Pharmacological Supplementation Research Articles

Les acides gras essentiels de la famille des oméga-3 et la santé de la mère et de l'enfant

Linoleic acid, precursor of omega-6, and alpha-linolenic acid, precursor of omega-3, undergo several transformations to form, respectively, arachidonic acid and eicosapentaenoic and docohexaenoic acids. A ratio of 5/1 between linoleic and alpha-linolenic acids intake is recommended. However, the dietary intake of the French population is far from matching this ratio, which is imbalanced in favor of linoleic acid. This omega-3 deficiency, that may play a role in the onset of cancers, cardiovascular and neurovascular diseases, is worsened in physiological situations such as pregnancy and breastfeeding. Omega-3 deficiency may enhance the risk of premature delivery and post-partum depression; omega-3 fortification of mother's milk may stimulate visual and cognitive functions in the baby. Pharmacological supplementation might be proposed in pregnant/breastfeeding women.

Glutamine: the first clinically relevant pharmacological regulator of heat shock protein expression?

It is well known that enhanced heat shock protein expression protects organisms against morbidity and mortality following experimental injury/illness. Presently, chemical/gene therapy based laboratory methods of enhancing heat shock protein expression are impractical for clinical application. Our laboratory has shown glutamine enhances heat shock protein expression following models of experimental illness/injury. The purpose of this review is to examine recent data supporting the use of glutamine as a clinically relevant enhancer of heat shock protein expression. Recent studies indicate glutamine induces heat shock protein-70, HO-1 (heat shock protein-32), and heat shock protein-27 in models of illness/injury. Enhanced expression of heat shock proteins correlates with improved outcome in these models. Further, in-vitro data reveal glutamine enhances DNA binding of heat shock factor-1 (heat shock protein transcription factor) to its promoter. Finally, recently published pilot data show that glutamine enhances serum heat shock protein-70 expression in critically ill patients and this enhanced expression correlates with improved outcome. Currently, extensive data support glutamine as a gene level regulator of heat shock protein expression. Glutamine depletion, following critical illness/injury, is likely to lead to a state in which organisms are unable to induce heat shock proteins appropriately. Further, pharmacologic supplementation of glutamine potentiates the heat shock protein response prior to and following a stress. Pharmacologic trials utilizing glutamine to enhance heat shock proteins in humans are indicated.

Pre-treatment with Irbesartan attenuates left atrial stunning after electrical cardioversion of atrial fibrillation

Left atrial (LA) stunning, the transient impairment of LA function, is responsible for an increased thrombo-embolic risk after cardioversion of atrial fibrillation (AF). Angiotensin receptor blockers (ARBs) attenuate atrial remodelling in AF and could theoretically influence LA stunning. We studied the effect of Irbesartan on LA stunning. We prospectively assigned 50 patients from the outpatient clinic undergoing electrical cardioversion for AF with duration of >4 weeks, into two matched groups: 25 patients were treated with Irbesartan (228+/-93 mg/day) for at least 2 weeks prior to cardioversion (Irbesartan group); 25 patients did not receive ARBs (control group). The groups did not differ concerning age (64+/-13 vs. 63+/-13 years, respectively), AF duration (20+/-18 vs. 20+/-19 weeks), underlying disease, LA diameter (46+/-7 vs. 47+/-9 mm), left ventricular dimensions, and ejection fraction (47.7+/-11.6 vs. 49.7+/-14.5%). We assessed LA appendage emptying velocities (LAAEV) and LA spontaneous echo contrast (LASEC) by transoesophageal echocardiography before and after cardioversion and at 2 weeks, and the A-wave by transthoracic echocardiography after cardioversion, at 2 and at 4 weeks. LA stunning was significantly attenuated in the Irbesartan group. The reduction of LAAEV immediately after cardioversion was significantly less in the Irbesartan group (LAAEV reduction of 9+/-49% from 28+/-9 cm/s before cardioversion to 25+/-13 cm/s immediately afterwards) than in the control group (reduction of 48+/-20% from 34+/-15 cm/s before cardioversion to 16+/-6 cm/s afterwards) (P = 0.048). New or increased LASEC occurred in eight patients (32%) in the Irbesartan vs. 16 patients (64%) in the control group (P = 0.046). Irbesartan significantly attenuates LA stunning after electrical cardioversion of AF. Therefore, ARBs may represent an important pharmacological supplementation in patients being prepared for cardioversion.

