Beneficial health effects of milk and fermented dairy products--review.

Milk is a complex physiological liquid that simultaneously provides nutrients and bioactive components that facilitate the successful postnatal adaptation of the newborn infant by stimulating cellular growth and digestive maturation, the establishment of symbiotic microflora, and the development of gut-associated lymphoid tissues. The number, the potency, and the importance of bioactive compounds in milk and especially in fermented milk products are probably greater than previously thought. They include certain vitamins, specific proteins, bioactive peptides, oligosaccharides, organic (including fatty) acids. Some of them are normal milk components, others emerge during digestive or fermentation processes. Fermented dairy products and probiotic bacteria decrease the absorption of cholesterol. Whey proteins, medium-chain fatty acids and in particular calcium and other minerals may contribute to the beneficial effect of dairy food on body fat and body mass. There has been growing evidence of the role that dairy proteins play in the regulation of satiety, food intake and obesity-related metabolic disorders. Milk proteins, peptides, probiotic lactic acid bacteria, calcium and other minerals can significantly reduce blood pressure. Milk fat contains a number of components having functional properties. Sphingolipids and their active metabolites may exert antimicrobial effects either directly or upon digestion.

Blood pressure prior to cardioversion predicts a conversion to sinus rhythm in patients with atrial fibrillation.

BACKGROUND: The effect of BP measured prior to the cardioversion has not been studied. METHODS: Eighty patients (mean age 62 +/- 11 yrs, 44 men) with atrial fibrillation (AF), who underwent 92 cardioversions, were included. Non-invasive BP was measured. We performed a retrospective review of clinical data. The variables included into logistic regression analysis were: BP, age, gender, arterial hypertension, coronary artery disease, heart failure, obesity, left atrial diameter, duration of AF, antiarrhythmic and antihypertensive therapy. RESULTS: A success rate of cardioversion was 60.9%. BP was lower in the group of patients with a successful cardioversion (mean BP 97 +/- 15 vs 104 +/- 10 mmHg, p = 0.02; systolic BP 130 +/- 21 vs 140 +/- 18 mmHg, p=0.02; diastolic BP 81 +/- 14 vs 86 +/- 8 mmHg, p = 0.07). Mean, systolic and diastolic BP cut-off levels with the highest sum of sensitivity and specificity were 103, 138 and 75 mmHg, respectively. CONCLUSIONS: Subjects with a successful cardioversion had lower BP measured immediately prior to the procedure. BP and concurrent antiarrhythmic treatment were the only predictors of a successful cardioversion (Tab. 1, Ref. 29). Full Text (Free, PDF) www.bmj.sk.

Inflammation--a lifelong companion. Attempt at a non-analytical holistic view.

Inflammation is a key component of the immune system. It has important functions in both defense and pathophysiological events maintaining the dynamic homeostasis of a host organism including its tissues, organs and individual cells. On the cellular level it is controlled by more than 400 currently known genes. Their polymorphisms and environmental conditions give rise to different genotypes in human population. Pro-inflammatory genotype, which dominates in the present population, may be advantageous in childhood but not in elderly people because it is characterized by an increased vulnerability to, and intensity of, inflammatory reactions. These reactions may be the possible reasons of chronic inflammatory diseases, especially in old age. Better understanding of complex molecular and cellular inflammatory mechanisms is indispensable for detailed knowledge of pathogenesis of many diseases, their prevention and directed drug therapy. Here we summarize the basic current knowledge on these mechanisms.

Neuroinflammation in Alzheimer's disease: protector or promoter?

Alzheimer's disease (AD) is an irreversible, progressive and degenerative disorder that destroys the higher structures of the brain. Prominent neuropathologic features of AD are senile plaques, neurofibrillary tangles, synaptic and neuronal loss. There is mounting evidence that chronic inflammatory processes play a fundamental role in the progression of neuropathological changes of AD. It has been shown, that there is a reciprocal relationship between the local inflammation and senile plaques (SPs) and neurofibrillary tangles (NFTs). The major players involved in the inflammatory process in AD are thought to be the microglia and the astrocytes. The process of the activation of glia is characteristized by upregulation or newly expression of a variety of molecules involved in inflammatory response including cytokines, various components of the complement cascade, acute phase reactants, proteases and protease inhibitors, and neurotoxic products. The importance of inflammation in the pathogenesis of AD was indirectly confirmed by epidemiological investigations that revealed a decreased incidence of AD in subjects using anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs). However clinical trials designed to inhibit inflammation have failed in the treatment of AD patients suggesting that anti-inflammatory agents have more protective than therapeutic effect. Despite the ongoing research the extent to which neuroinflammation contributes to disease pathogenesis is still not fully understood. Moreover it is also not clear whether the inflammation in AD brains represent a protective reaction to neurodegeneration or it is rather a destructive process that contributes to further loss of brain function. (Ref. 117).

