Development of polymorphic microsatellite markers suitable for genetic linkage mapping of olive flounder Paralichthys olivaceus

Microsatellite markers are important for gene mapping and for marker-assisted selection. Sixty-five polymorphic microsatellite markers were developed with an enriched partial genomic library from olive flounder Paralichthys olivaceus an important commercial fish species in Korea. The variability of these markers was tested in 30 individuals collected from the East Sea (Korea). The number of alleles for each locus ranged from 2 to 33 (mean, 17.1). Observed and expected heterozygosity as well as polymorphism information content varied from 0.313 to 1.000 (mean, 0.788), from 0.323 to 0.977 (mean, 0.820), and from 0.277 to 0.960 (mean, 0.787), respectively. Nine loci showed significant deviation from the Hardy-Weinberg equilibrium after sequential Bonferroni correction. Analysis with MICROCHECKER suggested the presence of null alleles at five of these loci with estimated null allele frequencies of 0.126-0.285. These new microsatellite markers from genomic libraries will be useful for constructing a P. olivaceus linkage map.

Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis

Objective. We have previously identified a single-nucleotide polymorphism (SNP) haplotype involving the lymphotoxin α (LTA) and tumor necrosis factor (TNF) loci (termed haplotype LTA-TNF2) on chromosome 6 that shows differential association with rheumatoid arthritis (RA) on HLA-DRB1*0404 and *0401 haplotypes, suggesting the presence of additional non-HLA-DRB1 RA susceptibility genes on these haplotypes. To refine this association, we performed a case-control association study using both SNPs and microsatellite markers in haplotypes matched either for HLA-DRB1*0404 or for HLA-DRB1*0401. Methods. Fourteen SNPs lying between HLA-DRB1 and LTA were genotyped in 87 DRB1*04-positive families. High-density microsatellite typing was performed using 24 markers spanning 2,500 kb centered around the TNF gene in 305 DRB1*0401 or *0404 cases and 400 DRB1*0401 or *0404 controls. Single-marker, 2-marker, and 3-marker minihaplotypes were constructed and their frequencies compared between the DRB1*0401 and DRB1*0404 matched case and control haplotypes. Results. Marked preservation of major histocompatibility complex haplotypes was seen, with chromosomes carrying LTA-TNF2 and either DRB1*0401 or DRB1*0404 both carrying an identical SNP haplotype across the 1-Mb region between TNF and HLA-DRB1. Using microsatellite markers, we observed two 3-marker minihaplotypes that were significantly overrepresented in the DRB1*0404 case haplotypes (P = 0.00024 and P = 0.00097). Conclusion. The presence of a single extended SNP haplotype between LTA-TNF2 and both DRB1*0401 and DRB1*0404 is evidence against this region harboring the genetic effects in linkage disequillbrium with LTA-TNF2. Two RA-associated haplotypes on the background of DRB1*0404 were identified in a 126-kb region surrounding and centromeric to the TNF locus.

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

Molecular mimicry: Can epitope mimicry induce autoimmune disease?

Mimicry of host antigens by infectious agents may induce cross-reactive autoimmune responses to epitopes within host proteins which, in susceptible individuals, may tip the balance of immunological response versus tolerance toward response and subsequently lead to autoimmune disease. Epitope mimicry may indeed be involved in the pathogenesis of several diseases such as post-viral myocarditis or Chagas disease, but for many other diseases in which it has been implicated, such as insulin-dependent diabetes mellitis or rheumatoid arthritis, convincing evidence is still lacking. Even if an epitope mimic can support a cross-reactive T or B cell response in vitro, its ability to induce an autoimmune disease in vivo will depend upon the appropriate presentation of the mimicked host antigen in the target tissue and, in the case of T cell mimics, the ability of the mimicking epitope to induce a proliferative rather than anergizing response upon engagement of the MHC-peptide complex with the T cell receptor. B cell presentation of mimicking foreign antigen to T cells is a possible mechanism for instigating an autoimmune response to self antigens that in turn can lead to autoimmune disease under particular conditions of antigen presentation, secondary signalling and effector cell repertoire. In this review evidence in support of epitope mimicry is examined in the light of the necessary immunological considerations of the theory.