Effects on Hippocampus of Lifelong Absence of Glucocorticoids in the Pro-Opiomelanocortin Null Mutant Mouse Reveal Complex Relationship Between Glucocorticoids and Hippocampal Structure and Function

In humans changes in serum cortisol levels have been observed with aging, stress, and with affective disorders such as major depression and post-traumatic stress disorder. Corticosteroids are known to influence hippocampal structure and function; specifically, plasma corticosteroid levels have been inversely correlated with hippocampal cell proliferation, cell death, and impaired memory function. The relationship between corticosteroids and structure and function of the hippocampus has been studied in experimental systems in adult animals by increasing or decreasing corticosterone levels through pharmacological supplementation and through surgical removal of the adrenal gland. Here, we utilized the genetically engineered pro-opiomelanocortin (POMC) null mutant mouse, which because of the lack of all POMC peptides has no corticosterone from birth throughout life. The effect of this lifelong absence of corticosterone on the dentate gyrus of the hippocampus is a decrease in granule cell density, which correlated with a decrease in cell proliferation but not an increase in cell degeneration. Fine morphology of granule cells was unaltered. Analyses of gene expression revealed no changes in POMC null mutant vs wild-type hippocampus with respect to levels of expression of corticoid receptor genes or genes known to be regulated by corticosterone. Spatial learning as tested by the Morris water maze was not altered in the POMC null mutant mouse. Taken together with findings from other studies of the effects of altered levels of corticosteroids on the hippocampus, our results argue for a complex homeostasis in which disturbances of any one factor can offset the system in varying ways.

Vitamins in aging, health, and longevity.

Evidence of epidemiological associations of vitamins and disease states have been found for nine vitamins. In observational studies, people with a high intake of antioxidant vitamins by regular diet or as food supplements generally have a lower risk of major chronic disease, such as myocardial infarction or stroke, than people who are low consumers of antioxidant vitamins. Prospectively, folate appears to reduce the incidence of neural tube defects. Vitamin D is associated with a decreased occurrence of fractures when taken with calcium. Zinc, betacarotene, and vitamin E appear to slow the progression of macular degeneration, but do not reduce the incidence. Vitamin E and lycopene may decrease the risk of prostate cancer. In other randomized controlled trials, the apparent beneficial results of a high intake of antioxidant vitamins seen in observational studies have not been confirmed. There is increasing concern from these trials that pharmacological supplementation of vitamins may be associated with a higher mortality risk.

Dietary fibre, glycaemic response, and diabetes

The much publicised global trend in rising levels of obesity and diabetes has refuelled interest in the dietary intake of the macronutrients (fat, protein, and carbohydrates) necessary to maintain the state of normalcy (good health) of an individual. Both scientific and public attention have focused on the dietary mediation of chronic health syndromes, either through use of dietary supplements, or a review of the whole diet situation. Dietary supplements have been used extensively both as pharmacological supplements, food ingredients, in processed foods to aid weight control, and the regulation of glucose control for diabetic patients. Particular interest has focused on the use of dietary fibres, especially soluble dietary fibres (such as guar gum, locust bean gum, and psyllium fibres), resistant starch, and slowly digestible carbohydrates. These have been shown to alter food structure, texture, and viscosity, and hence the rate of starch degradation during digestion. Research has also illustrated an association between the rate of carbohydrate degradation during digestion, and the regulation of postprandial blood sugar and insulin levels. The current paper explores the potential use of dietary fibres in the treatment of obesity and diabetes.

