The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda ≤ 1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.

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.

Limited utility of exercise stress testing in the evaluation of suspected acute coronary syndrome in patients aged less than 40 years with intermediate risk features

Objective National guidelines for management of intermediate risk patients with suspected acute coronary syndrome, in whom AMI has been excluded, advocate provocative testing to final risk stratify these patients into low risk (negative testing) or high risk (positive testing suggestive of unstable angina). Adults less than 40 years have a low pretest probability of acute coronary syndrome. The utility of exercise stress testing in young adults with chest pain suspected of acute coronary syndrome who have National Heart Foundation intermediate risk features was evaluated Methods A retrospective analysis of exercise stress testing performed on patients less than 40 years was evaluated. Patients were enrolled on a chest pain pathway and had negative serial ECGs and cardiac biomarkers before exercise stress testing to rule-out acute coronary syndrome. Chart review was completed on patients with positive stress tests. Results The 3987 patients with suspected intermediate risk acute coronary syndrome underwent exercise stress testing. One thousand and twenty-seven (25.8%) were aged less than 40 years (age 33.3 ± 4.8 years). Four of these 1027 patients had a positive exercise stress test (0.4% incidence of positive exercise stress testing). Of those, three patients had subsequent non-invasive functional testing that yielded a negative result. One patient declined further investigations. Assuming this was a true positive exercise stress test, the incidence of true positive exercise stress testing would have been 0.097% (95% confidence interval: 0.079–0.115%) (one of 1027 patients). Conclusions Routine exercise stress testing has limited value in the risk stratification of adults less than 40 years with suspected intermediate risk of acute coronary syndrome

Predictive models for water sources with high susceptibility for bromine-containing disinfection by-product formation: Implications for water treatment

This study examines a matrix of synthetic water samples designed to include conditions that favour brominated disinfection by-product (Br-DBP) formation, in order to provide predictive models suitable for high Br-DBP forming waters such as salinity-impacted waters. Br-DBPs are known to be more toxic than their chlorinated analogues, in general, and their formation may be favoured by routine water treatment practices such as coagulation/flocculation under specific conditions; therefore, circumstances surrounding their formation must be understood. The chosen factors were bromide concentration, mineral alkalinity, bromide to dissolved organic carbon (Br/DOC) ratio and Suwannee River natural organic matter concentration. The relationships between these parameters and DBP formation were evaluated by response surface modelling of data generated using a face-centred central composite experimental design. Predictive models for ten brominated and/or chlorinated DBPs are presented, as well as models for total trihalomethanes (tTHMs) and total dihaloacetonitriles (tDHANs), and bromide substitution factors for the THMs and DHANs classes. The relationships described revealed that increasing alkalinity and increasing Br/DOC ratio were associated with increasing bromination of THMs and DHANs, suggesting that DOC lowering treatment methods that do not also remove bromide such as enhanced coagulation may create optimal conditions for Br-DBP formation in waters in which bromide is present.

Proteogenomics of selective susceptibility to endotoxin using circulating acute phase biomarkers and bioassay development in sheep: a review

Scientists have injected endotoxin into animals to investigate and understand various pathologies and novel therapies for several decades. Recent observations have shown that there is selective susceptibility to Escherichia coli lipopolysaccharide (LPS) endotoxin in sheep, despite having similar breed characteristics. The reason behind this difference is unknown, and has prompted studies aiming to explain the variation by proteogenomic characterisation of circulating acute phase biomarkers. It is hypothesised that genetic trait, biochemical, immunological and inflammation marker patterns contribute in defining and predicting mammalian response to LPS. This review discusses the effects of endotoxin and host responses, genetic basis of innate defences, activation of the acute phase response (APR) following experimental LPS challenge, and the current approaches employed in detecting novel biomarkers including acute phase proteins (APP) and micro-ribonucleic acids (miRNAs) in serum or plasma. miRNAs are novel targets for elucidating molecular mechanisms of disease because of their differential expression during pathological, and in healthy states. Changes in miRNA profiles during a disease challenge may be reflected in plasma. Studies show that gel-based two-dimensional electrophoresis (2-DE) coupled with either matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) or liquid chromatography-mass spectrometry (LC-MS/MS) are currently the most used methods for proteome characterisation. Further evidence suggests that proteomic investigations are preferentially shifting from 2-DE to non-gel based LC-MS/MS coupled with data extraction by sequential window acquisition of all theoretical fragment-ion spectra (SWATH) approaches that are able to identify a wider range of proteins. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and most recently proteomic methods have been used to quantify low abundance proteins such as cytokines. qRT-PCR and next generation sequencing (NGS) are used for the characterisation of miRNA. Proteogenomic approaches for detecting APP and novel miRNA profiling are essential in understanding the selective resistance to endotoxin in sheep. The results of these methods could help in understanding similar pathology in humans. It might also be helpful in the development of physiological and diagnostic screening assays for determining experimental inclusion and endpoints, and in clinical trials in future

Towards development of a rapid and effective non-destructive testing strategy to identify brominated flame retardants in the plastics of consumer products

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants (BFRs) once extensively used in the plastics of a wide range of consumer products. The listing of certain congeners that are constituents of commercial PBDE mixtures (including c-octaBDE) in the Stockholm Convention and tightening regulation of many other BFRs in recent years have created the need for a rapid and effective method of identifying BFR-containing plastics. A three-tiered testing strategy comparing results from non-destructive testing (X-ray fluorescence (XRF)) (n = 1714), a surface wipe test (n = 137) and destructive chemical analysis (n = 48) was undertaken to systematically identify BFRs in a wide range of consumer products. XRF rapidly identified bromine in 92% of products later confirmed to contain BFRs. Surface wipes of products identified tetrabromobisphenol A (TBBPA), c-octaBDE congeners and BDE-209 with relatively high accuracy (> 75%) when confirmed by destructive chemical analysis. A relationship between the amounts of BFRs detected in surface wipes and subsequent destructive testing shows promise in predicting not only the types of BFRs present but also estimating the concentrations present. Information about the types of products that may contain persistent BFRs will assist regulators in implementing policies to further reduce the occurrence of these chemicals in consumer products.