The role of oxidative stress in the pathogenesis of Alzheimer's disease.

Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD) as a relevant marker of neuronal degeneration. However it plays an important role not only in the pathogenesis of neurodegenerative diseases but also in other critical disorders like heart diseases, carcinogenesis and others. Oxidative stress is also associated with normal aging. In this review we discuss a crucial question: to what extent oxidative stress may be a causative factor in pathogenesis of AD type of neurodegeneration. The results of several recent epidemiological studies appeared to be controversial at this point. It is believed that antioxidant therapies may have beneficial effects at least in delaying disease progression and appearance of AD specific clinical symptoms. Since there is no cure for AD recently, healthy life style and antioxidants enriched nutrition (or even antioxidant therapy) may provide an effective way of fighting against this deleterious disease (Ref. 102).

Long-term (56-week) oral administration of probiotic Enterococcus faecium M-74 decreases the expression of sICAM-1 and monocyte CD54, and increases that of lymphocyte CD49d in humans.

OBJECTIVES: To study the effects of long-term probiotic [Enterococcus faecium (EF) M-74 strain] application in humans with respect to adhesion molecules, both soluble forms (sICAM-1, sPECAM-1) and their expression on leukocytes. METHODS: Double-blinded randomized and placebo controlled study lasting for 60 weeks. A single capsule containing either 2x10(9) of bacteria EF M-74 with 50 microg of organically bound selenium (E-group) or placebo (P-group) was given to volunteers. Peripheral blood was analyzed for the expression of particular adhesive molecules. RESULTS AND CONCLUSIONS: We observed significant changes in CAMs expression in terms of a decrease in sICAM-1, CD54 on monocytes and CD11b on lymphocytes after one-year administration of Enterococcus faecium M-74 in humans. Anti-adhesion-aimed therapeutic modalities may provide the future approach to prevention and treatment of cardiovascular diseases. Application of probiotics may be part of such strategies. (Tab. 2, Fig. 6, Ref. 41.)

One-year application of probiotic strain Enterococcus faecium M-74 decreases serum cholesterol levels.

OBJECTIVES: To investigate the impact of long-term orally administered probiotic strain Enterococcus faecium (EF) M-74 enriched with selenium on lipid profile (total cholesterol, LDH, HDL, and triglycerides) in humans. BACKGROUND: The discovery that hypercholesterolemia plays a major role in the development of atherosclerosis has led to a number of pharmacological and non-pharmacological (including dietary) approaches resulting in its elimination. Up to now, the question of supposed hypocholesterolemic effect of probiotics has not been definitely established. METHODS: 43 volunteers were randomized into two groups. Participants were given single capsule a day containing 2x10(9) of EF M-74 plus 50 microg of organically bound selenium (E-group) or placebo (P-group). The study was double-blind and lasted 60 weeks. Peripheral blood was analyzed for lipid parameters before intervention, after 6, 12, 23, 44, and 56 weeks of capsule administration, and four weeks following interruption of administration. RESULTS: After 56 weeks of application, decrease in total cholesterol in E-group (17/3 women/men, mean age 75.4+/-1.5 year) was observed (5.94+/-0.29 mmol/l at week 0 vs 5.22+/-0.25 mmol/l after 56 weeks, p<0.001). This reduction was achieved mainly due to a fall in LDL cholesterol (3.85+/-0.27 vs 3.09+/-0.21 mmol/l, p<0.001), as no significant alterations in HDL and triglycerides were noted. In placebo group (14/4, 78.1+/-1.7 year), no statistically important changes were observed after one-year capsule administration. CONCLUSIONS: In our study, the administration of E. faecium M-74 probiotic strain was associated with reduction of serum cholesterol concentration by 12% after 56 weeks. The crescent amount of facts on this issue gives a solid reason to assume that probiotics will find their place as a therapeutic alternative in human medicine. (Tab. 4, Fig. 4, Ref: 36.)

