Publications by authors named "Daisy Zamora"

27 Publications

  • Page 1 of 1

Methodology for altering omega-3 EPA+DHA and omega-6 linoleic acid as controlled variables in a dietary trial.

Clin Nutr 2021 Jun 12;40(6):3859-3867. Epub 2021 May 12.

Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background & Aims: Increasing dietary intake of n-3 EPA+DHA and lowering dietary n-6 LA is under investigation as a therapeutic diet for improving chronic pain syndromes as well as other health outcomes. Herein we describe the diet methodology used to modulate intake of n-3 and n-6 PUFA in a free living migraine headache population and report on nutrient intake, BMI and diet acceptability achieved at week 16 of the intensive diet intervention and week 22 follow-up time-point.

Methods: A total of 178 participants were randomized and began one of three diet interventions: 1) a high n-3 PUFA, average n-6 PUFA (H3) diet targeting 1500 mg EPA+DHA/day and 7% of energy (en%) from n-6 linoleic acid (LA), 2) a high-n-3 PUFA, low-n-6 PUFA (H3L6) targeting 1500 mg EPA+DHA/day and <1.8 en% n-6 LA or 3) a Control diet with typical American intakes of both EPA+DHA (<150 mg/day) and 7 en% from n-6 LA. Methods used to achieve diet change to week 16 include diet education, diet counseling, supply of specially prepared foods, self-monitoring and access to online diet materials. Only study oils and website materials were provided for the follow-up week 16 to week 22 periods. Diet adherence was assessed by multiple 24 h recalls administered throughout the trial. Diet acceptability was assessed in a subset of participants at 4 time points by questionnaire.

Results: At week 16 H3 and H3L6 diet groups significantly increased median n-3 EPA+DHA intake from 48 mg/2000 kcals at baseline to 1484 mg/2000 kcals (p < 0.0001) and from 44 mg/2000 kcals to 1341 mg/2000 kcals (p < 0.0001), respectively. In the Control group, EPA+DHA intake remained below the typical American intake with baseline median at 60 mg/2000 kcals and 80 mg/2000 kcals (p = 0.6) at week 16. As desired, LA intake was maintained in the H3 and Control group with baseline median of 6.5 en% to 7.1 en% (p = 0.4) at week 16 and from 6.5 en% to 6.8 en% (p = 1.0) at week 16, respectively. In the H3L6 group, n-6 LA decreased from 6.3 en% at baseline to 3.2 en% (p < 0.0001) at week 16. There were no significant changes in BMI or diet acceptability throughout the trial or between diet groups.

Conclusions: We find this diet method to be acceptable to research participants and successful in altering dietary n-3 EPA+DHA with and without concurrent decreases in n-6 LA. If n-6 LA of less than 3 en% is desired, additional techniques to limit LA may need to be employed.
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http://dx.doi.org/10.1016/j.clnu.2021.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293619PMC
June 2021

Adjunctive Aspirin vs Placebo in Patients With Schizophrenia: Results of Two Randomized Controlled Trials.

Schizophr Bull 2021 Jul;47(4):1077-1087

Department of Psychiatry, University of Illinois, Chicago, IL.

Two previous randomized controlled trials (RCTs) suggested that adjunctive aspirin is efficacious in treating schizophrenia. We conducted two 16-week double-blind randomized placebo-controlled RCTs of adjunctive 1000 mg aspirin vs placebo in schizophrenia. Study 1 included 200 patients, with Positive and Negative Syndrome Scale (PANSS) total score as the primary outcome. Study 2 included 160 patients with C-reactive protein (CRP) >1 mg/L at baseline; the primary outcome was PANSS-positive score. Dropout rates for aspirin/placebo were 12% in study 1 and 20% in study 2. Differences in outcome between aspirin and placebo were calculated with linear regression, adjusting for the baseline value of the outcome. No statistically significant between-group differences were found in primary or secondary outcomes in either study. Study 1: mean difference in PANSS at 16 weeks was -3.9 (95% CI: -8.4 to 0.5, P = .10, effect size (ES) = -0.25) and at 8 weeks was -3.5 (95% CI: -7.5 to 0.5, P = .11, ES = -0.22). Study 2: mean difference in PANSS at 16 weeks was 0.3 (95% CI: -4.1 to 4.7, P = .90, ES = 0.02) and in positive PANSS was 0.5 (95% CI: -1.0 to 2.1, P = .50, ES = 0.11). A meta-analysis of these data with the existing studies, excluding one with large baseline differences in total PANSS, found that the overall estimate of the effect of adjunctive aspirin on the PANSS total score comparing group means at the end of the study was -2.9 (95% CI: -6.6 to 0.7; P = .21), favoring aspirin. Our studies and meta-analysis failed to find a statistically significant improvement in the symptoms of schizophrenia from adjunctive aspirin therapy in comparison to placebo in schizophrenia. Trial registration: study 1: Clinicaltrials.gov: NCT01320982; study 2 (high CRP): EudraCT Number: 2014-000757-36.
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http://dx.doi.org/10.1093/schbul/sbaa198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266648PMC
July 2021

Identifying oxidized lipid mediators as prognostic biomarkers of chronic posttraumatic headache.

Pain 2020 12;161(12):2775-2785

Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD, United States.

