 kU/l Pas n 1 IgE, the diagnostic sensitivity (92.4%) and specificity (93.1%) for the detection of BaGP allergy was high (area under receiver operator curve 0.960, p < 0.0001). The median concentrations of Pas n 1 IgE in non-Atopic subjects (0.01 kU/l, n = 67) and those with other allergies (0.02 kU/l, n = 59) showed no inter-group difference, whilst grass pollen-Allergic patients with allergic rhinitis showed elevated Pas n 1 IgE (6.71 kU/l, n = 182, p < 0.0001). The inter-Assay coefficient of variation for the BaGP-Allergic serum pool was 6.92%. Conclusions Pas n 1 IgE appears to account for most of the BaGP-specific IgE. This molecular component immunoassay for Pas n 1 IgE has potential utility to improve the sensitivity and accuracy of diagnosis of BaGP allergy for patients in subtropical regions.

Antibody reactivity to the transmembrane protein of the caprine arthritis encephalitis virus correlates with severity of arthritis: No evidence for the involvement of epitope mimicry

Serum and synovial antibody reactivities of caprine arthritis encephalitis virus (CAEV) infected goats were assessed by Western blotting against purified CAEV antigen and the greatest intensity of reactivity in the serum of arthritic goats was to the gp45 transmembrane protein (TM). The extracytoplasmic domain of the TM gene was cloned into a pGEX vector and expressed in Escherichia coil as a glutathione S transferase fusion protein (GST-TM). This clone was found to be 90.5 and 89.2% homologous to published sequences of CAEV TM gene. Serum of 16 goats naturally infected with CAEV were examined by Western blotting for reactivity to the fusion protein. Antibody reactivity to the GST-TM correlated with clinically detectable arthritis (R = 0.642, P ≤ 0.007). The hypothesis that the immune response to the envelope proteins of the CAEV contributes to the severity of arthritis in goats naturally infected with CAEV via epitope mimicry was tested. Antibodies from 5 CAEV infected goats were affinity purified against the GST-TM fusion protein and tested for cross-reactivity with a series of goat synovial extracts and proteogylcans. No serum antibody response or cross-reactivity of affinity purified antibodies could be detected. Peptides of the CAEV SU that were predicted to be linear epitopes and a similar heat shock protein 83 (HSP) peptide identified by database searching, were synthesized and tested for reactivity in CAEV goats using ELISA, in vitro lymphocyte proliferation and delayed type hypersensitivity (DTH) assays. Peripheral blood lymphocytes from 10 of 17 goats with long term natural CAEV infections proliferated in vitro in response to CAEV and in vivo 3 of 7 CAEV infected goats had a DTH reaction to CAEV antigen. However, none of the peptides elicited significant cell mediated immune responses from CAEV infected goats. No antibody reactivity to the SU peptides or HSP peptide was found. We observed that the antibody reactivity to the CAEV TM protein associated with severity of arthritis however epitope mimicry by the envelope proteins of CAEV is unlikely to be involved.

The application of building information modeling to enhance organisational learning

The construction industry is a knowledge-based industry where various actors with diverse expertise create unique information within different phases of a project. The industry has been criticized by researchers and practitioners as being unable to apply newly created knowledge effectively to innovate. The fragmented nature of the construction industry reduces the opportunity of project participants to learn from each other and absorb knowledge. Building Information Modelling (BIM), referring to digital representations of constructed facilities, is a promising technological advance that has been proposed to assist in the sharing of knowledge and creation of linkages between firms. Previous studies have mainly focused on the technical attributes of BIM and there is little evidence on its capability to enhance learning in construction firms. This conceptual paper identifies six ‘functional attributes’ of BIM that act as triggers to stimulate learning: (1) comprehensibility; (2) predictability; (3) accuracy; (4) transparency; (5) mutual understanding and; (6) integration.

