Beth MacIntosh

Randomized Study of the Safety and Efficacy of Fish Oil (Omega-3 Fatty Acid) Supplementation with Dietary and Exercise Counseling for the Treatment of Antiretroviral Therapy—Associated Hypertriglyceridemia

BACKGROUND Omega-3 fatty acids (fish oils) reduce fasting serum triglyceride levels and cardiovascular disease risk in individuals without HIV infection. Whether omega-3 fatty acid supplementation can reduce hypertriglyceridemia associated with antiretroviral therapy is not known. METHODS We conducted an open-label, randomized trial that enrolled 52 patients receiving > or =3 active antiretrovirals who had fasting triglyceride levels of >200 mg/dL and were randomized to receive nutritionist-administered dietary and exercise counseling with or without fish oil supplementation for 16 weeks. RESULTS Patients assigned to receive fish oil experienced a 25% mean decline in fasting triglyceride levels at week 4 (95% CI, -34.6% to -15.7% change), compared with a 2.8% mean increase among patients assigned to receive counseling alone (95% CI, -17.5% to +23.1% change) (P=.007). By week 16, the mean reduction in triglyceride levels in the fish oil arm remained significant, at 19.5% (95% CI, -34.9% to -4.0% change), whereas the mean decrease in the diet and exercise only arm was 5.7% (95% CI, -24.6% to +13.2% change); however, the difference between study arms was no longer statistically significant (P=.12). Low-density lipoprotein cholesterol levels had increased by 15.6% (95% CI, +4.8% to +26.4% change) at week 4 and by 22.4% (95% CI, +7.91% to +36.8% change) at week 16 in the fish oil arm but did not change in the diet and exercise only group. Fish oil was well tolerated; only 1 patient experienced treatment-limiting toxicity. Patients assigned to receive fish oil experienced a 25% mean decline in fasting triglyceride levels at week 4 (95% CI, -34.6% to -15.7% change), compared with a 2.8% mean increase in patients assigned to receive counseling alone (95% CI, -17.5% to 23.1% change) (P=.007). By week 16, the mean reduction in triglyceride levels in the fish oil arm remained significant, at 19.5% (95% CI, -34.9% to -4.0% change), whereas the mean decrease in the diet and exercise only arm was 5.7% (95% CI, -24.6% to 13.2% change); however, the difference between study arms was no longer statistically significant (P=.12). Low-density lipoprotein cholesterol levels had increased by 15.6% (95% CI, 4.8%-26.4% change) at week 4 and by 22.4% (95% CI, 7.91%-36.8% change) at week 16 in the fish oil arm but did not change in the diet and exercise only group. Fish oil was well tolerated; only 1 patient experienced treatment-limiting toxicity. CONCLUSIONS Supplementation with omega-3 fatty acids in combination with dietary and exercise counseling was well tolerated and reduced fasting triglyceride levels in patients receiving antiretrovirals. To what extent the increase in low-density lipoprotein cholesterol levels observed in patients assigned this intervention is attributable to omega-3 fatty acid supplementation and whether this increase attenuates any benefit in lowering triglyceride levels is unclear. Given these results, further investigation of omega-3 fatty acid supplementation for the treatment of hypertriglyceridemia in HIV-infected patients is warranted.

Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial.

Summary A dietary intervention increasing n‐3 and reducing n‐6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality of life in a chronic headache population. Abstract Omega‐3 and n‐6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties. We conducted a randomized, single‐blinded, parallel‐group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n‐3 and n‐6 fatty acids for treatment of chronic headaches. After a 4‐week preintervention phase, ambulatory patients with chronic daily headache undergoing usual care were randomized to 1 of 2 intensive, food‐based 12‐week dietary interventions: a high n‐3 plus low n‐6 (H3‐L6) intervention, or a low n‐6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT‐6, primary clinical outcome), Headache Days per month, and Headache Hours per day. Biochemical outcomes included the erythrocyte n‐6 in highly unsaturated fatty acids (HUFA) score (primary biochemical outcome) and bioactive n‐3 and n‐6 derivatives. Fifty‐six of 67 patients completed the intervention. Both groups achieved targeted intakes of n‐3 and n‐6 fatty acids. In intention‐to‐treat analysis, the H3‐L6 intervention produced significantly greater improvement in the HIT‐6 score (−7.5 vs −2.1; P < 0.001) and the number of Headache Days per month (−8.8 vs −4.0; P = 0.02), compared to the L6 group. The H3‐L6 intervention also produced significantly greater reductions in Headache Hours per day (−4.6 vs −1.2; P = 0.01) and the n‐6 in HUFA score (−21.0 vs −4.0%; P < 0.001), and greater increases in antinociceptive n‐3 pathway markers 18‐hydroxy‐eicosapentaenoic acid (+118.4 vs +61.1%; P < 0.001) and 17‐hydroxy‐docosahexaenoic acid (+170.2 vs +27.2; P < 0.001). A dietary intervention increasing n‐3 and reducing n‐6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality‐of‐life in this population.

Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans

Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in human diets, a major component of human tissues, and the direct precursor to the bioactive oxidized LA metabolites (OXLAMs), 9- and 13 hydroxy-octadecadienoic acid (9- and 13-HODE) and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE). These four OXLAMs have been mechanistically linked to pathological conditions ranging from cardiovascular disease to chronic pain. Plasma OXLAMs, which are elevated in Alzheimers dementia and non-alcoholic steatohepatitis, have been proposed as biomarkers useful for indicating the presence and severity of both conditions. Because mammals lack the enzymatic machinery needed for de novo LA synthesis, the abundance of LA and OXLAMs in mammalian tissues may be modifiable via diet. To examine this issue in humans, we measured circulating LA and OXLAMs before and after a 12-week LA lowering dietary intervention in chronic headache patients. Lowering dietary LA significantly reduced the abundance of plasma OXLAMs, and reduced the LA content of multiple circulating lipid fractions that may serve as precursor pools for endogenous OXLAM synthesis. These results show that lowering dietary LA can reduce the synthesis and/or accumulation of oxidized LA derivatives that have been implicated in a variety of pathological conditions. Future studies evaluating the clinical implications of diet-induced OXLAM reductions are warranted.

Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools.

BACKGROUND Dietary linoleic acid (LA, 18:2n-6) lowering in rats reduces n-6 polyunsaturated fatty acid (PUFA) plasma concentrations and increases n-3 PUFA (eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)) concentrations. OBJECTIVE To evaluate the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, alters unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache. DESIGN Secondary analysis of a randomized trial. Subjects with chronic headache were randomized for 12 weeks to (1) average n-3, low n-6 (L6) diet; or (2) high n-3, low n-6 LA (H3-L6) diet. Esterified and unesterified plasma fatty acids were quantified at baseline (0 weeks) and after 12 weeks on a diet. RESULTS Compared to baseline, the L6 diet reduced esterified plasma LA and increased esterified n-3 PUFA concentrations (nmol/ml), but did not significantly change plasma arachidonic acid (AA, 20:4n-6) concentration. In addition, unesterified EPA concentration was increased significantly among unesterified fatty acids. The H3-L6 diet decreased esterified LA and AA concentrations, and produced more marked increases in esterified and unesterified n-3 PUFA concentrations. CONCLUSION Dietary n-6 PUFA lowering for 12 weeks significantly reduces LA and increases n-3 PUFA concentrations in plasma, without altering plasma AA concentration. A concurrent increase in dietary n-3 PUFAs for 12 weeks further increases n-3 PUFA plasma concentrations and reduces AA.

Inhibition of Fried Meat-Induced Colorectal DNA Damage and Altered Systemic Genotoxicity in Humans by Crucifera, Chlorophyllin, and Yogurt

Dietary exposures implicated as reducing or causing risk for colorectal cancer may reduce or cause DNA damage in colon tissue; however, no one has assessed this hypothesis directly in humans. Thus, we enrolled 16 healthy volunteers in a 4-week controlled feeding study where 8 subjects were randomly assigned to dietary regimens containing meat cooked at either low (100°C) or high temperature (250°C), each for 2 weeks in a crossover design. The other 8 subjects were randomly assigned to dietary regimens containing the high-temperature meat diet alone or in combination with 3 putative mutagen inhibitors: cruciferous vegetables, yogurt, and chlorophyllin tablets, also in a crossover design. Subjects were nonsmokers, at least 18 years old, and not currently taking prescription drugs or antibiotics. We used the Salmonella assay to analyze the meat, urine, and feces for mutagenicity, and the comet assay to analyze rectal biopsies and peripheral blood lymphocytes for DNA damage. Low-temperature meat had undetectable levels of heterocyclic amines (HCAs) and was not mutagenic, whereas high-temperature meat had high HCA levels and was highly mutagenic. The high-temperature meat diet increased the mutagenicity of hydrolyzed urine and feces compared to the low-temperature meat diet. The mutagenicity of hydrolyzed urine was increased nearly twofold by the inhibitor diet, indicating that the inhibitors enhanced conjugation. Inhibitors decreased significantly the mutagenicity of un-hydrolyzed and hydrolyzed feces. The diets did not alter the levels of DNA damage in non-target white blood cells, but the inhibitor diet decreased nearly twofold the DNA damage in target colorectal cells. To our knowledge, this is the first demonstration that dietary factors can reduce DNA damage in the target tissue of fried-meat associated carcinogenesis. Trial Registration ClinicalTrials.gov NCT00340743.

