Influence of Flaxseed Lignan Supplementation to Older Adults on Biochemical and Functional Outcome Measures of Inflammation.

Evidence from the literature suggests that dietary flaxseed lignans have the ability to modulate inflammation, which is recognized as the underlying basis of multiple chronic human diseases in older adults. Our objective was to determine the effects of oral lignan supplementation on biochemical and functional indicators of inflammation as well as safety and tolerability in older healthy adults. We designed a randomized, double-blind, placebo-controlled clinical trial in older healthy adults (60-80 years) to assess flaxseed lignan-enriched complex (∼38% secoisolariciresinol diglucoside [SDG]; 600 mg SDG dose) oral supplementation effects on biochemical and functional indicators of inflammation and safety and tolerability in older healthy adults after 6 months of once-daily oral administration. The clinical trial confirmed that plasma concentration of total flaxseed lignans (free and conjugated forms) secoisolariciresinol (SECO), enterodiol (ED), and enterolactone (ENL) were significantly associated with daily oral supplementation of flaxseed lignan-enriched complex (p < 0.05). A significant decrease in systolic blood pressure (SBP; from a mean of 155 ± 13 mm Hg at baseline to 140 ± 11 mm Hg at 24 weeks) was observed in lignan-supplemented participants stratified into an SBP ≥140 mm Hg subcategory (p = 0.04). No differences were found between treatment or placebo groups in terms of cognition, pain, activity, physical measurements (calf, waist, and upper arm circumstances), and grip strength. With respect to blood inflammatory markers, lipid profiles, and biochemical parameters, no significant differences were found between treatment and placebo groups at the end of the 6-month supplementation. No adverse effects were reported during supplementation. These data further support the safety and tolerability of long-term flaxseed lignan-enriched complex supplementation in older adults and identify an ability to favorably modulate SBP, an important risk factor in cardiovascular disease.

Protocol for a 24-Week Randomized Controlled Study of Once-Daily Oral Dose of Flax Lignan to Healthy Older Adults.

BACKGROUND: Increased oxidative stress and inflammation are associated with aging, and contribute to an increased risk of chronic disease in older adults. Flaxseed lignans demonstrate antioxidant and anti-inflammatory activity, but their ability to reduce oxidative stress and inflammation markers in older adult populations has received limited investigation. OBJECTIVE: This is a chronic intervention trial of community-dwelling healthy older adults to examine the effects of a flaxseed lignan (secoisolariciresinol diglucoside; SDG) enriched supplement (BeneFlax) compared to a placebo. The primary aim was to demonstrate the safety of BeneFlax and confirm its anti-inflammatory efficacy on markers of oxidative stress and inflammation, and subsequent functional outcomes, including those associated with its anti-inflammatory efficacy. A secondary aim was to determine flaxseed lignan metabolite concentrations in blood. METHODS: A double-blind randomized clinical trial was conducted. Subjects were healthy community-dwelling adults aged 60-80 years. Testing was performed at baseline, 8, 16, and 24 weeks. The 24-week intervention consisted of 600 milligrams (mg) of SDG daily or an equivalent amount (volume) of placebo. All participants received 1000 international units of vitamin D to ensure adequate vitamin D status. Measurements consisted of blood pressure, hematology, and tolerability for safety assessments; blood oxidative stress and inflammatory biomarkers for efficacy; and cognition, muscle strength, and pain as functional outcomes. Secondary endpoints of plasma levels of lignan metabolites were analyzed by mass spectrometry. Other tests, such as bone turnover markers and fecal levels of flax cyclolinopeptides, will be performed at a later date. RESULTS: Thirty-two participants were recruited (19 intervention and 13 control) and all completed the trial. Numerous Health Canada-imposed exclusion criteria limited recruitment success. Analyses are ongoing, but the baseline data available for a number of parameters indicate no differences between treatment groups. Safety measures (vital signs) did not change from baseline and were not significantly different between treatment and placebo groups at 24 weeks. CONCLUSIONS: Preliminary results indicate that no safety concerns are associated with administering 600 mg SDG for 24 weeks to adults between the ages of 60 and 80 years. TRIAL REGISTRATION: Clinicaltrials.gov NCT01846117; https://clinicaltrials.gov/ct2/show/NCT01846117 (Archived by WebCite at http://www.webcitation.org/6nlDZNjmA).

Blood concentrations of remifentanil during and after infusion in horses anesthetized with isoflurane and dexmedetomidine.

