A clinical risk score to identify patients at high risk of very late stent thrombosis

Objectives

The aim of this study was to determine predictors of very late stent thrombosis (VLST; >1 year after stenting), and to evaluate whether addition of these predictors to the dual antiplatelet therapy (DAPT) score would improve the ability to identify patients at high risk of VLST who might benefit from DAPT.

Background

VLST is a severe complication of percutaneous coronary intervention (PCI). Extended knowledge about the predictors of VLST is needed to prevent this life‐threatening complication. Recent data showed a reduction in VLST after treatment with prolonged DAPT. The DAPT study developed a prediction score to identify patients after PCI who might benefit from prolonged DAPT duration.

Methods

The Dutch stent thrombosis study is a multi‐center case‐control study. Consecutive patients with definite VLST were included between 2007 and 2014. Baseline characteristics from the index PCI were collected. Independent predictors of VLST were identified and added to the DAPT score to develop the VLST score.

Results

In total, 155 VLST cases and 155 matched controls were included. Suboptimal result of stenting, right coronary artery as target vessel, and diffuse coronary artery ectasia were independent predictors of VLST, and added to the DAPT score. The power of the VLST score to identify patients who experienced VLST was increased (AUC, 95%CI; DAPT score: 0.64, 0.57‐0.70; VLST score: 0.70, 0.63‐0.76, P = 0.010).

Conclusions

Addition of newly identified independent predictors of VLST resulted in a prediction model with a higher ability to identify patients at high risk of VLST who might benefit from prolonged DAPT.     

Gene‐diet interactions in exposure to heterocyclic aromatic amines and bulky DNA adduct levels in blood leukocytes

Heterocyclic aromatic amines (HAAs), carcinogens produced in meat when cooked at high temperatures, are an emerging biologic explanation for the meat‐colorectal cancer relationship. HAAs form DNA adducts; left unrepaired, adducts can induce mutations, which may initiate/promote carcinogenesis. The purpose of this research was to investigate the relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct levels. Least squares regression was used to examine the relationship between dietary HAA exposure and bulky DNA adduct levels in blood measured using ³²P‐postlabeling among 99 healthy volunteers. Gene‐diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair were also examined. No main effects of dietary HAAs on bulky DNA adduct levels was found. However, those with the putative NAT1 rapid acetylator phenotype had lower adduct levels than those with the slow acetylator phenotype (P = 0.02). Furthermore, having five or more 'at‐risk' genotypes was associated with higher bulky DNA adduct levels (P = 0.03). Gene‐diet interactions were observed between NAT1 polymorphisms and dietary HAAs (P < 0.05); among the slow acetylator phenotype, higher intakes of HAAs were associated with an increase in DNA adduct levels compared to lower intakes. This study provides evidence of a biologic relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct formation. However, the lack of a strong main effect of HAAs suggests that dietary HAAs are not a large contributor to bulky DNA adducts in this population; future studies should consider relevant gene‐diet interactions to clarify the role of HAAs in carcinogenesis. Environ. Mol. Mutagen. 56:609–620, 2015. © 2015 Wiley Periodicals, Inc.     

A comparison of electric and magnetic compound action signals as quantitative assays of peripheralo nerve regeneration

The evaluation of peripheral nerve regeneration is of great interest in clinical as well as in experimental situations. However, there are few techniques that give early and quantitative information on the states of the regeneration process. If quantitative assays would be available, different surgical techniques and medications could be evaluated more accurately in relation to axonal ingrowth and functional recovery. The purpose of this study was to investigate the merits of nerve compound action signals (NCASs) recorded electrically and signals recorded with a novel magnetic recording technique. We compared the two techniques in the rabbit peroneal nerve, 2, 4, 6, and 8 weeks after a nerve reconstruction. Our conclusions are that the signals recorded with the magnetic sensor are far more reproducible and less prone to stimulus artifact than the electrically recorded signals. Furthermore, the magnetic recording shows that the number of axons that have regenerated increases with time. Previously, this could only be determined with histological studies. Other ingrowth parameters that can be quantified are the average ingrowth distance, and the variation between axons in ingrowth velocity. © 1993 John Wiley & Sons, Inc.     

Assessment of accuracy and applicability of a portable electronic diary card spirometer for asthma treatment

A pocked-sized turbine flowmeter and spirometer device, integrated with an electronic diary card (EDC-spirometer, Micro Medical, U.K.), was tested with a mechanical calibrator, in an outpatient clinic and in the home situation. A screen pneumotachometer was used as flow and volume reference.Ten devices were tested; interdevice variability was small with a mean variation coefficient of 1·1% for both forced expiratory volume in 1 s (FEV₁) and peak expiratory flow (PEF) ( 0·5 and 0·4, respectively) for eight settings of the calibrator. Mean difference from reference was −0·131 ( 0·04) for FEV₁ (range 0·38–3·16) and 0·091 s⁻¹ ( 0·09) for PEF (range 4·2–11·7). No significant deviation from linearity was present.Results obtained in the outpatient clinic confirmed the accuracy of FEV₁ and PEF data obtained with the calibrator. However, linear regression analysis showed a mean underestimation of 0·451 ( of estimate 0·29) for forced vital capacity over the whole measurement range, probably due to a restricted integration time.In 10 optimally-treated chronic obstructive pulmonary disease patients in a family practice, PEF measurements were done in the home situation, both with the EDC spirometer and a mini-Wright peak flow meter. No significant differences in the diurnal variation of PEF were found. The PEF data from the mini-Wright meter were corrected for earlier reported flow-dependent systematic deviations. In the home situation, patients preferred the EDC spirometer. It is concluded that this device is applicable in the follow-up and treatment of asthma at home.     

