Plant extracts, polymers and new approach methods: Practical experience with skin sensitization assessment.

Over the last decade, research into methodologies to identify skin sensitization hazards has led to the adoption of several non-animal methods as OECD test guidelines. However, predictive accuracy beyond the chemical domains of the individual validation studies remains largely untested. In the present study, skin sensitization test results from in vitro and in chemico methods for 12 plant extracts and 15 polymeric materials are reported and compared to available in vivo skin sensitization data. Eight plant extracts were tested in the DPRA and h-CLAT, with the 2 out of 3 approach resulting in a balanced accuracy of 50%. The balanced accuracy for the 11 plant extracts assessed in the SENS-IS was 88%. Excluding 5 polymers inconclusive in vitro, the remainder, assessed using the 2 out of 3 approach, resulted in 63% balanced accuracy. The SENS-IS method, excluding one polymeric material due to technical inapplicability, showed 68% balanced accuracy. Although based on limited numbers, the results presented here indicate that some substance subgroups may not be in the applicability domains of the method used and careful analysis is required before positive or negative results can be accepted.

Cardiovascular mortality attributable to dietary risk factors in 51 countries in the WHO European Region from 1990 to 2016: a systematic analysis of the Global Burden of Disease Study.

This study was performed to highlight the relationship between single dietary risk factors and cardiovascular diseases (CVDs) in the WHO European Region. We used the comparative risk assessment framework of the Global Burden of Disease Study to estimate CVD mortality attributable to diet; comprising eleven forms of CVDs, twelve food and nutrient groups and 27 risk-outcome pairs in four GBD regions including 51 countries by age and sex between 1990 and 2016. In 2016, dietary risks were associated with 2.1 million cardiovascular deaths (95% uncertainty interval (UI), 1.7-2.5 million) in the WHO European Region, accounting for 22.4% of all deaths and 49.2% of CVD deaths. In terms of single dietary risks, a diet low in whole grains accounted for approximately 429,000 deaths, followed by a diet low in nuts and seeds (341,000 deaths), a diet low in fruits (262,000 deaths), a diet high in sodium (251,000 deaths), and a diet low in omega-3 fatty acids (227,000 deaths). Thus, with an optimized, i.e. balanced diet, roughly one in every five premature deaths could be prevented. Although age-standardized death rates decreased over the last 26 years, the absolute number of diet-related cardiovascular deaths increased between 2010 and 2016 by 25,600 deaths in Western Europe and by 4300 deaths in Central Asia. In 2016, approximately 601,000 deaths (28.6% of all diet-related CVD deaths) occurred among adults younger than 70 years. Compared to other behavioural risk factors, a balanced diet is a potential key lever to avoid premature deaths.

Omega-3 fatty acids and mortality in patients referred for coronary angiography. The Ludwigshafen Risk and Cardiovascular Health Study.

BACKGROUND AND AIMS: There is an ongoing debate whether omega-3-fatty acids protect from cardiovascular disease mortality. We examined the associations of erythrocyte omega-3 fatty acids with mortality in patients referred for coronary angiography. METHODS: Erythrocyte omega-3 fatty acid proportions were measured at baseline in 3259 participants of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) using the HS-Omega-3 Index method. Associations of omega-3 fatty acid proportions with mortality were investigated using Cox proportional hazards regression. RESULTS: During a median follow-up of 9.9 years, 975 patients (29.9%) died, 614 patients (18.8%) from cardiovascular causes. Proportions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were inversely associated with all-cause and cardiovascular mortality in models adjusted for conventional cardiovascular risk factors. The strongest association was observed for EPA with a hazard ratio (HR) of 0.89 (0.83-0.96) per increase of one standard deviation. Furthermore, we obtained evidence for a non-linear relation between EPA and mortality. CONCLUSIONS: EPA and DHA were associated with reduced mortality in LURIC, independent of other risk factors, with the association of EPA with mortality being non-linear.

The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism.

Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By combining data from a GWAS screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the AA metabolome as an important regulator of cholesterol homeostasis. Pharmacological modulation of AA metabolism by aspirin induced hepatic generation of leukotrienes (LTs) and lipoxins (LXs), thereby increasing hepatic expression of the bile salt export pump Abcb11. Induction of Abcb11 translated in enhanced reverse cholesterol transport, one key function of HDL. Further characterization of the bioactive AA-derivatives identified LX mimetics to lower plasma LDL-C. Our results define the AA metabolomeasconserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.

Association of 25-hydroxyvitamin D with type 2 diabetes among patients undergoing coronary angiography: cross-sectional findings from the LUdwigshafen Risk and Cardiovascular Health (LURIC) Study.

OBJECTIVE: Evidence suggests that vitamin D may protect against the onset of diabetes. However, the mechanisms underlying the role of vitamin D on glycaemic status are unclear and warrant further investigation. We sought to determine the relationship between serum 25-hydroxyvitamin D (25[OH]D) and glycaemic status among intermediate-to-high-risk patients scheduled for coronary angiography. METHODS: Participants were 3316 male and female patients (mean ± SD age, 62·7 ± 10·6 years). Four categories were formed according to serum 25[OH]D levels. The association between serum 25[OH]D and diabetes was assessed using multivariable logistic regression. RESULTS: Fasting and 2 h post-load glucose, HbA1c and the HOMA-IR indices diminished with increasing serum 25[OH]D levels (P < 0·001). However, no associations were observed between insulin, pro-insulin or C-peptide and serum 25[OH]D concentrations. The pro-inflammatory markers IL-6 and hs-CRP also decreased considerably with higher vitamin D levels (P < 0·001). After full adjustment, those with optimal serum 25[OH]D levels had a reduced odds for fasting diabetes (OR = 0·63; 95% CI, 0·46-0·86; Ptrend = 0·01), 2 h post-load diabetes (OR = 0·46; 95% CI, 0·29-0·74; Ptrend = 0·004), both fasting/2 h post-load diabetes (OR = 0·61; 95% CI, 0·42-0·87; Ptrend = 0·001) and all of the combined hyperglycaemic states (OR = 0·68; 95% CI, 0·52-0·80; Ptrend = 0·01). CONCLUSIONS: Higher serum 25[OH]D levels were associated with better glycaemic status and lower inflammation. Should these observations be confirmed in future studies, vitamin D supplementation may prove a useful adjunct in attenuating the onset of diabetes.

Vitamin D levels predict all-cause and cardiovascular disease mortality in subjects with the metabolic syndrome: the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

OBJECTIVE: Optimal vitamin D levels are associated with reduced cardiovascular and all-cause mortality. We investigated whether optimal 25-hydroxyvitamin D (25[OH]D) is protective in individuals with the metabolic syndrome. RESEARCH DESIGN AND METHODS: The Ludwigshafen Risk and Cardiovascular Health (LURIC) study is a cohort study of subjects referred for coronary angiography between 1997 and 2000, from which 1,801 with the metabolic syndrome were investigated. Mortality was tracked for a median of 7.7 years. Multivariable survival analysis was used to estimate the association between 25(OH)D levels and mortality. RESULTS: Most subjects (92%) had suboptimal levels of 25(OH)D (<75 nmol/L), with 22.2% being severely deficient (<25 nmol/L). During follow-up, 462 deaths were recorded, 267 (57.8%) of which were cardiovascular in origin. After full adjustment, including the metabolic syndrome components, those with optimal 25(OH)D levels showed a substantial reduction in all-cause (hazard ratio [HR] 0.25 [95% CI 0.13-0.46]) and cardiovascular disease mortality (0.33 [0.16-0.66]) compared with those with severe vitamin D deficiency. For specific cardiovascular disease mortality, there was a strong reduction for sudden death (0.15 [0.04-0.63]) and congestive heart failure (0.24 [0.06-1.04]), but not for myocardial infarction. The reduction in mortality was dose-dependent for each of these causes. CONCLUSIONS: Optimal 25(OH)D levels substantially lowered all-cause and cardiovascular disease mortality in subjects with the metabolic syndrome. These observations call for interventional studies that test whether vitamin D supplementation provides a useful adjunct in reducing mortality in these subjects.