Using the factors that have a positive impact on the retention of low socioeconomic students to prepare accelerated enrolled nurses for the science units of a nursing degree : a practice report

At a campus in a low socioeconomic (SES) area, our University allows enrolled nurses entry into the second year of a Bachelor of Nursing, but attrition is high. Using the factors, described by Yorke and Thomas (2003) to have a positive impact on the attrition of low SES students, we developed strategies to prepare the enrolled nurses for the pharmacology and bioscience units of a nursing degree with the aim of reducing their attrition. As a strategy, the introduction of review lectures of anatomy, physiology and microbiology, was associated with significantly reduced attrition rates. The subsequent introduction of a formative website activity of some basic concepts in bioscience and pharmacology, and a workshop addressing study skills and online resources, were associated with a further reduction in attrition rates of enrolled nursing students in a Bachelor of Nursing.

The dependence of computed tomography number to relative electron density conversion on phantom geometry and its impact on planned dose

A computed tomography number to relative electron density (CT-RED) calibration is performed when commissioning a radiotherapy CT scanner by imaging a calibration phantom with inserts of specified RED and recording the CT number displayed. In this work, CT-RED calibrations were generated using several commercially available phantoms to observe the effect of phantom geometry on conversion to electron density and, ultimately, the dose calculation in a treatment planning system. Using an anthropomorphic phantom as a gold standard, the CT number of a material was found to depend strongly on the amount and type of scattering material surrounding the volume of interest, with the largest variation observed for the highest density material tested, cortical bone. Cortical bone gave a maximum CT number difference of 1,110 when a cylindrical insert of diameter 28 mm scanned free in air was compared to that in the form of a 30 × 30 cm2 slab. The effect of using each CT-RED calibration on planned dose to a patient was quantified using a commercially available treatment planning system. When all calibrations were compared to the anthropomorphic calibration, the largest percentage dose difference was 4.2 % which occurred when the CT-RED calibration curve was acquired with heterogeneity inserts removed from the phantom and scanned free in air. The maximum dose difference observed between two dedicated CT-RED phantoms was ±2.1 %. A phantom that is to be used for CT-RED calibrations must have sufficient water equivalent scattering material surrounding the heterogeneous objects that are to be used for calibration.

The ovarian response to controlled stimulation in IVF cycles may be predictive of the age at menopause

STUDY QUESTION Can the number of oocytes retrieved in IVF cycles be predictive of the age at menopause? SUMMARY ANSWER The number of retrieved oocytes can be used as an indirect assessment of the extent of ovarian reserve to provide information on the duration of the reproductive life span in women of different ages. WHAT IS KNOWN ALREADY Menopause is determined by the exhaustion of the ovarian follicular pool. Ovarian reserve is the main factor influencing ovarian response in IVF cycles. As a consequence the response to ovarian stimulation with the administration of gonadotrophins in IVF treatment may be informative about the age at menopause. STUDY DESIGN, SIZE, DURATION In the present cross-sectional study, participants were 1585 infertile women from an IVF clinic and 2635 menopausal women from a more general population. PARTICIPANTS/MATERIALS, SETTING, METHODS For all infertile women, the response to ovarian stimulation with gonadotrophins was recorded. For menopausal women, relevant demographic characteristics were available for the analysis. MAIN RESULTS AND THE ROLE OF CHANCE A cubic function described the relationship between mean numbers of oocytes and age, with all terms being statistically significant. From the estimated residual distribution of the actual number of oocytes about this mean, a distribution of the age when there would be no oocytes retrieved following ovarian stimulation was derived. This was compared with the distribution of the age at menopause from the menopausal women, showing that menopause occurred about a year later. LIMITATIONS, REASONS FOR CAUTION The retrieved oocyte data were from infertile women, while the menopausal ages were from a more general population. WIDER IMPLICATIONS OF THE FINDINGS In the present study, we have shown some similarity between the distributions of the age when no retrieved oocytes can be expected after ovarian stimulation and the age at menopause. For a given age, the lower the ovarian reserve, the lower the number of retrieved oocytes would be and the earlier the age that menopause would occur.

Visual fingerprints of the acoustic environment: The use of acoustic indices to characterise natural habitats

Acoustic recordings play an increasingly important role in monitoring terrestrial environments. However, due to rapid advances in technology, ecologists are accumulating more audio than they can listen to. Our approach to this big-data challenge is to visualize the content of long-duration audio recordings by calculating acoustic indices. These are statistics which describe the temporal-spectral distribution of acoustic energy and reflect content of ecological interest. We combine spectral indices to produce false-color spectrogram images. These not only reveal acoustic content but also facilitate navigation. An additional analytic challenge is to find appropriate descriptors to summarize the content of 24-hour recordings, so that it becomes possible to monitor long-term changes in the acoustic environment at a single location and to compare the acoustic environments of different locations. We describe a 24-hour ‘acoustic-fingerprint’ which shows some preliminary promise.