Interaction between cadmium and aromatic DNA adducts in hprt mutagenesis during foetal development

The foetus is exposed to multiple xenobiotics through the mother's circulation and this is possibly involved in the development of diseases in later life. Heavy metals and lipophilic genotoxins in umbilical cord blood of newborns may have synergistic effects on mutagenesis in the hypoxanthine-phosphoribosyltransferase (HPRT) reporter gene. Concentrations of zinc (Zn), lead (Pb) and cadmium (Cd) were determined in the peripheral and cord blood of 16 non-smoking and 9 smoking healthy mothers by atomic absorption spectrometry. Lipophilic DNA adducts in lymphocytes were determined in the same subjects by 32P-postlabelling and the HPRT-variant frequency was assessed by the evaluation of 6-thioguanine resistant cells. Although the Cd/Zn ratio was 2.5-fold higher in the blood of smoking women than in non-smoking women (1.0 +/- 0.2 and 0.4 +/- 0.1, respectively, P = 0.007), this difference could not be observed in umbilical cord blood (0.3 +/- 0.1 and 0.3 +/- 0.1, respectively, P = 0.66). Similarly, mean DNA adduct levels were increased in the lymphocytes of smoking women compared with non-smoking controls (0.99 +/- 0.31 adducts/10(8) nt and 0.43 +/- 0.12, respectively, P = 0.009), but were only marginally higher in the neonates of smokers than in their non-smoking counterparts (0.57 +/- 0.29 and 0.24 +/- 0.09, respectively, P = 0.38). Since Cd is known to effectively inhibit DNA repair, we hypothesized that concomitant exposure of neonates to Cd and genotoxic compounds may result in an increased fixation of DNA damage into somatic mutations. Indeed, the number of HPRT-variants per adduct (i.e. the mutagenic efficiency of adducts) correlated positively with the Cd concentrations in cord blood (r = 0.61, P = 0.001). These data suggest a molecular link between DNA damage, inhibition of DNA repair by Cd and in vivo mutagenesis during foetal development. Thus, exposure to heavy metals may enhance the mutagenic potential of DNA-damaging compounds and results in biologically relevant genotoxic effects in neonates.     

Modulation of plasma lipid levels affects benzo[a]pyrene-induced DNA damage in tissues of two hyperlipidemic mouse models

The role of plasma lipids in the uptake, transportation, and distribution of lipophilic carcinogens like benzo[a]pyrene (B[a]P) remains unclear. Therefore, we studied the effects of dietary-modulated plasma lipids on B[a]P-induced DNA damage in several organs of two hyperlipidemic mouse models. Male apolipoprotein E (ApoE)*3-Leiden (n = 22) and ApoE knockout (ApoE-KO) mice (n = 20) were fed a high-fat cholesterol (HFC) diet or low-fat cholesterol (LFC; standard mouse chow) diet for 3 weeks, after which the animals were exposed to a single oral dose of 5 mg/kg bw B[a]P or vehicle and killed 4 days later. Plasma lipids were determined and DNA adducts were measured in aorta, heart, lung, liver, brain, and stomach. Total cholesterol and low-density lipoprotein (LDL) cholesterol were increased in all animals on a HFC diet, whereas a decrease of triglycerides was seen only in the ApoE-KO mice. In ApoE-KO mice on a normal diet, DNA-adduct levels were highest in aorta (10.8 +/- 1.4 adducts/10(8) nucleotides), followed by brain (7.8 +/- 1.3), lung (3.3 +/- 0.7), heart (3.1 +/- 0.6), liver (1.5 +/- 0.2) and stomach (1.2 +/- 0.2). In the ApoE*3-Leiden mice, adduct levels were equally high in aorta, heart, and lung (4.6 +/- 0.7, 5.0 +/- 0.5 and 4.6 +/- 0.4, respectively), followed by stomach (2.7 +/- 0.4), brain (2.3 +/- 0.2), and liver (1.7 +/- 0.2). In the ApoE-KO mice, the HFC diet intervention resulted in lower adduct levels in lung (2.1 +/- 0.2), heart (1.9 +/- 0.2), and brain (2.9 +/- 0.5), as compared with the LFC group. In contrast, a nonsignificant increase of adducts was found in aorta (13.1 +/- 1.5). A similar but nonsignificant trend was observed in the ApoE*3-Leiden mice. Multiple regression analysis showed that in aorta, DNA adducts were inversely related to plasma triglycerides (P = 0.004) and were also modulated by the ApoE genotype (P < 0.001). The results of the present study support further investigation into the role of dietary modulation of plasma lipids, ApoE, and polycyclic aromatic hydrocarbon exposure on the formation of DNA adducts in chronic degenerative diseases.     

Behaviour of neurons in monkey peri-arcuate and precentral cortex before and during visually guided arm and hand movements

Summary Neuron activity was recorded in monkey cerebral cortex during a visually guided reaching task. Cells located in the banks of the arcuate sulcus at its curvature changed their activity during the period in which the monkey saw a food reward in a certain position, but before it moved to retrieve the reward. A role of these neurons in visual guidance of arm and hand movements is postulated.Part of this work was funded by grant 13-46-15 of Fungo-ZWO (Dutch Organisation for Fundamental Research)