Urinary albumin and 8-oxo-7,8-dihydroguanosine as markers of mortality and cardiovascular disease during 19 years after diagnosis of type 2 diabetes:A comparative study of two markers to identify high risk patients

Urinary albumin is an important biomarker used to identify high risk patients with diabetes, but there is a need for new biomarkers that alone or in combination with urinary albumin could give an even better prediction of clinical patient outcomes. One promising biomarker is 8-oxo-7,8-dihydroguanosine (8-oxoGuo) that represents intracellular oxidative stress. We investigated the ability of microalbuminuria (MA) and urinary 8-oxoGuo, alone and in combination, to predict mortality and cardiovascular disease (CVD) in patients with type 2 diabetes. We used data from 1381 newly diagnosed diabetes patients, and urinary albumin and 8-oxoGuo were assessed in morning urine collected at the time of diabetes diagnosis and at a follow-up visit 6 years later. Associations between the urinary markers and mortality and CVD were assessed in Cox proportional hazards regression models. Test performance was assessed using sensitivity, specificity, positive predictive value and negative predictive value for 10-year mortality and 10-year incidence of CVD. Both 8-oxoGuo and urinary albumin were statistically significantly associated with all-cause mortality at diagnosis as well as at 6-year follow-up. At diagnosis only urinary albumin was associated with CVD. In contrast, only 8-oxoGuo was associated with CVD at 6-year follow-up. When investigating test performance, we found that by combining information from MA and 8-oxoGuo the ability to correctly identify patients at risk could be improved. The findings suggest that measurement of urinary 8-oxoGuo provides additional information about risk to that obtained from urinary albumin, and that the combined use of 8-oxoGuo and urinary albumin could be useful for a better identification of patients at risk of CVD and death

Association Between Urinary Markers of Nucleic Acid Oxidation and Mortality in Type 2 Diabetes:A population-based cohort study

OBJECTIVE: We recently showed that RNA oxidation, estimated by urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo), independently predicted mortality in a cohort of 1,381 treatment-naive patients with newly diagnosed type 2 diabetes. In the present investigation, we analyzed urine collected 6 years after the diagnosis to assess the association between urinary markers of nucleic acid oxidation and mortality in patients with established and treated diabetes. RESEARCH DESIGN AND METHODS: We used data from the 970 patients who attended the screening for diabetes complications 6 years after the diagnosis. Cox proportional hazards regression was used to examine the relationship between urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine [8-oxodG] [n = 938]) and RNA oxidation (8-oxoGuo [n = 936]) and mortality. RESULTS: During a median of 9.8 years of follow-up, 654 patients died. Urinary 8-oxoGuo assessed 6 years after the diagnosis was significantly associated with mortality. The multivariate-adjusted hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.86 (95% CI 1.34–2.58) and 1.72 (1.11–2.66), respectively. Conversely, 8-oxodG was not associated with mortality. In addition, we found an association between changes in 8-oxoGuo from diagnosis to 6-year follow-up and mortality, with increased risk in patients with an increase and decreased risk in patients with a decrease in 8-oxoGuo. CONCLUSIONS: The RNA oxidation marker 8-oxoGuo is an independent predictor of mortality in patients with established and treated type 2 diabetes, and changes in 8-oxoGuo during the first 6 years after diagnosis are associated with mortality

Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations

BACKGROUND:The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. METHODS:1599 individuals (mean age 64 years [min-max 29-96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010-2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. RESULTS:Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively. CONCLUSIONS:Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a "missing heritability" in early-onset CAD warrants more research

Insulin resistance genetic risk score and burden of coronary artery disease in patients referred for coronary angiography

AimsInsulin resistance associates with development of metabolic syndrome and risk of cardiovascular disease. The link between insulin resistance and cardiovascular disease is complex and multifactorial. Confirming the genetic link between insulin resistance, type 2 diabetes, and coronary artery disease, as well as the extent of coronary artery disease, is important and may provide better risk stratification for patients at risk. We investigated whether a genetic risk score of 53 single nucleotide polymorphisms known to be associated with insulin resistance phenotypes was associated with diabetes and burden of coronary artery disease.Methods and resultsWe genotyped patients with a coronary angiography performed in the capital region of Denmark from 2010-2014 and constructed a genetic risk score of the 53 single nucleotide polymorphisms. Logistic regression using quartiles of the genetic risk score was performed to determine associations with diabetes and coronary artery disease. Associations with the extent of coronary artery disease, defined as one-, two- or three-vessel coronary artery disease, was determined by multinomial logistic regression. We identified 4,963 patients, of which 17% had diabetes and 55% had significant coronary artery disease. Of the latter, 27%, 14% and 14% had one, two or three-vessel coronary artery disease, respectively. No significant increased risk of diabetes was identified comparing the highest genetic risk score quartile with the lowest. An increased risk of coronary artery disease was found for patients with the highest genetic risk score quartile in both unadjusted and adjusted analyses, OR 1.21 (95% CI: 1.03, 1.42, p = 0.02) and 1.25 (95% CI 1.06, 1.48, pConclusionsAmong patients referred for coronary angiography, only a strong genetic predisposition to insulin resistance was associated with risk of coronary artery disease and with a greater disease burden

Implementation of the EU CCS Directive in Europe: results and development in 2013

