BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

Both type 2 diabetes (T2DM) and Bβ448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BβArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BβArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BβArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BβArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bβ448Lys was longer than Bβ448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bβ448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bβ448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies

Liquid-gas phase transition in nuclear multifragmentation

The equation of state of nuclear matter suggests that at suitable beam energies the disassembling hot system formed in heavy ion collisions will pass through a liquid-gas coexistence region. Searching for the signatures of the phase transition has been a very important focal point of experimental endeavours in heavy ion collisions, in the last fifteen years. Simultaneously theoretical models have been developed to provide information about the equation of state and reaction mechanisms consistent with the experimental observables. This article is a review of this endeavour.Comment: 63 pages, 27 figures, submitted to Adv. Nucl. Phys. Some typos corrected, minor text change

Selection of Diethylstilbestrol-Specific Single-Chain Antibodies from a Non-Immunized Mouse Ribosome Display Library

Single chain variable fragments (scFvs) against diethylstilbestrol (DES) were selected from the splenocytes of non-immunized mice by ribosome display technology. A naive library was constructed and engineered to allow in vitro transcription and translation using an E. coli lysate system. Alternating selection in solution and immobilization in microtiter wells was used to pan mRNA-ribosome-antibody (ARM) complexes. After seven rounds of ribosome display, the expression vector pTIG-TRX containing the selected specific scFv DNAs were transformed into Escherichia coli BL21 (DE3) for expression. Twenty-six positive clones were screened and five clones had high antibody affinity and specificity to DES as evidenced by indirect competitive ELISA. Sequence analysis showed that these five DES-specific scFvs had different amino acid sequences, but the CDRs were highly similar. Surface plasmon resonance (SPR) analysis was used to determine binding kinetics of one clone (30-1). The measured KD was 3.79 µM. These results indicate that ribosome display technology can be used to efficiently isolate hapten-specific antibody (Ab) fragments from a naive library; this study provides a methodological framework for the development of novel immunoassays for multiple environmental pollutants with low molecular weight detection using recombinant antibodies

Seasonality in pulmonary tuberculosis among migrant workers entering Kuwait

<p>Abstract</p> <p>Background</p> <p>There is paucity of data on seasonal variation in pulmonary tuberculosis (TB) in developing countries contrary to recognized seasonality in the TB notification in western societies. This study examined the seasonal pattern in TB diagnosis among migrant workers from developing countries entering Kuwait.</p> <p>Methods</p> <p>Monthly aggregates of TB diagnosis results for consecutive migrants tested between January I, 1997 and December 31, 2006 were analyzed. We assessed the amplitude (<it>α</it>) of the sinusoidal oscillation and the time at which maximum (<it>θ</it>°) TB cases were detected using Edwards' test. The adequacy of the hypothesized sinusoidal curve was assessed by <it>χ</it>²goodness-of-fit test.</p> <p>Results</p> <p>During the 10 year study period, the proportion (per 100,000) of pulmonary TB cases among the migrants was 198 (4608/2328582), (95% confidence interval: 192 – 204). The adjusted mean monthly number of pulmonary TB cases was 384. Based on the observed seasonal pattern in the data, the maximum number of TB cases was expected during the last week of April (<it>θ</it>° = 112°; <it>P </it>< 0.001). The amplitude (± se) (<it>α </it>= 0.204 ± 0.04) of simple harmonic curve showed 20.4% difference from the mean to maximum TB cases. The peak to low ratio of adjusted number of TB cases was 1.51 (95% CI: 1.39 – 1.65). The <it>χ</it>²goodness-of-test revealed that there was no significant (<it>P </it>> 0.1) departure of observed frequencies from the fitted simple harmonic curve. Seasonal component explained 55% of the total variation in the proportions of TB cases (100,000) among the migrants.</p> <p>Conclusion</p> <p>This regularity of peak seasonality in TB case detection may prove useful to institute measures that warrant a better attendance of migrants. Public health authorities may consider re-allocation of resources in the period of peak seasonality to minimize the risk of <it>Mycobacterium tuberculosis </it>infection to close contacts in this and comparable settings in the region having similar influx of immigrants from high TB burden countries. Epidemiological surveillance for the TB risk in the migrants in subsequent years and required chemotherapy of detected cases may contribute in global efforts to control this public health menace.</p

Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.

BACKGROUND: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis. METHODS: We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy. FINDINGS: In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04-1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08-1·29), 1·10 (1·00-1·22), and 1·05 (0·92-1·20), respectively, per 1 SD increment in plasma urate. INTERPRETATION: Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions. FUNDING: UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council

The Edinburgh Type 2 Diabetes Study:study protocol

Peer reviewedPublisher PD

Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (<i>N</i>=112 151) and 24 GWAS consortia

Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular–metabolic, neuropsychiatric, physiological–anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112 151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer’s disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples

Assessing the genetic overlap between BMI and cognitive function

Obesity and low cognitive function are associated with multiple adverse health outcomes across the life course. They have a small phenotypic correlation (r=-0.11; high body mass index (BMI)-low cognitive function), but whether they have a shared genetic aetiology is unknown. We investigated the phenotypic and genetic correlations between the traits using data from 6815 unrelated, genotyped members of Generation Scotland, an ethnically homogeneous cohort from five sites across Scotland. Genetic correlations were estimated using the following: same-sample bivariate genome-wide complex trait analysis (GCTA)-GREML; independent samples bivariate GCTA-GREML using Generation Scotland for cognitive data and four other samples (n=20 806) for BMI; and bivariate LDSC analysis using the largest genome-wide association study (GWAS) summary data on cognitive function (n=48 462) and BMI (n=339 224) to date. The GWAS summary data were also used to create polygenic scores for the two traits, with within- and cross-trait prediction taking place in the independent Generation Scotland cohort. A large genetic correlation of -0.51 (s.e. 0.15) was observed using the same-sample GCTA-GREML approach compared with -0.10 (s.e. 0.08) from the independent-samples GCTA-GREML approach and -0.22 (s.e. 0.03) from the bivariate LDSC analysis. A genetic profile score using cognition-specific genetic variants accounts for 0.08% (P=0.020) of the variance in BMI and a genetic profile score using BMI-specific variants accounts for 0.42% (P=1.9 × 10 -7) of the variance in cognitive function. Seven common genetic variants are significantly associated with both traits at

Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice

10.1038/srep03754Scientific Reports4

Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

Hair cortisol concentration (HCC) is a promising measure of long-Term hypothalamus-pituitary-Adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables