No abstract

Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10−7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.

The increasing interest in a healthy diet is stimulating innovative development of novel scientific products in the food industry. The viable lactic acid bacteria in fermented milk products, such as yoghurt, have been associated with increased lactose tolerance, a well-balanced intestinal microflora, antimicrobial activity, stimulation of the immune system and antitumoural, anticholesterolaemic and antioxidative properties in human subjects. Recently, we have studied a human Lactobacillus spp. strain that possesses antioxidative activity. The aim of the present pilot study was to develop goats' milk fermented with the human antioxidative lactobacilli strain, Lactobacillus fermentum ME-3, and to test the effect of the fermented probiotic goats' milk on oxidative stress markers (including markers for atherosclerosis) in human blood and urine and on the gut microflora. Twenty-one healthy subjects were assigned to two treatment groups: goats' milk group and fermented goats' milk group (150 g/d) for a period of 21 d. Consumption of fermented goats' milk improved anti-atherogenicity in healthy subjects: it prolonged resistance of the lipoprotein fraction to oxidation, lowered levels of peroxidized lipoproteins, oxidized LDL, 8-isoprostanes and glutathione redox ratio, and enhanced total antioxidative activity. The consumption of fermented goats' milk also altered both the prevalence and proportion of lactic acid bacteria species in the gut microflora of the subjects. We conclude that the goats' milk fermented with our special antioxidative lactobacilli strain Lactobacillus fermentum ME-3 exhibits anti-atherogenic effects.

Aims: To use antioxidative activity and antagonistic properties of lactobacilli against selected pathogens and members of the normal microflora as a basis for screening probiotic candidates. Methods and Results: Antagonistic activity of lactobacilli against target bacteria in both microaerobic and anaerobic environments was tested. Production of antagonistic metabolites (ethanol, hydrogen peroxide (H 2 O 2 ), acetic, lactic and succinic acid) by lactobacilli as well as their total antioxidative activity were assessed. In general, the lactobacilli tested were most effective against Gram-negative bacteria and their antagonistic activity was strainspecific. However, obligately heterofermentative lactobacilli had the strongest activity when tested in a microaerobic environment. Additionally, facultatively heterofermentative lactobacilli were equally effective in either milieu and produced significant levels of acetic and lactic acid. Moreover, obligately homofermentative lactobacilli had high H 2 O 2 production and total antioxidative activity but weak antagonistic activity. Conclusions: Antioxidative and antagonistic activity of intestinal lactobacilli is strain-specific but typically can be related to their fermentation type which may be used for rapidly screening large numbers of lactobacilli for probiotic candidates. Significance and Impact of the Study: This study represents the first report on the utilization of group characteristics to screen lactobacilli intended for specific probiotic use. Such uses include the targeting of particular gut niches and pathogens as well as allowing for long-term benefits to the host.

Abstract-The aim of this study was to investigate the effects of the vasodilating ␤-blocker nebivolol and the cardioselective ␤-blocker metoprolol succinate on aortic blood pressure and left ventricular wall thickness. We conducted a randomized, double-blind study on 80 hypertensive patients. The patients received either 5 mg of nebivolol or 50 to 100 mg of metoprolol succinate daily for 1 year. Their heart rate, central and brachial blood pressures, mean arterial pressure, augmentation index, carotid-femoral pulse wave velocity, and left ventricular wall thickness were measured at baseline and at the end of the study. Nebivolol and metoprolol significantly reduced heart rate, brachial blood pressure, and mean arterial pressure to the same degree. However, reductions in central systolic and diastolic blood pressures, central pulse pressure, and left ventricular wall thickness were significant only in the nebivolol group. The change in left ventricular septal wall thickness was significantly correlated with central systolic blood pressure change (rϭ0.41; Pϭ0.001) and with central pulse pressure change (rϭ0.32; Pϭ0.01). No significant changes in augmentation index or carotid-femoral pulse wave velocity were detected in either treatment group. This proof-ofprinciple study provides evidence to suggest that ␤-blockers with vasodilating properties may offer advantages over conventional ␤-blockers in antihypertensive therapy; however, this remains to be tested in a larger trial. lood pressure (BP) varies throughout the arterial tree because of pulse wave amplification, a phenomenon of wave reflection and arterial stiffness. 1 Because of pulse wave amplification, reduction in brachial BP does not reflect changes in central BP, which may become a more important target in the treatment of hypertension. Recent data from the Strong Heart Study 2 confirm earlier results from smaller studies on high-risk patients 3,4 that central pulse pressure is superior to brachial pulse pressure in the prediction of further cardiovascular events. Moreover, several studies have demonstrated that brachial BP is not a good surrogate for the hemodynamic effects of drug therapies on central circulation. The recently published EX-PLOR Study 5 and the Conduit Artery Function Evaluation Study 6 clearly demonstrated that angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers have a more pronounced effect on reducing central BP compared with the cardioselective ␤-blocker (BB) atenolol. Different effects of BB on central BP can explain the findings of a recent meta-analysis published by Law et al, 7 which demonstrates a slight inferiority of BB in preventing stroke. The detrimental effect of BB on central BP has generated criticism regarding its use as first line therapy for essential hypertension. Dhakam et al 8 questioned the hypothesis that the inferiority of atenolol in reducing central BP is a class effect of BB. They demonstrated that the novel vasodilating BB nebivolol (NEB) reduces central BP si...

Background: In persons without clinical symptom it is difficult to assess an impact of probiotics regarding its effect on health. We evaluated the functional efficacy of the probiotic Lactobacillus fermentum ME-3 in healthy volunteers by measuring the influence of two different formulations on intestinal lactoflora, fecal recovery of the probiotic strain and oxidative stress markers of blood and urine after 3 weeks consumption.

Reactive oxygen and nitrogen species produced by metabolism and immune defenses can cause extensive damage to biomolecules. To counteract this damage, organisms rely on exogenous and endogenous antioxidants, although their relative importance in maintaining redox balance is unclear. We supplemented captive greenfinches with dietary antioxidants--carotenoids and vitamin E--and injected them with an inflammatory agent, phytohemagglutinin. Compared to controls, immune-challenged birds circulated more lipid peroxidation products but also increased total plasma antioxidativity. Carotenoid (but not vitamin E) supplementation generally reduced lipid peroxidation, but this did not compensate for the effects of immune activation. Levels of an endogenous antioxidant--uric acid--strongly contributed to plasma antioxidativity. We found no evidence that dietary antioxidants are immunostimulatory. These results demonstrate the antioxidant function of carotenoids in birds and show that simultaneous assessment of oxidative stress-driven damage, antioxidant barrier, and individual antioxidants is critical for explaining the potential costs of immune system activation.

The paper lays out the short scientific history and characteristics of the new probiotic Lactobacillus fermentum strain ME-3 DSM-14241, elaborated according to the regulations of WHO/FAO (2002). L. fermentum ME-3 is a unique strain of Lactobacillus species, having at the same time the antimicrobial and physiologically effective antioxidative properties and expressing health-promoting characteristics if consumed. Tartu University has patented this strain in Estonia (priority June 2001, patent in 2006), Russia (patent in 2006) and the USA (patent in 2007). The paper describes the process of the identification and molecular typing of this probiotic strain of human origin, its deposition in an international culture collection, and its safety assessment by laboratory tests and testing on experimental animals and volunteers. It has been established that L. fermentum strain ME-3 has double functional properties: antimicrobial activity against intestinal pathogens and high total antioxidative activity (TAA) and total antioxidative status (TAS) of intact cells and lysates, and it is characterized by a complete glutathione system: synthesis, uptake and redox turnover. The functional efficacy of the antimicrobial and antioxidative probiotic has been proven by the eradication of salmonellas and the reduction of liver and spleen granulomas in Salmonella Typhimurium-infected mice treated with the combination of ofloxacin and L. fermentum strain ME-3. Using capsules or foodstuffs enriched with L. fermentum ME-3, different clinical study designs (including double-blind, placebo-controlled, crossover studies) and different subjects (healthy volunteers, allergic patients and those recovering from a stroke), it has been shown that this probiotic increased the antioxidative activity of sera and improved the composition of the low-density lipid particles (LDL) and post-prandial lipids as well as oxidative stress status, thus demonstrating a remarkable anti-atherogenic effect. The elaboration of the probiotic L. fermentum strain ME-3 has drawn on wide international cooperative research and has taken more than 12 years altogether. The new ME-3 probiotic-containing products have been successfully marketed and sold in Baltic countries and Finland.