Directive 2009/31/EC of the European Parliament on the geological storage of carbon dioxide, entered into force on June 25th 2009. By the end 2013 the CCS Directive has been fully transposed into national law to the satisfaction of the EC in 20 out of 28 EU Member States, while six EU countries (Austria, Cyprus, Hungary, Ireland, Sweden and Slovenia) had to complete transposing measures. In July 2014 the European Commission closed infringement procedures against Cyprus, Hungary and Ireland, which have notified the EC that they have taken measures to incorporate the CCS Directive into national law. Among other three countries Sweden has updated its legislation and published a new law in their country in March 2014, permitting CO2 storage offshore. The evaluation of the national laws in Poland, which were accepted at national level in November 2013, and Croatia, which entered the EU on 7 July 2013 and simultaneously transposed the CCS directive, is still ongoing in 2014. The first storage permit under the Directive (for the ROAD Project in the offshore Netherlands) has been approved by the EC. While CO2 storage is permitted in a number of European countries, temporary restrictions were applied in Czech Republic, Denmark and Poland. CO2 storage is prohibited except for research and development in Estonia, Finland, Luxembourg, two regions in Belgium and Slovenia due to their geological conditions, but also forbidden in Austraia, Ireland and Latvia. The size of exploration areas for CO2 storage sites is limited in Bulgaria and Hungary. In Germany, only limited CO2 storage will be permitted until 2018 (up to 4 Mt CO2 annually)

Inducing Persistent Flow Disturbances Accelerates Atherogenesis and Promotes Thin Cap Fibroatheroma Development in \u3ci\u3eD374Y\u3c/i\u3e-PCSK9 Hypercholesterolemic Minipigs

Background—Although disturbed flow is thought to play a central role in the development of advanced coronary atherosclerotic plaques, no causal relationship has been established. We evaluated whether inducing disturbed flow would cause the development of advanced coronary plaques, including thin cap fibroatheroma (TCFA). Methods and Results—D374Y-PCSK9 hypercholesterolemic minipigs (N=5) were instrumented with an intracoronary shear-modifying stent (SMS). Frequency-domain optical coherence tomography was obtained at baseline, immediately post-stent, 19, and 34 weeks and used to compute shear stress metrics of disturbed flow. At 34 weeks, plaque type was assessed within serially-collected histological sections and co-registered to the distribution of each shear metric. The SMS caused a flow-limiting stenosis and blood flow exiting the SMS caused regions of increased shear stress on the outer curvature and large regions of low and multidirectional shear stress on the inner curvature of the vessel. As a result, plaque burden was ~3-fold higher downstream of the SMS compared to both upstream of the SMS and in the control artery (pppp\u3c0.005). Conclusions—These data support a causal role for lowered and multidirectional shear stress in the initiation of advanced coronary atherosclerotic plaques. Persistently lowered shear stress appears to be the principal flow disturbance needed for the formation of TCFA

A comparative study of cranial, blunt trauma fractures as seen at medicolegal autopsy and by Computed Tomography

<p>Abstract</p> <p>Background</p> <p>Computed Tomography (CT) has become a widely used supplement to medico legal autopsies at several forensic institutes. Amongst other things, it has proven to be very valuable in visualising fractures of the cranium. Also CT scan data are being used to create head models for biomechanical trauma analysis by Finite Element Analysis. If CT scan data are to be used for creating individual head models for retrograde trauma analysis in the future we need to ascertain how well cranial fractures are captured by CT scan. The purpose of this study was to compare the diagnostic agreement between CT and autopsy regarding cranial fractures and especially the precision with which cranial fractures are recorded.</p> <p>Methods</p> <p>The autopsy fracture diagnosis was compared to the diagnosis of two CT readings (reconstructed with Multiplanar and Maximum Intensity Projection reconstructions) by registering the fractures on schematic drawings. The extent of the fractures was quantified by merging 3-dimensional datasets from both the autopsy as input by 3D digitizer tracing and CT scan.</p> <p>Results</p> <p>The results showed a good diagnostic agreement regarding fractures localised in the posterior fossa, while the fracture diagnosis in the medial and anterior fossa was difficult at the first CT scan reading. The fracture diagnosis improved during the second CT scan reading. Thus using two different CT reconstructions improved diagnosis in the medial fossa and at the impact points in the cranial vault. However, fracture diagnosis in the anterior and medial fossa and of hairline fractures in general still remained difficult.</p> <p>Conclusion</p> <p>The study showed that the forensically important fracture systems to a large extent were diagnosed on CT images using Multiplanar and Maximum Intensity Projection reconstructions. Difficulties remained in the minute diagnosis of hairline fractures. These inconsistencies need to be resolved in order to use CT scan data of victims for individual head modelling and trauma analysis.</p

Variability and connectivity of plaice populations from the Eastern North Sea to the Western Baltic Sea, and implications for assessment and management

An essential prerequisite of sustainable fisheries is the match between biologically relevant processes and management action. Various populations may however co-occur on fishing grounds, although they might not belong to the same stock, leading to poor performance of stock assessment and management. Plaice in Kattegat and Skagerrak have traditionally been considered as one stock unit. Current understanding indicates that several plaice components may exist in the transition area between the North Sea and the Baltic Sea. A comprehensive review of all available biological knowledge on plaice in this area is performed, including published and unpublished literature together with the analyses of commercial and survey data and historical tagging data. The results suggest that plaice in Skagerrak is closely associated with plaice in the North Sea, although local populations are present in the area. Plaice in Kattegat, the Belts Sea and the Sound can be considered a stock unit, as is plaice in the Baltic Sea. The analyses revealed great heterogeneity in the dynamics and productivity of the various local components, and suggested for specific action to maintain biodiversity