Low- n -6 and low- n -6 plus high- n -3 diets for use in clinical research

Few trials have evaluated the metabolic effects and health outcomes of lowering dietary n-6 PUFA. The objectives of the present paper were (1) to report the methods employed to lower dietary n-6 PUFA, while either increasing or maintaining n-3 PUFA intake and (2) to validate our methods with 24 h recalls and erythrocyte fatty acid analyses. A total of sixty-seven subjects were randomised to either (1) an average-n-3 PUFA, low-n-6 PUFA (L6) intervention designed to lower linoleic acid (LA; #2·5% of energy (en%)) and arachidonic acid (#60 mg/d), while maintaining an average US intake of n-3 PUFA or (2) a high-n-3 PUFA, low-n-6 PUFA (H3-L6) intervention designed to lower n-6 LA, while increasing the n-3 PUFA a-linolenic acid (ALA;

Low omega-6 vs. low omega-6 plus high omega- 3 dietary intervention for Chronic Daily Headache: Protocol for a randomized clinical trial

1·5 en%) and EPA þ DHA (

Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: A secondary analysis of a randomized trial

1000 mg/d). Pre- and intraintervention nutrient intakes were estimated with six 24 h dietary recalls per subject. Both groups achieved the targeted reductions in dietary LA to #2·5 en% (median LA 2·45 (2·1, 3·1); P,0·001). Intakes of n-3 PUFA did not change for the L6 group. Target increases in n-3 ALA (median 1·6 en%, (1·3, 2·0), P,0·001) and EPA þ DHA (1482 mg, (374, 2558), P,0·001) were achieved in the H3-L6 group. Dietary changes were validated by corresponding changes in erythrocyte n-6 and n-3 fatty acid composition. Dietary LA can be lowered to #2·5 en%, with or without concurrent increases in dietary n-3 PUFA, in an outpatient clinical trial setting using this integrated diet method.

Effect of Glycemic Load on Peptide‐YY Levels in a Biracial Sample of Obese and Normal Weight Women

BackgroundTargeted analgesic dietary interventions are a promising strategy for alleviating pain and improving quality of life in patients with persistent pain syndromes, such as chronic daily headache (CDH). High intakes of the omega-6 (n-6) polyunsaturated fatty acids (PUFAs), linoleic acid (LA) and arachidonic acid (AA) may promote physical pain by increasing the abundance, and subsequent metabolism, of LA and AA in immune and nervous system tissues. Here we describe methodology for an ongoing randomized clinical trial comparing the metabolic and clinical effects of a low n-6, average n-3 PUFA diet, to the effects of a low n-6 plus high n-3 PUFA diet, in patients with CDH. Our primary aim is to determine if: A) both diets reduce n-6 PUFAs in plasma and erythrocyte lipid pools, compared to baseline; and B) the low n-6 plus high n-3 diet produces a greater decline in n-6 PUFAs, compared to the low n-6 diet alone. Secondary clinical outcomes include headache-specific quality-of-life, and headache frequency and intensity.MethodsAdults meeting the International Classification of Headache Disorders criteria for CDH are included. After a 6-week baseline phase, participants are randomized to a low n-6 diet, or a low n-6 plus high n-3 diet, for 12 weeks. Foods meeting nutrient intake targets are provided for 2 meals and 2 snacks per day. A research dietitian provides intensive dietary counseling at 2-week intervals. Web-based intervention materials complement dietitian advice. Blood and clinical outcome data are collected every 4 weeks.ResultsSubject recruitment and retention has been excellent; 35 of 40 randomized participants completed the 12-week intervention. Preliminary blinded analysis of composite data from the first 20 participants found significant reductions in erythrocyte n-6 LA, AA and %n-6 in HUFA, and increases in n-3 EPA, DHA and the omega-3 index, indicating adherence.Trial RegistrationClinicalTrials.gov (NCT01157208)

Low-Glycemic Load Decreases Postprandial Insulin and Glucose and Increases Postprandial Ghrelin in White but Not Black Women

Abstract Omega-3 and omega-6 fatty acids are precursors of bioactive lipid mediators posited to modulate both physical pain and psychological distress. In a randomized trial of 67 subjects with severe headaches, we recently demonstrated that targeted dietary manipulation—increasing omega-3 fatty acids with concurrent reduction in omega-6 linoleic acid (the H3-L6 intervention)—produced major reductions in headache compared with an omega-6 lowering (L6) intervention. Because chronic pain is often accompanied by psychological distress and impaired health-related quality of life (HRQOL), we used data from this trial to examine whether the H3-L6 intervention favorably impacted these domains. Additionally, we examined the effect of the interventions on the number of cases with substantial physical or mental impairments as defined by cutoff values in the Brief Symptom Inventory (BSI-18), Medical Outcomes Study Short Forms 12 (SF-12), Headache Impact Test (HIT-6), and the number of headache days per month. In the intention-to-treat analysis, participants in the H3-L6 group experienced statistically significant reductions in psychological distress (BSI-18 mean difference: −6.56; 95% confidence interval [CI]: −11.43 to −1.69) and improvements in SF-12 mental (mean difference: 6.01; 95% CI: 0.57 to 11.45) and physical (mean difference: 6.65; 95% CI: 2.14 to 11.16) health summary scores. At 12 weeks, the proportion of subjects experiencing substantial impairment according to cutoff values in the BSI-18, SF-12 physical, HIT-6, and headache days per month was significantly lower in the H3-L6 group. Dietary manipulation of n-3 and n-6 fatty acids, previously shown to produce major improvements in headache, was found to also reduce psychological distress and improve HRQOL and function.