Fiber Bragg grating accelerometer based on a transversely rotating stick

Fiber Bragg Grating (FBG) accelerometers using transverse forces with an inertial object placed at the middle of the FBG have a high sensitivity but low resonant frequency. The resonant frequency 26 Hz and sensitivity at 6 Hz 1.29 nm/g were reported based on a 50mm-long FBG accelerometer. We demonstrate that the first FBG accelerometer based on a transversely rotating stick, which can, at the same or even larger size, keep the high sensitivity and significantly increase the low resonant frequency. In our experiments, a 77.5mm-long FBG accelerometer has achieved a similar sensitivity but 65% higher resonant frequency. This novel structure not only significantly widens the potential applications of FBG accelerometers by increasing their resonant frequencies but also provides a new route to design other accelerometers, e.g. micro accelerometers.

Genetics of ankylosing spondylitis

Purpose of Review Over the past 3 years, several new genes and gene deserts have been identified that are associated with ankylosing spondylitis (AS). The purpose of this review is to discuss the major findings of these studies, and the answers they provide and questions they raise about the pathogenesis of this common condition. Recent Findings: Five genes/genetic regions have now definitively been associated with AS [the major histocompatibility complex (MHC), IL23R, ERAP1, 2p15 and 21q22]. Strong evidence to support association with the disease has been demonstrated for the genes IL1R2, ANTXR2, TNFSF15, TNFR1 and a region on chromosome 16q including the gene TRADD. There is an overrepresentation of genes involved in Th17 lymphocyte differentiation/activation among genes associated with AS and the related diseases inflammatory bowel disease and psoriasis, pointing strongly to this pathway as playing a major causative role in the disease. Increasing information about differential association of HLA-B27 subtypes with disease suggests a hierarchy of strength of association of those alleles with AS, providing a useful test as to the validity of different potential mechanisms of association of HLA-B27 with AS. The mechanism underlying the association of the gene deserts, 2p15 and 21q22, suggests the involvement of noncoding RNA in AS etiopathogenesis. Summary: The increasing list of genes identified as being definitely involved in AS provides a useful platform for hypothesis-driven research in the field, providing a potential alternative route to determining the underlying mechanisms involved in the disease to research focusing on HLA-B27 alone.

The association between ambient temperature and children's lung function in Baotou, China

The objective of this study is to examine the association between ambient temperature and children’s lung function in Baotou, China. We recruited 315 children (8–12 years) from Baotou, China in the spring of 2004, 2005, and 2006. They performed three successive forced expiratory measurements three times daily (morning, noon, and evening) for about 5 weeks. The highest peak expiratory flow (PEF) was recorded for each session. Daily data on ambient temperature, relative humidity, and air pollution were monitored during the same period. Mixed models with a distributed lag structure were used to examine the effects of temperature on lung function while adjusting for individual characteristics and environmental factors. Low temperatures were significantly associated with decreases in PEF. The effects lasted for lag 0–2 days. For all participants, the cumulative effect estimates (lag 0–2 days) were −1.44 (−1.93, −0.94) L/min, −1.39 (−1.92, −0.86) L/min, −1.40 (−1.97, −0.82) L/min, and −1.28 (−1.69, −0.88) L/min for morning, noon, evening, and daily mean PEF, respectively, associated with 1 °C decrease in daily mean temperature. Generally, the effects of temperature were slightly stronger in boys than in girls for noon, evening, and daily mean PEF, while the effects were stronger in girls for morning PEF. PM2.5 had joint effects with temperature on children’s PEF. Higher PM2.5 increased the impacts of low temperature. Low ambient temperatures are associated with lower lung function in children in Baotou, China. Preventive health policies will be required for protecting children from the cold weather.

Does adolescent's exposure to parental intimate partner conflict and violence predict psychological distress and substance use in young adulthood? A longitudinal study

Little is known about the extent to which parental conflict and violence differentially impact on offspring mental health and substance use. Using data from a longitudinal birth cohort study this paper examines: whether offspring exposure to parental intimate partner violence (involving physical violence which may include conflicts and/or disagreements) or parental intimate partner conflict (conflicting interactions and disagreements only) are associated with offspring depression, anxiety and substance use in early adulthood (at age 21); and whether these associations are independent of maternal background, depression and anxiety and substance use. Data (n = 2,126 women and children) were taken from a large-scale Australian birth-cohort study, the Mater University of Queensland Study of Pregnancy (MUSP). IPC and IPV were measured at the 14-year follow-up. Offspring mental health outcomes – depression, anxiety and substance use were assessed at the 21-year follow-up using the Composite International Diagnostic Interview (CIDI). Offspring of women experiencing IPV at the 14-year follow-up were more likely to manifest anxiety, nicotine, alcohol and cannabis disorders by the 21-year follow-up. These associations remained after adjustment for maternal anxiety, depression, and other potential confounders. Unlike males who experience anxiety disorders after exposure to IPV, females experience depressive and alcohol use disorders. IPV predicts offspring increased levels of substance abuse and dependence in young adulthood. Gender differences suggest differential impact.