Arginase Plays a Pivotal Role in Polyamine Precursor Metabolism in Leishmania: CHARACTERIZATION OF GENE DELETION MUTANTS

The polyamine pathway of protozoan parasites has been successfully targeted in anti-parasitic therapies and is significantly different from that of the mammalian host. To gain knowledge into the metabolic routes by which parasites synthesize polyamines and their precursors, the arginase gene was cloned from Leishmania mexicana, and Deltaarg null mutants were created by double targeted gene replacement and characterized. The ARG sequence exhibited significant homology to ARG proteins from other organisms and predicted a peroxisomal targeting signal (PTS-1) that steers proteins to the glycosome, an organelle unique to Leishmania and related parasites. ARG was subsequently demonstrated to be present in the glycosome, whereas the polyamine biosynthetic enzymes, in contrast, were shown to be cytosolic. The Deltaarg knockouts expressed no ARG activity, lacked an intracellular ornithine pool, and were auxotrophic for ornithine or polyamines. The ability of the Deltaarg null mutants to proliferate could be restored by pharmacological supplementation, either with low putrescine or high ornithine or spermidine concentrations, or by complementation with an arginase episome. Transfection of an arg construct lacking the PTS-1 directed the synthesis of an arg that mislocalized to the cytosol and notably also complemented the genetic lesion and restored polyamine prototrophy to the Deltaarg parasites. This molecular, biochemical, and genetic dissection of ARG function in L. mexicana promastigotes establishes: (i) that the enzyme is essential for parasite viability; (ii) that Leishmania, unlike mammalian cells, expresses only one ARG activity; (iii) that the sole vital function of ARG is to provide polyamine precursors for the parasite; and (iv) that ARG is present in the glycosome, but this subcellular milieu is not essential for its role in polyamine biosynthesis.

Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease.

Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is a key signaling molecule in vascular homeostasis. Loss of NO bioavailability due to reduced synthesis and increased scavenging by reactive oxygen species is a cardinal feature of endothelial dysfunction in vascular disease states. The pteridine cofactor tetrahydrobiopterin (BH4) has emerged as a critical determinant of eNOS activity: when BH4 availability is limiting, eNOS no longer produces NO but instead generates superoxide. In vascular disease states, there is oxidative degradation of BH4 by reactive oxygen species. However, augmentation of BH4 concentrations in vascular disease by pharmacological supplementation, by enhancement of its rate of de novo biosynthesis or by measures to reduce its oxidation, has been shown in experimental studies to enhance NO bioavailability. Thus, BH4 represents a potential therapeutic target in the regulation of eNOS function in vascular disease.

Clinical Applications of l‐Glutamine: Past, Present, and Future

This review will attempt to summarize recent clinical data on glutamine's use. It will present the concept of glutamine as a "drug" or "nutraceutical," given in addition to standard nutrition support. Key references will be discussed, and clinical recommendations with regard to patients who may benefit and dosing are also provided. Glutamine, traditionally considered a nonessential amino acid, now is considered "conditionally essential" after critical illness, stress, and injury. States of illness or injury can lead to a significant decrease in plasma levels of glutamine, and when this decrease is severe, it has been correlated with increased mortality. Laboratory data have demonstrated numerous benefits of glutamine in experimental models of critical illness, cancer, and cardiac injury. The mechanism of these protective effects includes attenuated proinflammatory cytokine expression, improved gut barrier function, enhanced ability to mount a stress response, improved immune cell function, and decreased mortality. Over the last 10 years, clinical trials of glutamine supplementation in critical illness, surgical stress, and cancer have shown benefit with regard to mortality, length of stay, and infectious morbidity. However, data demonstrating a lack of benefit with glutamine supplementation in some patients have been presented as well. It appears that dose and route of administration clearly influence the benefit observed from glutamine administration, with high-dose parenteral glutamine demonstrating an advantage over low-dose enteral glutamine. High-dose or parenteral (> 0.25 to 0.30 g/kg/day IV or >or=30 g/day enterally) glutamine appears to demonstrate the greatest potential for benefit in hospitalized patients. No evidence of harm has been observed in studies conducted to date; thus, further clinical trials using glutamine as a pharmacologic supplement to standard nutrition are warranted.

Role of L-glutamine in critical illness: new insights.

