Increased coagulation factor VIII,IX, XI and XII activities in non‐alcoholic fatty liver disease

Background and aims: Obesity and the metabolic syndrome are established risk factors of venous thromboembolism. As most coagulation factors are produced exclusively by the liver and non‐alcoholic fatty liver disease (NAFLD) is tightly related to metabolic disorders, we aimed at studying the association of liver fat with various coagulation factor activities. Methods: Plasma prothrombin (PT) and activated partial thromboplastin time, activities of vWF:RCo, FVII, FVIII, FIX, FXI, FXII, FXIII, fibrinogen and D‐dimer concentrations were measured in 54 subjects with and 44 without NAFLD diagnosed by proton magnetic resonance spectroscopy. Subjects were recruited retrospectively for metabolic studies in our laboratory. The body composition and features of insulin resistance were measured in all subjects. Results: FVIII (107±30 vs. 84±22%, P<0.001), FIX (110±14 vs. 94±16%, P<0.001), FXI (109±16 vs. 96±19%, P=0.001) and FXII (113±21 vs. 99±32%, P=0.002) activities were consistently elevated in subjects with as compared with those without NAFLD. Liver fat percentage was positively related to FVIII (r=0.28, P=0.005), FIX (r=0.36, P=0.0003), FXI (r=0.29, P=0.004) and FXII (r=0.30, P=0.003) activities, again independent of age, gender and body mass index (BMI). PT%, vWF:RCo activity and fibrinogen were higher in subjects with as compared with those without NAFLD, but this difference disappeared after adjusting for age, gender and BMI. Conclusion: FVIII, FIX, FXI and FXII activities are increased in human NAFLD and correlate with the features of insulin resistance. The relationships between NAFLD and these coagulation factors are independent of age, gender and BMI, suggesting that the fatty liver can contribute to the risk of thrombosis.     

Facilitation of tactile working memory by top-down suppression from prefrontal to primary somatosensory cortex during sensory interference

Tactile working memory (WM) is improved by increasing top-down suppression of interfering sensory processing in S1 via a link from the middle frontal gyrus (MFG) to S1. Here we studied in healthy subjects whether the efficacy of top-down suppression varies with submodality of sensory interference. Navigated stimulation of the MFG-S1 link significantly improved tactile WM performance when accompanied by tactile but not visual interference of memory maintenance.     

Identification of Deep Sleep and Awake with Computational EEG Measures

The objective of the present work was to examine identification of deep sleep and awake with computational analysis of sleep EEG traces from central brain regions. All-night EEG traces from a total of 56 male subjects, 22 healthy control subjects and 34 age-matched apnea patients, were examined. A spectral mean frequency measure, a Hilbert transform based EEG amplitude and a correlation coefficient method were compared. The EEG amplitude provided a good identification of deep sleep, reaching 86.25% but was relatively poor in the identification of wakefulness, reaching 39.06%. Mean frequency provided a relatively good identification of deep sleep and awake, reaching 84.66% and 77.67%, respectively, while the correlation coefficient produced the lowest results of 37.89% and 44.43%. Optimal threshold values for deep sleep and awake identification were determined as 4.20 and 9.76 Hz, respectively, for the mean frequency measure. Mean frequency measure can be used to provide overall context information about sleep depth for automated sleep EEG analysis methods.     

Effects of 34 risk loci for type 2 diabetes or hyperglycemia on lipoprotein subclasses and their composition in 6,580 nondiabetic Finnish men

OBJECTIVE

We investigated the effects of 34 genetic risk variants for hyperglycemia/type 2 diabetes on lipoprotein subclasses and particle composition in a large population-based cohort.

RESEARCH DESIGN AND METHODS

The study included 6,580 nondiabetic Finnish men from the population-based Metabolic Syndrome in Men (METSIM) study (aged 57 ± 7 years; BMI 26.8 ± 3.7 kg/m²). Genotyping of 34 single nucleotide polymorphism (SNPs) for hyperglycemia/type 2 diabetes was performed. Proton nuclear magnetic resonance spectroscopy was used to measure particle concentrations of 14 lipoprotein subclasses and their composition in native serum samples.

RESULTS

The glucose-increasing allele of rs780094 in GCKR was significantly associated with low concentrations of VLDL particles (independently of their size) and small LDL and was nominally associated with low concentrations of intermediate-density lipoprotein, all LDL subclasses, and high concentrations of very large and large HDL particles. The glucose-increasing allele of rs174550 in FADS1 was significantly associated with high concentrations of very large and large HDL particles and nominally associated with low concentrations of all VLDL particles. SNPs rs10923931 in NOTCH2 and rs757210 in HNF1B genes showed nominal or significant associations with several lipoprotein traits. The genetic risk score of 34 SNPs was not associated with any of the lipoprotein subclasses.

CONCLUSIONS

Four of the 34 risk loci for type 2 diabetes or hyperglycemia (GCKR, FADS1, NOTCH2, and HNF1B) were significantly associated with lipoprotein traits. A GCKR variant predominantly affected the concentration of VLDL, and the FADS1 variant affected very large and large HDL particles. Only a limited number of risk loci for hyperglycemia/type 2 diabetes significantly affect lipoprotein metabolism.Hyperglycemia is closely related to lipid and lipoprotein metabolism. Elevated levels of fasting and 2-h plasma glucose or the presence of type 2 diabetes are associated with an increase in total triglyceride (TG) concentrations, a decrease in HDL cholesterol (1,2), and the formation of small, dense LDL cholesterol particles (2). Several population-based studies have shown that high levels of TG and low levels of HDL cholesterol predict the development of type 2 diabetes (3–6). Therefore, hyperglycemia and dyslipidemia are likely to share similar pathophysiologic mechanisms, at least in part. One of these mechanisms is insulin resistance, which leads to hepatic overproduction of VLDL particles (especially large, TG-rich VLDL), attributable to an increased flux of free fatty acids from adipocytes into the liver, an increased rate of apolipoprotein B synthesis and degradation in the liver, and enhanced hepatic de novo lipogenesis by hyperinsulinemia (7).Genomewide association studies (GWAS) have identified a number of gene variants reproducibly associated with hyperglycemia or type 2 diabetes (8–10). Because hyperglycemia and dyslipidemia partly share similar pathophysiologic mechanisms, the effects of hyperglycemia or type 2 diabetes single nucleotide polymorphisms (SNPs) on lipid and lipoprotein levels and composition are of great interest. However, none of the previous studies has systematically examined this question using modern methods to measure lipoprotein particle size and composition. Compared with conventional methods, the measurement of lipoprotein subclasses and particle composition provides more detailed information on the genes regulating hyperglycemia or type 2 diabetes and their effects on lipid metabolism.We investigated the effects of the 34 risk loci for hyperglycemia or type 2 diabetes on lipoprotein subclasses and particle composition. To this aim, we determined a total of 60 lipoprotein traits, including 14 lipoprotein subclasses and their components, in 6,580 nondiabetic Finnish men.