Estimating daily and diurnal variations of illicit drug use in Hong Kong: A pilot study of using wastewater analysis in an Asian metropolitan city

The measurement of illicit drug metabolites in raw wastewater is increasingly being adopted as an approach to objectively monitor population-level drug use, and is an effective complement to traditional epidemiological methods. As such, it has been widely applied in western countries. In this study, we utilised this approach to assess drug use patterns over nine days during April 2011 in Hong Kong. Raw wastewater samples were collected from the largest wastewater treatment plant serving a community of approximately 3.5 million people and analysed for excreted drug residues including cocaine, ketamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and key metabolites using liquid chromatography coupled with tandem mass spectrometry. The overall drug use pattern determined by wastewater analysis was consistent with that have seen amongst people coming into contact with services in relation to substance use; among our target drugs, ketamine (estimated consumption: 1400–1600 mg/day/1000 people) was the predominant drug followed by methamphetamine (180–200 mg/day/1000 people), cocaine (160–180 mg/day/1000 people) and MDMA (not detected). The levels of these drugs were relatively steady throughout the monitoring period. Analysing samples at higher temporal resolution provided data on diurnal variations of drug residue loads. Elevated ratios of cocaine to benzoylecgonine were identified unexpectedly in three samples during the evening and night, providing evidence for potential dumping events of cocaine. This study provides the first application of wastewater analysis to quantitatively evaluate daily drug use in an Asian metropolitan community. Our data reinforces the benefit of wastewater monitoring to health and law enforcement authorities for strategic planning and evaluation of drug intervention strategies.

Predicting the performance of LSF walls made of hollow flange channel sections in fire

Fire resistance of load bearing Light Gauge Steel Frame (LSF) wall systems is important to protect lives and properties in fire accidents. Recent fire tests of LSF walls made of the new cold-formed and welded hollow flange channel (HFC) section studs and the commonly used lipped channel section (LCS) studs have shown the influence of stud sections on the fire resistance rating (FRR) of LSF walls. To advance the use of HFC section studs and to verify the outcomes from the fire tests, finite element models were developed to predict the structural fire performance of LSF walls made of welded HFC section studs. The developed models incorporated the measured non-uniform temperature distributions in LSF wall studs due to the exposure of standard fire on one side, and accurate elevated temperature mechanical properties of steel used in the stud sections. These models simulated the various complexities involved such as thermal bowing and neutral axis shift caused by the non-uniform temperature distribution in the studs. The finite element analysis (FEA) results agreed well with the full scale fire test results including the FRR, outer hot and cold flange temperatures at failure and axial deformation and lateral displacement profiles. They also confirmed the superior fire performance of LSF walls made of HFC section studs. The applicability of both transient and steady state FEA of LSF walls under fire conditions was verified in this study, which also investigated the effects of using various temperature distribution patterns across the cross-section of HFC section studs on the FRR of LSF walls. This paper presents the details of this numerical study and the results.

MRI-based fatigue analysis predicts plaque vulnerability: A study comparing symptomatic and asymptomatic individuals

BACKGROUND: Rupture of atheromatous plaque in the carotid artery often leads to thrombosis and subsequent stroke. The mechanism of plaque rupture is not entirely clear but is thought to be a multi-factorial process involving thinning and weakening of the fibrous cap and biomechanical stress as the trigger leading to plaque rupture. As the cardiovascular system is a classic fatigue environment, the weakening of plaque leading to rupture may be a fatigue process, which is a symptomatically quiescent but potentially progressive failure process. In this study, we used a fatigue analysis based on in vivo magnetic resonance imaging (MRI) to investigate the rupture initiation location, crack propagation path and fatigue life within plaques of asymptomatic and symptomatic individuals. METHODS: Forty non-consecutive subjects (20 symptomatic and 20 asymptomatic) underwent high-resolution multi-sequence in vivo MRI of the carotid bifurcation. Fatigue analysis was performed based on the plaque geometry derived from in vivo MRI of the carotid artery at the point of maximum stenosis. Paris’ Law in fracture mechanics is adopted to determine the fatigue crack growth rate. Incremental crack propagation was dynamically simulated based on stress distributions. Plaque initiation location, crack propagation path and fatigue cycle of symptomatic and asymptomatic individuals were compared. RESULTS: Cracks were often found to begin at the lumen wall at areas of stress concentration. The preferred rupture direction was radial from the lumen center. The crack initially advanced slowly but accelerated as it developed, depending on plaque morphology. The fatigue cycles of symptomatic plaques were significantly less than those in the asymptomatic group (2.3 ± 0.9 vs 3.1 ± 0.7 (x106); p = 0.003). CONCLUSIONS: The number of cycles to rupture in symptomatic patients was higher than those predicted in asymptomatic patients by fatigue analysis, suggesting the possibility that plaques with a less fatigue life may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, fatigue analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma.