OBJECTIVE: To determine blood remifentanil concentration in isoflurane-anesthetized horses during and after a 1h remifentanil and dexmedetomidine infusion. STUDY DESIGN: Prospective study. ANIMALS: Six adult mixed breed horses with (mean±SD) bodyweight of 507±61kg and 14±4years of age. METHODS: Following sedation with xylazine IV, anesthesia was induced with ketamine IV mixed with diazepam IV. Anesthesia was maintained with isoflurane in oxygen. After 52±7min for instrumentation, dexmedetomidine (0.25µgkg(-1) followed by 1.0µg(-1)kg(-1)h(-1)) and remifentanil infusions (6µgkg(-1)h(-1)) were administered for a minimum of 60min and horses recovered from anesthesia. Drug infusions were administered into the left jugular vein. Blood was sampled (4mL) from the right jugular vein at predefined intervals before and during administration of remifentanil infusion. Following catheter flush, blood was sampled from the left jugular vein after the infusion was terminated while the horse was recovering from anesthesia. Blood was placed into tubes containing sodium heparin with citric acid, flash frozen in liquid nitrogen, and stored at -80°C until analysis. Blood remifentanil concentration was measured using high performance liquid chromatography and tandem mass spectrometry. RESULTS: Mean peak remifentanil concentration was 7.14ηgmL(-1) at 50min after start of infusion. Mean volume of distribution was 268±40mLkg(-1) and mean half-life was 12.8min. Blood concentration decreased to 1ηgmL(-1) 27min after termination of infusion. Limit of quantification was 0.2ηgmL(-1).

Challenges in planning long-term care menus that meet dietary recommendations.

PURPOSE: Long-term care (LTC) homes plan menus based on Eating Well with Canada's Food Guide (CFG) recommendations for older adults. To determine whether recommended CFG servings and nutrients were being provided, we analyzed the menu of a large LTC facility in a metropolitan area and compared our analysis with a similar one conducted in 2000. METHODS: A full week's menu from a large Saskatoon LTC facility was analyzed and compared with CFG and recent Dietary Recommended Intake nutrient recommendations. The menu was analyzed using The Food Processor SQL. The 2011 menu was compared with the similar 2000 menu analysis to permit an evaluation of changes over a decade. RESULTS: The 2011 menu demonstrated a significant improvement in servings of vegetables and fruit (4.6 to 7.2 servings). Servings of grain products had declined from 4.9 to 3.6 and servings of milk and alternatives had declined from 2.4 to 1.2 since 2000. Servings of meat and alternatives, total carbohydrate, and protein were not significantly different. Foods on the 2011 menu were lower in fat and higher in dietary fibre and offered more vitamins and minerals. CONCLUSIONS: Greater attention to the planning of LTC menus may explain improvements in the 2011 LTC menu. The current menu, however, needs to overcome the challenges that prevent it from meeting CFG recommendations for older adults.

No evidence of hypoglycemia or hypotension in older adults during 6 months of flax lignan supplementation in a randomized controlled trial: a safety evaluation.

CONTEXT: The natural health product, BeneFlax, is a standardized flaxseed [Linum usitatissimum L. (Linaceae)] lignan enriched product with evidence of product quality and known quantity of the bioactive component, lignan. The acceptance of this natural health product for its various health benefits requires greater evidence of its safety in the general population. OBJECTIVE: We determined whether flaxseed lignan causes clinical hypoglycemia or hypotension in healthy older adults as an important aspect of safety. MATERIALS AND METHODS: Participants aged 49-87 years were randomized in a double-blind trial to receive flaxseed lignan (543 mg/day in BeneFlax) or placebo while completing a 6-month walking program. The 94 participants who completed the study were stratified by age (<65 years versus ≥65 years) and treatment category to determine whether older adults were more susceptible to adverse effects. RESULTS: After 6 months of treatment, average plasma glucose level (5.4 ± 0.6 mmol/L), systolic blood pressure (127 ± 14 mm Hg), and diastolic blood pressure (80 ± 9 mm Hg) were within normal clinical range. Controlling for sex and body mass index covariates resulted in no observed differences between plasma glucose or blood pressure measurements between treatment or age groups (p > 0.05). No incidents of hypoglycemia or hypotension were observed during BeneFlax treatment, suggesting that 543 mg falls at or below the no observable adverse effect level (NOAEL). DISCUSSION AND CONCLUSION: These data suggest the flaxseed lignan product BeneFlax does not pose a risk of hypoglycemia or hypotension in healthy adults aged 49-87 years.

Use of vitamin and mineral supplements in long-term care home residents.

Vitamin-mineral supplementation may offer older adults health and cognition-related benefits but overuse may contribute to polypharmacy. We examined the prevalence of supplement usage in long-term care facility (LTC) residents (≥ 65 years of age). As cognition may be affected by nutrition, we also examined use in those with diagnosis of dementia and those with no dementia diagnosis. The prevalence of supplement usage and overall "pill count" from pharmaceutical use was assessed in 189 LTC residents and a subsample of 56 older adults with dementia diagnosis, respectively. Participants were residing in an LTC facility of a mid-size metropolitan area during 2009. The average use of supplements was 1.0 per day for all residents, with 35% taking vitamin D supplements, 20% multivitamins, and 26% calcium. Supplement use was similar (p ≥ 0.05) for those with dementia diagnosis (53%, average 2.0 per day) and for those without such diagnosis (45%, average 2.2 per day). Usage ranged between 1-6 supplements per day. In both of these groups, ∼73% of users were taking vitamin D. The number of prescribed medications ranged from 4 to 24 (average 10.2) in a subsample of residents whose supplement intake was 0 to 6 (average 2). These findings suggest an overall low rate of supplement use, with no significant differences (p ≥ 0.05) in use between residents with and without dementia diagnosis. However, some residents were at risk for supplement overuse.

Nordihydroguaiaretic acid autoxidation produces a schisandrin-like dibenzocyclooctadiene lignan.

The lignan meso-nordihydroguaiaretic acid is known to undergo spontaneous oxidation in alkaline solution. In the presence of the trapping agent glutathione, the major oxidation products are consistent with the formation of a meso-nordihydroguaiaretic acid ortho-quinone. In the absence of a trapping agent however, the major oxidation product of meso-nordihydroguaiaretic acid in aqueous solution is a unique, stable schisandrin-like dibenzocyclooctadiene lignan that may be responsible for some of the biological effects of nordihydroguaiaretic acid.

Oxidation of the lignan nordihydroguaiaretic acid.

The naturally occurring antioxidant lignan nordihydroguaiaretic acid has been used in traditional medicine to treat a variety of conditions and more recently has been investigated for its anticancer and antimicrobial properties. Nordihydroguaiaretic acid has also been shown to cause kidney toxicity in rats and there is evidence to suggest that chronic nordihydroguaiaretic acid consumption may cause liver toxicity in humans. Nordihydroguaiaretic acid likely undergoes biotransformation to a reactive quinone species, either an ortho-quinone or a para-quinone methide, which is responsible for its toxicity. In an effort to probe the toxicity of nordihydroguaiaretic acid, we oxidized nordihydroguaiaretic acid with both chemical and enzymatic systems and trapped the resultant products with glutathione. The nordihydroguaiaretic acid-glutathione adducts were compared with the products found when nordihydroguaiaretic acid was incubated in rat hepatic microsomes in the presence of glutathione. Glutathione metabolites consistent with ortho-quinone formation were the only oxidation products observed. Control experiments in microsomes however suggested that a majority of the nordihydroguaiaretic acid ortho-quinone glutathione adducts were formed as the result of nordihydroguaiaretic acid autoxidation. We measured the rate of this autoxidation process over a range of pH values and determined that the autoxidation reaction is base-catalyzed. We suggest that caution must be exercised when using nordihydroguaiaretic acid in experiments above pH 7.4 as relatively little of the parent compound may be left in incubations longer than 3 h.

Steady-state kinetics and molecular evolution of Escherichia coli MenD [(1R,6R)-2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate synthase], an anomalous thiamin diphosphate-dependent decarboxylase-carboligase.

(1R,6R)-2-Succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate (SHCHC) synthase, or MenD, catalyzes the thiamin diphosphate- (ThDP-) dependent decarboxylation of 2-oxoglutarate, the subsequent addition of the resulting succinyl-ThDP moiety to isochorismate, and the delta-elimination of pyruvate to yield SHCHC, pyruvate, and carbon dioxide. The enzyme is part of a superfamily of ThDP-dependent 2-oxo acid decarboxylases that includes pyruvate decarboxylase, benzoylformate decarboxylase, and acetohydroxy acid synthase, among others. However, this is the only enzyme known to catalyze a Stetter-like 1,4-addition of a ThDP adduct to the beta-carbon of an unsaturated carboxylate. Herein we report properties of the MenD protein from Escherichia coli, including the results of the first steady-state kinetic studies of the SHCHC synthase reaction. The protein is a dimer and shows cooperativity with respect to both substrates. The enzyme prefers divalent manganese as its metal ion cofactor and shows no dependence on FAD. MenD, required for biosynthesis of menaquinone and phylloquinone, is found in the genomes of a wide range of bacteria, as well as that of the archaeon Halobacterium sp. NRC-1 and the eukaryote Arabidopsis thaliana. Sequence alignments with other members of the superfamily are used to predict amino acid residues likely to be important in the binding and activation of ThDP. A site-directed mutant that replaces the conserved glutamic acid residue (E55), predicted to interact with N1' of the aminopyrimidine ring, with glutamine was generated, with catastrophic results for catalysis. There is no evidence for the release of succinate semialdehyde as a product; therefore, EC 4.1.1.71 should not be used for this enzyme.