Australia's disabling income support system: Tracing the history of the disability pension from 1908 to today

This article is based on a historical-comparative policy and discourse analysis of the principles underpinning the Australian disability income support system. It determines that these principles rely on a conception of disability that sustains a system of coercion and paternalism that perpetuates disability and referred to as disablism. The article examines the construction of disability in Australian income support across four major historical epochs spanning the period 1908-2007. Contextualisation of the policy trajectory and discourses of the contemporary disability pension regime for the time period 2008-now is also provided. Two major themes were found to have interacted with the ideology of disablism. This article argues that a non-disabling provision based on social citizenship, rather than responsible or productive citizenship, counters the tendency for authoritarian and paternal approaches. [Abridged]

Mapping the regulatory sequences controlling 93 breast cancer-associated miRNA genes leads to the identification of two functional promoters of the Hsa-mir-200b cluster, methylation of which is associated with metastasis or hormone receptor status in advanced breast cancer

MicroRNAs (miRNAs) are small non-coding RNAs of 20 nt in length that are capable of modulating gene expression post-transcriptionally. Although miRNAs have been implicated in cancer, including breast cancer, the regulation of miRNA transcription and the role of defects in this process in cancer is not well understood. In this study we have mapped the promoters of 93 breast cancer-associated miRNAs, and then looked for associations between DNA methylation of 15 of these promoters and miRNA expression in breast cancer cells. The miRNA promoters with clearest association between DNA methylation and expression included a previously described and a novel promoter of the Hsa-mir-200b cluster. The novel promoter of the Hsa-mir-200b cluster, denoted P2, is located 2 kb upstream of the 5′ stemloop and maps within a CpG island. P2 has comparable promoter activity to the previously reported promoter (P1), and is able to drive the expression of miR-200b in its endogenous genomic context. DNA methylation of both P1 and P2 was inversely associated with miR-200b expression in eight out of nine breast cancer cell lines, and in vitro methylation of both promoters repressed their activity in reporter assays. In clinical samples, P1 and P2 were differentially methylated with methylation inversely associated with miR-200b expression. P1 was hypermethylated in metastatic lymph nodes compared with matched primary breast tumours whereas P2 hypermethylation was associated with loss of either oestrogen receptor or progesterone receptor. Hypomethylation of P2 was associated with gain of HER2 and androgen receptor expression. These data suggest an association between miR-200b regulation and breast cancer subtype and a potential use of DNA methylation of miRNA promoters as a component of a suite of breast cancer biomarkers.

Polymorphism in codon 17 of the CTLA-4 gene (+49 A/G) is not associated with susceptibility to rheumatoid arthritis in British Caucasians

The role of the CTLA-4 antigen in the development of autoimmune diseases is well documented, with several autoimmune disorders showing association or linkage with the CTLA-4 locus. Its role in the aetiology of rheumatoid arthritis (RA) however, remains unclear, as the functional studies of the B7-CTLA-4 pathway in mouse models of RA and genetic studies in humans have given contrasting results. We have studied the single nucleotide polymorphism at position +49 (A/G) of the CTLA-4 gene, in a cohort of 421 RA cases and 452 healthy controls from the UK. Despite the high statistical power to detect even a weak susceptibility effect, no significant association was found. We also analysed the distribution of the allele and genotype frequencies with respect to the presence of the shared epitope (a known RA susceptibility factor) and found no statistically significant differences. We conclude that, although the importance of the B7-CTLA-4 interaction in the development of RA can not be excluded, the CTLA-4 gene is unlikely to be a predisposing factor to this disease.

Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis

Ankylosing spondylitis (AS) is a common and highly familial rheumatic disorder. The sibling recurrence risk ratio for the disease is 63 and heritability assessed in twins > 90%. Although MHC genes, including HLA-B27, contribute only 20-50% of the genetic risk for the disease, no non-MHC gene has yet been convincingly demonstrated to influence either susceptibility to the disease or its phenotypic expression. Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13.1. We performed a linkage study of chromosome 22 in 200 families with AS affected sibling-pairs. Association of alleles of the CYP2D6 gene was examined by both case-control and within-family means. For case-control studies, 617 unrelated individuals with AS (361 probands from sibling-pair and parent-case trio families and 256 unrelated non-familial sporadic cases) and 402 healthy ethnically matched controls were employed. For within-family association studies, 361 families including 161 parent-case trios and 200 affected sibling-pair families were employed. Homozygosity for poor metabolizer alleles was found to be associated with AS. Heterozygosity for the most frequent poor metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. We postulate that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.

Suggestive linkage of the parathyroid receptor type 1 to osteoporosis

We have investigated the role of 23 candidate genes in the control of bone mineral density (BMD) by linkage studies in families of probands with osteoporosis (lumbar spine [LS] or femoral neck [FN] BMD T score < -2.5) and low BMD relative to an age- and gender-matched cohort (Z score < -2.0). One hundred and fifteen probands (35 male, 80 female) and 499 of their first- or second-degree relatives (223 males and 276 females) were recruited for the study. BMD was measured at the LS and FN using dual-energy X-ray absorptiometry and expressed as age- and gender-matched Z scores corrected for body mass index. The candidate genes studied were the androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony-stimulating factor 1, calcium-sensing receptor, epidermal growth factor (EGF), estrogen receptor 1 (ESR1), fibrillin type 1, insulin-like growth factor 1, interleukin-1 alpha (IL-1α), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-11 (IL-11), osteopontin, parathyroid hormone (PTH), PTH-related peptide, PTH receptor type 1 (PTHR1), transforming growth factor-beta 1, and tumor necrosis factors alpha and beta. Sixty-four microsatellites lying close to or within these genes were investigated for linkage with BMD. Using the program MapMaker/Sibs there was suggestive evidence of linkage between BMD and PTHR1 (maximum LOD score obtained [MLS] 2.7-3.5). Moderate evidence of linkage was also observed with EGF (MLS 1.8), COLIA1 (MLS 1.7), COLIIA1/VDR (MLS 1.7), ESR1 (MLS 1.4), IL-1α (MLS 1.4), IL-4 (MLS 1.2), and IL-6 (MLS 1.2). Variance components analysis using the program ACT, correcting for proband-wise ascertainment, also showed evidence of linkage (p ≤0.05) at markers close to or within the candidate genes IL- 1α, PTHR1, IL-6, and COLIIA1/VDR. Further studies will be required to confirm these findings, to refine the location of gene responsible for the observed linkage, and to screen the candidate genes targeted at these loci for mutations.

SecB binds only to a late native-like intermediate in the folding pathway of barstar and not to the unfolded state

SecB is a cytosolic, tetrameric chaperone of Escherichia coli which maintains precursor proteins in a translocation competent state. We have investigated the effect of SecB on the refolding kinetics of the small protein barstar in I M guanidine hydrochloride at pH 7.0 and 25 degrees C using fluorescence spectroscopy. We show that SecB does not bind either the native or the unfolded states of barstar but binds to a late near-native intermediate along the folding pathway. For barstar, polypeptide collapse and formation of a hydrophobic surface are required for binding to SecB. SecB does not change the apparent rate constant of barstar refolding. The kinetic data for SecB binding to barstar are not consistent with simple kinetic partitioning models.

An investigation into drink driving among aboriginal and Torres strait islander peoples in regional and remote Queensland and the development of the 'Hero to Healing' program

This program of research investigated the factors facilitating drink driving in Indigenous communities in Far North Queensland. Drink driving-related road crashes are a significant health burden for Indigenous people, as they die in road crashes at three times the rate of other Australians and are 30% more likely to be seriously injured. This research provided information to develop and pilot a culturally-specific program, 'Hero to Healing'. The main motivation to drink drive was related to 'kinship pressure; where drivers were pressured by family members to drive after drinking. The underlying responsibility for transporting family members was related to cultural values and involved responding to family needs as a priority. Exposure to older family members drink driving was considered to play a role in normalising the behaviour, leading to imitation into adulthood. The research highlighted the need to treat drink driving as a community issue, rather than an individual phenomenon.