Detection of drug-induced, superoxide-mediated cell damage and its prevention by antioxidants.

The mode of the cytotoxic activity of three benzo(c)fluorene derivatives was characterized. The observed morphological changes of lysosomes or variations of mitochondrial activity are assumed to be the consequence of cell protection against oxidative damage and/or the part of the damage process. To establish the relationship between the quantity of superoxide (O2*-) generated and the degree of damage resulting from O2*-, a simple system based on measurement of 3-(4-iodophenyl)-2-(4-nitrophenyl)-5-phenyltetrazolium chloride (INT) reductase activity in the presence of superoxide dismutase (SOD) was used. The functionality of the chosen battery of in vitro tests was proved using several known superoxide inducers: cyclosporin A (CsA) and benzo(a)pyrene (BP), as well as noninducers: citrinin (CT) and cycloheximide (CH). From the results followed that the cell growth tests are much better indices of toxicity than the other tests. The model system for the evaluation of the protective capacity of antioxidants against superoxide-induced cytotoxicity included simultaneous exposure of HeLa cells to cytotoxic drugs and to quercetin (Qe), an antioxidant of plant origin. The complete abolishment of the inhibition of cell proliferation and clonogenic survival was concluded to be due to the protective effect of the antioxidant. These observations correlated with the decrease of superoxide content as estimated by the INT-reductase assay in the presence of SOD using the same model system, as well as with the increase of intracellular SOD content and its activity.

Amphiphilic detergents inhibit production of IgG and IgM by human peripheral blood mononuclear cells.

All types (cationic, anionic and non-ionic) amphiphilic detergents significantly inhibited the production of both IgG and IgM by human peripheral blood mononuclear cells after polyclonal activation in vitro. The most potent inhibitors were didodecyldimethylammonium bromide (DDAB) and (1-methyldodecyl)dimethylamine N-oxide (2-ATDNO). They were able to suppress effectively the immunoglobulin production in 10(-3)-10(-8) M concentrations. A medium inhibitory effect was observed with Slovapon, sodium dodecyl sulphate (SDS) and Triton X-100, while Slovanik showed an inhibition only in concentrations higher than 10(-2)%. These results suggest that amphiphilic detergents may be characterized as potential immunotoxic substances with very negative effects on the immunoglobulin production.

Immunomodulatory effect of sodium dodecyl sulfate on human neutrophils and the human promyelocytic HL-60 cell line.

The effect of sodium dodecyl sulfate (SDS), an anionic amphiphilic detergent, on the function of human neutrophils and of the human promyelocytic leukemia cell line HL-60 was investigated. SDS modulated the respiratory burst in human neutrophils and HL-60 cells which were stimulated with phorbol 12-myristate 13-acetate (PMA). In concentrations above 1 X 10(-6) M it also caused release of lysosomal enzymes (beta-D-glucuronidase, myeloperoxidase and lysozyme) from neutrophils. Our results demonstrate that SDS at concentrations 1 X 10(-6) M-1 X 10(-4) M strongly affect properties of human phagocytic cells.

Chemistry, physiology and pathology of free radicals.

The superoxide anion radical and other reactive oxygen species (ROS) are formed in all aerobic organisms by enzymatic and nonenzymatic reactions. ROS arise in both physiological and pathological processes, but efficient mechanisms have evolved for their detoxification. Similarly, reactive nitrogen intermediates (RNI) have physiological activity, but can also react with different types of molecules, including superoxide, to form toxic products. ROS and RNI participate in the destruction of microorganisms by phagocytes, as in the formation of a myeloperoxidase-hydrogen peroxide-chloride/iodide complex which can destroy many cells, including bacteria. It is known that the cellular production of ROS and RNI is controlled by different mechanisms. These free radicals can react with key cellular structures and molecules, thus altering their biological function. An imbalance between the systems producing and removing ROS and RNI may result in pathological consequences.