Isotonic designs for phase I trials

The purpose of a phase I trial in cancer is to determine the level (dose) of the treatment under study that has an acceptable level of adverse effects. Although substantial progress has recently been made in this area using parametric approaches, the method that is widely used is based on treating small cohorts of patients at escalating doses until the frequency of toxicities seen at a dose exceeds a predefined tolerable toxicity rate. This method is popular because of its simplicity and freedom from parametric assumptions. In this payer, we consider cases in which it is undesirable to assume a parametric dose-toxicity relationship. We propose a simple model-free approach by modifying the method that is in common use. The approach assumes toxicity is nondecreasing with dose and fits an isotonic regression to accumulated data. At any point in a trial, the dose given is that with estimated toxicity deemed closest to the maximum tolerable toxicity. Simulations indicate that this approach performs substantially better than the commonly used method and it compares favorably with other phase I designs.

Subsampling multi-species trawl catches from tropical northern Australia: Does it matter which part of the catch is sampled?

Subsampling is a common method for estimating the abundance of species in trawl catches. However, the accuracy of subsampling in representing the total catch has not been assessed. To estimate one possible source of bias due to subsampling, we tested whether the position on trawler sorting trays from which subsamples were taken affected their ability to represent species in catches. This was done by sorting catches into 10 kg subsamples and comparing subsamples taken from different positions on the sorting tray. Comparisons were made after species were grouped into three categories of abundance, either 'rare', 'common' or 'abundant'. A generalised linear model analysis showed that taking subsamples from different positions on the sorting tray had no major effect on estimating the total numbers or weights of fish or invertebrates, or the total number of fish or invertebrate taxa, recorded in each position. Some individual taxa showed differences between positions on the sorting tray (11.5% of taxa ina three-position design; 25% in a five-position design). But consistent and meaningful patterns in the position of these taxa on the sorting tray could only be seen for the pony fish Leiognathus moretoniensis and the saucer scallop Amusium pleuronectes. Because most bycatch laxa are well mixed throughout the catch, subsamples can be taken from any position on trawler sorting trays without introducing bias.

Sequential allocation in clinical trials

Suppose two treatments with binary responses are available for patients with some disease and that each patient will receive one of the two treatments. In this paper we consider the interests of patients both within and outside a trial using a Bayesian bandit approach and conclude that equal allocation is not appropriate for either group of patients. It is suggested that Gittins indices should be used (using an approach called dynamic discounting by choosing the discount rate based on the number of future patients in the trial) if the disease is rare, and the least failures rule if the disease is common. Some analytical and simulation results are provided.

Impaired physical function associated with childhood obesity: How should we intervene?

- Background This study examined relationships between adiposity, physical functioning and physical activity. - Methods Obese (N=107) and healthy-weight (N=132) children aged 10-13 years underwent assessments of percent body fat (%BF, dual energy X-ray absorptiometry), knee extensor strength (KE, isokinetic dynamometry), cardiorespiratory fitness (CRF, peak oxygen uptake by cycle ergometry), physical health-related quality of life (HRQOL), worst pain intensity and walking capacity [six-minute walk (6MWT)]. Structural equation modelling was used to assess relationships between variables. - Results Moderate relationships were observed between %BF and 6MWT, KE strength corrected for mass and CRF relative to mass (r -.36 to -.69, P≤.007). Weak relationships were found between: %BF and physical HRQOL (r -.27, P=.008); CRF relative to mass and physical HRQOL (r -.24, P=.003); physical activity and 6MWT (r .17, P=.004). Squared multiple correlations showed that 29.6% variance in physical HRQOL was explained by %BF, pain and CRF relative to mass, while 28% variance in 6MWT was explained by %BF and physical activity. - Conclusions It appears that children with a higher body fat percentage have poorer KE strength, CRF and overall physical functioning. Reducing percent fat appears to be the best target to improve functioning. However, a combined approach to intervention, targeting reductions in body fat percentage, pain and improvements in physical activity and CRF may assist physical functioning.