This review will attempt to summarize recent clinical and experimental data on glutamine's use in critical illness. It will try to present the concept of glutamine as a 'drug' or 'nutraceutical', given in addition to standard nutritional support. Glutamine, traditionally considered to be a nonessential amino acid, is now considered as 'conditionally essential' following critical illness and injury. States of critical illness lead to significant decreases in plasma levels of glutamine and when this decrease is severe it has been correlated with increased mortality. Laboratory data have demonstrated numerous benefits of glutamine in experimental models of critical illness, including attenuated proinflammatory cytokine expression, improved gut barrier function, enhanced ability to mount a stress response, improved immune cell function, and decreased mortality. Over the last 10 years clinical trials of glutamine supplementation in critical illness have shown benefit with regard to mortality, length of stay, and infectious morbidity. However, data demonstrating a lack of benefit with glutamine supplementation in the critically ill have been presented as well. It appears that dose and route of administration clearly influence the benefit observed from glutamine administration, with high-dose, parenteral glutamine demonstrating an advantage over low-dose, enteral glutamine. High-dose or parenteral (>0.20-0.30 g/kg/day or > or =30 g/day) glutamine appears to demonstrate the greatest potential for benefit in critically ill patients. No evidence of harm has been observed in studies conducted to date, thus further clinical trials utilizing glutamine as a pharmacologic supplement to standard nutrition are warranted.

Nitric oxide, platelet function, myocardial infarction and reperfusion therapies.

Platelets play an important role in physiologic hemostasis and pathologic thrombosis that complicate the course of vascular disorders. A number of platelet functions including adhesion, aggregation and recruitment are controlled by nitric oxide (NO) generated by platelets and the endothelial cells. Derangements in this generation may contribute to the pathogenesis of thrombotic complications of vascular disorders. The pharmacologic supplementation of the diseased vasculature with drugs releasing NO may help to restore the hemostatic balance.

The Effect of Surface Modification and Aprotinin on Cellular Injury during Simulated Cardiopulmonary Bypass

Cardiopulmonary bypass (CPB) elicits derangements to the formed elements of blood because of the physical stresses of extracorporeal flow. Methods of reducing the impact of CPB include circuit surface modification and pharmacological supplementation. The purpose of this study was to examine the effects of aprotinin in combination with surface modification during simulated CPB. Fresh whole bovine blood was used to prime standard CPB circuits divided into four groups (N = 3): control (CTR), aprotinin 300 KIU/mL (APR), Poly (2-methoxyethylacrylate) coating (PMEA), and APR with PMEA (APR–PMEA). Physical stresses included venous reservoir negative pressure (−85 mmHg), arterial line pressure of 150 mmHg at 5 LPM, and air–blood interface, applied over a 90-minute period. Samples were drawn at the following times: 0, 10, 45, and 90 minutes. Endpoints included platelet count (PLT), plasma-free hemoglobin (PFHb), and thromboelastography (TEG). PLT did not change (138.9 ± 15.0 vs. 102.9 ± 21.0, p = ns) throughout the 90-minute experimental periods in any group. PFHb increased significantly (mean of 19- fold) throughout the experiment, but was not affected by any treatment. The TEG index declined in the CTR (3.6 ± 0.4 vs. −16.2 ± 2.9, p < .0003), PMEA (5.9 ± 0.8 vs. −2.7 ± 3.8, p < .02), and APR–PMEA (4.6 ± 1.0 vs. −2.8 ± 0.3 p < .0003) groups, but not in the APR group (3.6 ± 2.2 vs. −1.3 ± 3.3 p = .10). In conclusion, neither APR nor PMEA had an effect on either red cell hemolysis or PLT, but APR treatment alone significantly attenuated the derangements in coagulation induced in this extracorporeal model.

Niacin deficiency increases spontaneous and etoposide-induced chromosomal instability in rat bone marrow cells in vivo

Poly(ADP-ribose) polymerase (PARP) binds to DNA single and double strand breaks and uses NAD in the synthesis of poly(ADP-ribose) (pADPr). Niacin deficiency in rats decreases bone marrow NAD + and limits pADPr synthesis in response to DNA damage, while pharmacological supplementation with nicotinic acid (NA) increases bone marrow NAD + and pADPr. The purpose of this study was to determine if niacin status alters the extent of DNA damage and chromosomal instability before and after treatment with the chemotherapy drug etoposide (ETO). Genotoxicity was evaluated using the comet, micronucleus and sister chromatid exchange (SCE) assays. Male Long–Evans rats were fed niacin deficient (ND), or pair-fed (PF) niacin replete (30 mg niacin/kg) or NA supplemented (4 g niacin/kg) diets for 3 weeks. Rats were gavaged with ETO (1–25 mg/kg) suspended in corn oil or an equal volume of vehicle (CON). Comet analysis demonstrated that ETO-induced DNA damage (mean tail moment (MTM) and proportion of cells with significant damage) was greater in bone marrow cells from ND rats, compared to PF or NA rats. Surprisingly, niacin deficiency alone caused 6.2- and 2.8-fold increases in spontaneous micronucleus formation and SCE frequency, respectively. As expected, ETO treatment increased the level of micronuclei (MN) and SCEs in all diet groups; however, the absolute increases were greater in ND bone marrow. These data show that niacin is required for the maintenance of chromosomal stability and may facilitate DNA repair in vivo, in a tissue that is sensitive to niacin depletion and impaired pADPr metabolism. Pharmacological intakes of niacin do not appear to be further protective compared to adequate intakes. Niacin supplementation may help to protect the bone marrow cells of cancer patients with compromised nutritional status from the side effects of genotoxic chemotherapy drugs.

A simple assay for the measurement of plasma antioxidant status using spontaneous autoxidation of homovanillic acid

Introduction: Reactive oxygen species (ROS) contribute to the development of pathophysiological processes, hence the increasing interest in modulating the antioxidant status of patient by nutritional or pharmacological intervention. Antioxidants act by preventing the formation of ROS (inhibitory effect) and/or by trapping these species (scavenger effect). We have developed a simple, sensitive, and reliable test to measure the total antioxidative efficiency of plasma or other biological fluids using microliter samples. Methods: Autoxidation of homovanillic acid (HVA) gives rise to fluorescent dimers. Antioxidants contained in the plasma (or free aqueous solutions) scavenge the ROS involved in this process and transiently stop the linear increase in fluorescence intensity during a time (delay) proportional to the total concentration of antioxidants and their scavenging efficiency. In addition to this scavenging effect, the kinetics of HVA autoxidation, restarting after the delay, reflects the ability of the plasma antioxidants to inhibit the ROS-triggered autoxidation. Results: The rate of the HVA autoxidation depended on the temperature, the protonation of the phenolic group, and on the presence of peroxide, peroxyl radicals, and peroxidase as well as metal ions. This Fenton-like reaction was transiently stopped by various ROS scavengers including quercetin, ascorbic acid, and thiol derivatives (glutathione and N-acetylcystein) while metal chelating agents such as desferrioxamine, ethylene diamine tetracetic acid (EDTA), and polyamine only reduced its rate. Discussion: The main advantages of this new assay are its versatility to investigate in a single run both the scavenging and inhibitory components of the antioxidant capacity, and its relevance to the reactive hydroxyl radical. As shown in this study, the increase in the antioxidant capacity of human plasma during pharmacological supplementation with antioxidant illustrates one of the various fields of application of this assay.

Dietary Biotin Intake Modulates the Pool of Free and Protein-Bound Biotin in Rat Liver

The current studies were undertaken to analyze the relationships among dietary biotin intake, hepatic free biotin and hepatic protein-bound biotin in rats. The biotin status of rats was manipulated through dietary intervention to model moderate biotin deficiency, adequacy, supplementation and pharmacologic biotin supplementation (0, 0.06, 0.6 and 100 mg/kg, respectively). Urinary biotin excretion was directly related to biotin intake, but no difference between biotin-adequate and biotin-supplemented rats was detected. In contrast, plasma biotin was directly and significantly regulated by biotin intake at every intake level. A hepatic free biotin pool was directly demonstrated in these studies, and like plasma, its size was directly related to dietary biotin intake. The relationship between dietary biotin intake and protein-bound biotin was also analyzed. Moderate biotin deficiency markedly decreased the abundance of each biotinylated polypeptide in rat liver. Biotin supplementation did not significantly elevate the abundance of biotinylated pyruvate, propionyl CoA, methylcrotonyl CoA or acetyl CoA carboxylase 1. The abundance of biotinylated acetyl CoA carboxylase 2, however, was significantly higher in biotin-supplemented rats. Pharmacologic biotin intake significantly reduced the abundance of biotinylated propionyl CoA and methylcrotonyl CoA carboxylase. These results indicate the following: 1) moderate biotin deficiency reduces free and protein bound biotin; 2) biotin intakes in rats that mimic the currently recommended daily value (DV) do not result in full protein biotinylation; and 3) pharmacologic supplementation may reduce the abundance of functional carboxylases.

N-3 Fatty acids and the inflammatory response ? biological background

Inflammation can be defined as the reaction of a living vascularized tissue to a localized damage, and plays a role in both normal repair reactions and in the pathogenesis of disease. Inflammatory phenomena are at the basis of a number of disease processes in virtually any systemic or organ-specific disease, ranging from classical rheumatic diseases to bronchial airway hyper-responsiveness, inflammatory bowel disease, kidney diseases, psoriasis and atopic eczema. Modulation of long-chain polyunsaturated fatty acid intake, mostly by increasing the relative proportions of n-3 versus n-6 fatty acids, is the clearest example of how diet may modulate the inflammatory process. It is possible that many of the environmentally attributable epidemiological differences in the incidence of inflammatory diseases among different populations can be tracked back to different nutritional intake of selected, quantitatively minor nutritional components such as omega-3 fatty acids. The increase in dietary intake of these compounds, or their pharmacological supplementation, leads to a moderate quenching of the inflammatory reaction which may prove useful in selected clinical conditions. The clarification of the mechanisms of the biological action of these, as well as of other dietary components, and a better documentation of the spectrum of clinical possibilities offered by dietary manipulation in the intake of such compounds, linking together classical nutritional science, molecular biology, epidemiology and clinical medicine, are a frontier for nutritional research in the years to come. This nutritional approach promises to gain a place in the therapy of some inflammatory disorders.

?Protective nutrients? and up-to-date dietary recommendations

In the past, dietary recommendations were focused on reductions in the consumption of foods and nutrients deemed bad for health, such as saturated fat, dietary cholesterol and salt. In more recent years, an increased consumption of foods and nutrients deemed good for health has also been emphasized, e.g., increased consumption of vegetables, fruits, legumes, fish, dietary fibre and polyunsaturated fatty acids. Another major development has been the change from dietary recommendations for specific diseases, such as coronary heart disease and diabetes, to integrated, comprehensive dietary recommendations for chronic diseases and health in general. A healthy diet forms an important component of a healthy lifestyle. This also includes advice not to smoke and to be physically active for at least 30 min each day. Such a lifestyle prevents coronary heart disease and is important for both primary and secondary prevention. Observational studies and clinical trials on n-3 polyunsaturated fatty acids suggest that besides a diet low in saturated and trans fatty acids and in cholesterol, a healthy diet also needs to contain adequate amounts of alpha-linolenic acid (2 g.day -1 ) and EPA and DHA (200 mg.day -1 ). Evidence that a diet rich in fruits and vegetables may protect against coronary heart disease is increasing. Fruits and vegetables are plentiful sources of antioxidants. Until recently, most research in this area was focused on the so-called nutritive antioxidants, vitamins with antioxidant properties such as tocopherol (vitamin E), carotenoids and vitamin C. Recently, there is an increasing interest in the so-called non-nutritive antioxidants. These are polyphenols present in plant foods and have strong antioxidant properties, Clinical trials with vitamin E supplements were mainly negative. High-dose, pharmacological supplementation of diet with so-called protective' nutrients, however, do not relate to the nutritional domain. In future trials a dose corresponding to a multiple of the recommended dietary allowance of 10 mg.day -1 should be used rather than the high, pharmacological doses used so far.

Plasmatic homocysteine response to vitamin supplementation in elderly people

Homocysteine (Hcy) increase is now widely accepted as a risk factor for vascular disease. The effects of folic acid (FA) and vitamins B 12 and B 6 in lowering Hcy have been extensively studied, but there is still little data on the response to FA dietary administration. Our purpose was to evaluate the impact of the diet and the degree of response to different doses of pharmacological FA supplementation. In a prospective, randomized, and simple blind study, 50 elderly subjects were given a 400-μg/day FA diet and were randomly assigned to one of the following treatments: Group I=placebo tablet; Group II=tablet containing 1-mg folic acid, 1-mg B 12, and 25-mg B 6; and Group III=tablet containing 2.5-mg folic acid and same B 6 and B 12 doses as Group II. Forty-four subjects completed the study, and their plasmas were evaluated. Hcy concentration significantly decreased even in patients with normal basal values, and there were no differences in the response between individuals receiving diet plus placebo and those receiving diet plus pharmacological supplementation. After the treatment, the mean decrease of plasmatic Hcy levels was 10.8 (9.4, 12.5) μmol/l, geometric mean [95% confidence interval (95% CI)], and particularly, the values for Group I were 10.6 (7.4, 14.8) μmol/l. In 31% of the subjects, the post-treatment Hcy levels were ≤5 μmol/l. These results show that a special diet, with or without pharmacological FA and B 12 and B 6 supplementation, significantly decreases the Hcy levels in elderly people. Therefore, a diet with high contents of FA might have an enormous impact on the morbidity and mortality of atherothrombosis.

Mechanisms of cell injury and death in hyperoxia: role of cytokines and Bcl-2 family proteins.

Prevailing concepts of pulmonary oxygen toxicity pathogenesis and hyperoxic tolerance have evolved over the past two decades. The “free radical” theory stating that lung cells poison themselves by producing an endogenous excess of reactive oxygen species (ROS) within various organelles had garnered considerable experimental support in the 1980s (1). The possible role of inflammation in compounding or propagating injury during sublethal hyperoxic exposure was also acknowledged. Subsequently, considerable evidence was obtained to support an association between increasing lung antioxidant enzyme activities and acquired tolerance to hyperoxia. Studies using pharmacologic supplementation and genetically altered mice have provided additional support for the importance of antioxidant enzymes, particularly the mitochondrial MnSOD. Nonetheless, certain inevitable intramitochondrial events, such as inactivation of aconitase with concomitant liberation of ferrous iron from the active site in the matrix and an associated decline in respiration (2), cannot be prevented by MnSOD induction via cytokines or genetic manipulation (3).

Quality assessment of platelet concentrates supplemented with second-messenger effectors.

While reducing the potential for bacterial contamination, the storage of platelet concentrates (PCs) at refrigerated temperatures is not routine, because of the induction of the so-called platelet storage lesion. As the modulation of second-messenger levels might help to overcome this drawback, a quality assessment of PCs treated with a mixture of second-messengers effectors known as ThromboSol was performed. The PCs were supplemented with ThromboSol or phosphate-buffered saline, and stored in parallel at 22 degrees C with continuous agitation or at 4 degrees C. At 1, 5, and 9 days, an in vitro quality assessment of the PCs was performed, including measurement of cell number, metabolic and integrity markers, platelet surface expression of glycoproteins, platelet response to ristocetin and thrombin, and levels of cyclic adenosine 3', 5' monophosphate (cAMP) and thromboxane B2 (TxB2). Control PCs stored at 4 degrees C underwent aggregation and displayed a significant decrease in the platelet number (40% on Day 5). By contrast, the ThromboSol-treated PCs maintained 80 percent of their initial platelet concentration after 9 days of storage at 4 degrees C. Compared to PCs stored at 22 degrees C, refrigerated PCs exhibited minor changes in metabolic values throughout storage, but the addition of ThromboSol induced a rise in metabolic rate during storage at 22 degrees C. Platelet responsiveness to both ristocetin and thrombin was maximally preserved in the ThromboSol-treated PCs stored at 4 degrees C. These units also maintained high levels of cAMP and low concentrations of TxB2 during storage. The pharmacologic supplementation of PCs with ThromboSol significantly favors the maintenance of in vitro integrity and responsiveness of platelets during extended storage at refrigerated temperature. This protective effect seems to be a consequence of the ability of ThromboSol's components to sustain high levels of cAMP and to inhibit TxB2 production during the entire extended-storage period.