Endogenous control and modulation of inflammation.

Inflammation is the body's reaction to invasion by an infectious agent, antigen challenge or even just physical, chemical or traumatic damage. To avoid damage of the surrounding tissue, inflammatory responses must be well ordered and controlled. The development of inflammatory reactions is mainly controlled by vasoactive substances, cytokines, products of the plasma enzyme systems, bioactive lipids, and adhesive reactions between individual inflammatory cells or between them and molecules of extracellular matrix. The mediators of inflammation controlling different types of inflammatory reactions differ. This review briefly describes the role of proinflammatory and anti-inflammatory cytokines, including chemoattractant cytokines (chemokines), acute phase reactants, and the molecular mechanism of leucocyte emigration from the postcapillary venules.

Immunomodulatory effect of some amphiphilic detergents on the human promyelocytic HL-60 cells.

The effect of two anionic (sodium dodecyl sulfate (SDS) and sodium laurate), two cationic (didodecyldimethylammonium bromide (DDAB) and [(1-methyldodecyl)-trimethylammonium bromide (2-ATDBr)] and a nonionic [(1-methyldodecyl)-dimethyl-amine N-oxide (2-ATDNO)] amphiphilic detergents on the metabolic activation of phagocytes derived from human promyelocytic leukemia cell line HL-60 was investigated. SDS in the concentrations of 10(-4) M significantly stimulated the INT-reduction and superoxide production by HL-60 cells which were preincubated with phorbol 12-myristate 13-acetate (PMA) for a macrophage-like differentiation. This effect was not significant in the case of cells differentiated along monocyte-like and granulocyte-like pathways. A similar influence was observed by sodium laurate, but this effect was significant (P < 0.01) by INT-reduction only. Concentrations higher than 5 x 10(-5) M DDAB, 2-ATDBr and 2-ATDNO inhibited INT-reduction and superoxide generation in HL-60 cells differentiated along all three ways. Our results indicated that differentiated HL-60 cells may be used for in vitro testing of immunotoxic effects on respiratory burst in phagocytes.

Modulatory effect of glucans on the functional and biochemical activities of guinea-pig macrophages.

The particulate and soluble glucan preparations isolated from Saccharomyces cerevisiae and Candida albicans affected various activities of guinea-pig macrophages. The stimulation of INT reduction and superoxide production were observed in the presence of all insoluble and some soluble glucans in vitro, but most of the preparations under study had an inhibitory effect on phagocytic activity. On the other hand, the stimulation of both metabolic and functional activities was obtained in vivo. Macrophages from guinea-pigs treated with glucans exerted an increased ability to reduce INT and to produce superoxide. Their candidacidal capacity was rapidly elevated, and peritoneal macrophages had raised phagocytic activity as well. A more pronounced stimulatory effect was observed in the presence of insoluble rather than soluble glucans, and this was more expressive in vitro than in vivo.

Modulatory effects of selenium and zinc on the immune system.

Almost all nutrients in the diet play a crucial role in maintaining an "optimal" immune response, and both insufficient and excessive intakes can have negative consequences on the immune status and susceptibility to a variety of pathogens. We summarize the evidence for the importance of two micronutrients, selenium and zinc, and describe the mechanisms through which they affect the immune status and other physiological functions. As a constituent of selenoproteins, selenium is needed for the proper functioning of neutrophils, macrophages, NK cells, T lymphocytes and some other immune mechanisms. Elevated selenium intake may be associated with reduced cancer risk and may alleviate other pathological conditions including oxidative stress and inflammation. Selenium appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Selenium deficiency has been linked to adverse mood states and some findings suggest that selenium deficiency may be a risk factor in cardiovascular diseases. Zinc is required as a catalytic, structural and regulatory ion for enzymes, proteins and transcription factors, and is thus a key trace element in many homeostatic mechanisms of the body, including immune responses. Low zinc ion bioavailability results in limited immunoresistance to infection in aging. Physiological supplementation of zinc for 1-2 months restores immune responses, reduces the incidence of infections and prolongs survival. However, in every single individual zinc supplementation of food should be adjusted to the particular zinc status in views of the great variability in habitat conditions, health status and dietary requirements.