ISPCAN child abuse screening tool children's version (ICAST-C): Instrument development and multi-national pilot testing

Objective To develop a child victimization survey among a diverse group of child protection experts and examine the performance of the instrument through a set of international pilot studies. Methods The initial draft of the instrument was developed after input from scientists and practitioners representing 40 countries. Volunteers from the larger group of scientists participating in the Delphi review of the ICAST P and R reviewed the ICAST C by email in 2 rounds resulting in a final instrument. The ICAST C was then translated and back translated into six languages and field tested in four countries using a convenience sample of 571 children 12–17 years of age selected from schools and classrooms to which the investigators had easy access. Results The final ICAST C Home has 38 items and the ICAST C Institution has 44 items. These items serve as screeners and positive endorsements are followed by queries for frequency and perpetrator. Half of respondents were boys (49%). Endorsement for various forms of victimization ranged from 0 to 51%. Many children report violence exposure (51%), physical victimization (55%), psychological victimization (66%), sexual victimization (18%), and neglect in their homes (37%) in the last year. High rates of physical victimization (57%), psychological victimization (59%), and sexual victimization (22%) were also reported in schools in the last year. Internal consistency was moderate to high (alpha between .685 and .855) and missing data low (less than 1.5% for all but one item). Conclusions In pilot testing, the ICAST C identifies high rates of child victimization in all domains. Rates of missing data are low, and internal consistency is moderate to high. Pilot testing demonstrated the feasibility of using child self-report as one strategy to assess child victimization. Practice implications The ICAST C is a multi-national, multi-lingual, consensus-based survey instrument. It is available in six languages for international research to estimate child victimization. Assessing the prevalence of child victimization is critical in understanding the scope of the problem, setting national and local priorities, and garnering support for program and policy development aimed at child protection.

Design and flight testing of an integrated solar powered UAV and WSN for greenhouse gas monitoring emissions in agricultural farms

There is an increased interest in measuring the amount of greenhouse gases produced by farming practices . This paper describes an integrated solar powered Unmanned Air Vehicles (UAV) and Wireless Sensor Network (WSN) gas sensing system for greenhouse gas emissions in agricultural lands. The system uses a generic gas sensing system for CH4 and CO2 concentrations using metal oxide (MoX) and non-dispersive infrared sensors, and a new solar cell encapsulation method to power the unmanned aerial system (UAS)as well as a data management platform to store, analyze and share the information with operators and external users. The system was successfully field tested at ground and low altitudes, collecting, storing and transmitting data in real time to a central node for analysis and 3D mapping. The system can be used in a wide range of outdoor applications at a relatively low operational cost. In particular, agricultural environments are increasingly subject to emissions mitigation policies. Accurate measurements of CH4 and CO2 with its temporal and spatial variability can provide farm managers key information to plan agricultural practices. A video of the bench and flight test performed can be seen in the following link: https://www.youtube.com/watch?v=Bwas7stYIxQ

Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus

To discover quantitative trait loci for intraocular pressure, amajor risk factor for glaucoma and the only modifiable one,weperformed agenome-wide association studyonadiscoverycohort of2175individualsfromSydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10-8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30-0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.

Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P combined = 2.76 × 10 -17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species. © 2013 Nature America, Inc. All rights reserved.

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense. © 2012 Nature America, Inc. All rights reserved.

ANKH and susceptibility to and severity of ankylosing spondylitis

Objective. Unconfirmed reports describe association of ankylosing spondylitis (AS) with several candidate genes including ANKH. Cellular export of inorganic pyrophosphate is regulated by the ANK protein, and mutant mice (ank/ank), which have a premature stop codon in the 3′ end of the ank gene, develop severe ankylosis. We tested the association between single-nucleotide polymorphisms (SNP) in these genes and susceptibility to AS in a population of patients with AS. We investigated the role of these genes in terms of functional (BASFI) and metrological (BASMI) measures, and the association with radiological severity (mSASSS). Methods. Our study was conducted on 355 patients with AS and 95 ethnically matched healthy controls. AS was defined according to the modified New York criteria. Four SNP in ANKH (rs27356, rs26307, rs25957, and rs28006) were genotyped. Association analysis was performed using Cochrane-Armitage and linear regression tests for dichotomous and quantitative variables. Analyses of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASFI, and mSASSS were controlled for sex and disease duration. Results. None of the 4 markers showed significant single-locus disease associations (p > 0.05), suggesting that ANKH was not a major determinant of AS susceptibility in our population. No association was observed between these SNP and age at symptom onset, BASDAI, BASFI, BASMI, or mSASSS. Conclusion. These results confirm data in white Europeans that ANKH is probably not a major determinant of susceptibility to AS. ANKH polymorphisms do not markedly influence AS disease severity, as measured by BASMI and mSASSS. The Journal of Rheumatology

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10-8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10-6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10-10) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10-9). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10-14, OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10-14, OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma. © 2011 Nature America, Inc. All rights reserved.