Functional and metabolic changes of guinea pig peritoneal macrophages induced by bacterial vaccines.

Phagocytic activity of peritoneal macrophages of guinea pigs injected subcutaneously with bacterial vaccines was found to be increased. The phagocytic index remained unchanged or was decreased. In addition, a decreased candidacidal activity was observed. Metabolic activation of macrophages, measured by the INT test, was inhibited in unstimulated cells while cells stimulated with zymosan or opsonized zymosan exhibited higher values of the INT test as compared with control animals. After injection of vaccines the number of peritoneal macrophages was increased, but the spleen mass decreased.

Hypocholesterolemic and immunostimulatory effects of orally applied Enterococcus faecium M-74 in man.

Lyophilized Enterococcus faecium M-74 was administered to 12 adult subjects in a daily oral dose of 5 x 10(9) bacteria for six weeks. The bacterium temporarily colonized the host intestine and its excretion with stool persisted for five weeks after the last does. The mean levels of serum cholesterol and LDL showed a a biphasic effect--an elevation followed by a sharp decrease (on day 64 of investigation). The decrease corresponded in time with a significant increase in the ability to reduce iodonitrotetrazolium and superoxide production by peripheral neutrophils incubated with zymosan or phorbol myristate acetate, and also with an elevated production of IgG by peripheral blood mononuclear cells. Hence, intake of E. faecium may have a hypocholesterolemic and immunostimulatory effect. It was also demonstrated that E. faecium significantly reduced the average activity of beta-D-glucuronidase in stools.

The effect of soluble glucan derivates on spleen colony-forming units in sublethally irradiated mice.

We examined the effects of 5 soluble derivatives of yeast glucan on the formation of exogenous (CFU-S) and endogenous (E-CFU) colony-forming units in the spleens of sublethally irradiated (60Co, 6.5-7.0 Gy) mice of two inbred strains. For the estimation of CFU-S, glucans were administered intravenously either to donors or recipients of spleen cells 24 h prior to irradiation or removal of the spleen. The number of CFU-S was increased when both the donors and recipients were treated with glucan; the highest increase was obtained with glucans S, P and K. All glucan preparations increased significantly also the number of E-CFU even when administered 90 min after irradiation. There exist differences in the response to the stimulatory effect of glucans among individual mouse strains. Thus, for example, the stimulatory effect of glucan KM on the E-CFU number was significantly more pronounced in strain A/Ph than in strain C57Bl/6.

The immunoadjuvant effect of soluble glucan derivatives in mice.

We examined the effect of soluble derivatives of yeast glucan on the humoral immune response of various strains of inbred mice after administration of different doses according to various schedules. Glucan was injected i.v. or s.c. in a single dose or repeatedly. The immune response was examined by determining the titres of serum hemagglutinins against sheep erythrocytes (SRBC-Ab). The immunoadjuvant effect of glucan derivatives depends on the inbred strain used, on the dose of glucan, mode and time of administration with respect to antigen injection. The results have shown that the stimulatory effect of glucan derivatives occurred already after a single injection, the optimum dose being 10-20 mg/kg. Intravenous injection was more efficient than the subcutaneous one. In some cases, a slight increase of the spleen mass was observed.

Lysosomal enzyme activities in polymorphonuclear leukocytes, macrophages, serum, and spleen of conventional, germ-free, and antigen-free Minnesota miniature swine.

The activities of lysozyme, myeloperoxidase, and elastase were lower in PMNs and AMs from GF and AF Minnesota miniature piglets than in the leukocytes from their CONV counterparts. In the spleen and serum of gnotobiotic piglets only the levels of lysozyme were slightly reduced. Substantially depressed activities of these LEs were found also in PMNs from precolostral piglets in comparison with PMNs from their CONV mother. The bisassociation of GF piglets with Enterococcus liquefaciens and Escherichia coli caused an increase of LE activities in their AMs, spleens, and sera. Fewer LEs were released after phygocytic stimulation with zymosan from PMNs of GF, AF, and precolostral piglets than from PMNs of CONV animals of the same age. These data suggest that the antigenic-microbial stimulation is important for the development of normal lysosomal enzyme activities in PMNs and AMs from gnotobiotic animals.