Chronic posttraumatic headache (PTH) is among the most common and disabling sequelae of traumatic brain injury (TBI). Current PTH treatments are often only partially effective and have problematic side effects. We previously showed in a small randomized trial of patients with chronic nontraumatic headaches that manipulation of dietary fatty acids decreased headache frequency, severity, and pain medication use. Pain reduction was associated with alterations in oxylipins derived from n-3 and n-6 fatty acids, suggesting that oxylipins could potentially mediate clinical pain reduction. The objective of this study was to investigate whether circulating oxylipins measured in the acute setting after TBI could serve as prognostic biomarkers for developing chronic PTH. Participants enrolled in the Traumatic Head Injury Neuroimaging Classification Protocol provided serum within 3 days of TBI and were followed up at 90 days postinjury with a neurobehavioral symptom inventory (NSI) and satisfaction with life survey. Liquid chromatography-tandem mass spectrometry methods profiled 39 oxylipins derived from n-3 docosahexaenoic acid (DHA), and n-6 arachidonic acid and linoleic acid. Statistical analyses assessed the association of oxylipins with headache severity (primary outcome, measured by headache question on NSI) as well as associations between oxylipins and total NSI or satisfaction with life survey scores. Among oxylipins, 4-hydroxy-DHA and 19,20-epoxy-docosapentaenoate (DHA derivatives) were inversely associated with headache severity, and 11-hydroxy-9-epoxy-octadecenoate (a linoleic acid derivative) was positively associated with headache severity. These findings support a potential for DHA-derived oxylipins as prognostic biomarkers for development of chronic PTH.
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http://dx.doi.org/10.1097/j.pain.0000000000001983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669546PMC
December 2020

Are Patients With Schizophrenia Better Off With Lifetime Antipsychotic Medication?: Replication of a Naturalistic, Long-Term, Follow-Up Study of Antipsychotic Treatment.

J Clin Psychopharmacol 2020 Mar/Apr;40(2):145-148

From the Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Stanford, CA.

Purpose/background: The question of whether people with schizophrenia should be treated with antipsychotics for life has been debated for decades. We recently reported results of 2 retrospective long-term naturalistic studies examining the association of medication adherence and global outcomes in different demographic samples. In both, we found that patients with a history of better adherence to antipsychotic medication had better quality of life outcomes. Using similar methodology, here we present such associations for a very different sample-patients with chronic schizophrenia with a long past history of antipsychotic treatment that had been treated for 19 to 53 years in a Veterans Affairs clinic.

Methods: This is a retrospective, naturalistic, longitudinal 19- to 53-year (mean average, 33.5 years) lifetime follow-up of a consecutive series of patients with schizophrenia, who had at least 8 years of antipsychotic treatment. Lifetime data were collected on (1) their medication adherence, (2) long-term global outcome, and (3) life satisfaction. Outcomes were rated by 2 different clinicians, one with information on medication adherence (nonblind rater) and one without (blind rater). Linear regression models, adjusted for age, family support, substance use disorder, race, marital status, and number of years in treatment were used to estimate the association between adherence and each outcome.

Results: A total of 20 patients were assessed. Medication adherence was positively associated with the blind clinician's rating of global outcome (P = 0.049) and the Global Assessment of Functioning (P = 0.021). In the nonblinded clinician's rating, medication adherence was positively related to global outcome (P = 0.001) and to the patient's report of life satisfaction (P = 0.028).

Implications/conclusions: This replication study, together with our previous 2 studies, is consistent with the recommendation for continuous, long-term treatment for chronic schizophrenia over many years of a patient's lifetime unless medically contraindicated.
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http://dx.doi.org/10.1097/JCP.0000000000001171DOI Listing
November 2020

Plasma oxylipins and unesterified precursor fatty acids are altered by DHA supplementation in pregnancy: Can they help predict risk of preterm birth?

Prostaglandins Leukot Essent Fatty Acids 2020 02 13;153:102041. Epub 2019 Dec 13.

School of Agriculture, Food and Wine, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

Oxidized lipids derived from omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids, collectively known as oxylipins, are bioactive signaling molecules that play diverse roles in human health and disease. Supplementation with n-3 docosahexaenoic acid (DHA) during pregnancy has been reported to decrease the risk of preterm birth in singleton pregnancies, which may be due to effects of DHA supplementation on oxylipins or their precursor n-6 and n-3 fatty acids. There is only limited understanding of the levels and trajectory of changes in plasma oxylipins during pregnancy, effects of DHA supplementation on oxylipins and unesterified fatty acids, and whether and how oxylipins and their unesterified precursor fatty acids influence preterm birth. In the present study we used liquid chromatography-tandem mass spectrometry to profile oxylipins and their precursor fatty acids in the unesterified pool using plasma samples collected from a subset of pregnant Australian women who participated in the ORIP (Omega-3 fats to Reduce the Incidence of Prematurity) study. ORIP is a large randomized controlled trial testing whether daily supplementation with n-3 DHA can reduce the incidence of early preterm birth compared to control. Plasma was collected at study entry (≈pregnancy week 14) and again at ≈week 24, in a subgroup of 48 ORIP participants-12 cases with spontaneous preterm (<37 weeks) birth and 36 matched controls with spontaneous term (≥40 weeks) birth. In the combined preterm and term pregnancies, we observed that in the control group without DHA supplementation unesterified AA and AA-derived oxylipins 12-HETE, 15-HETE and TXB2 declined between weeks 14-24 of pregnancy. Compared to control, DHA supplementation increased unesterified DHA, EPA, and AA, DHA-derived 4-HDHA, 10-HDHA and 19,20-EpDPA, and AA-derived 12-HETE at 24 weeks. In exploratory analysis independent of DHA supplementation, participants with concentrations above the median for 5-lipoxygenase derivatives of AA (5-HETE, Odds Ratio (OR) 8.2; p = 0.014) or DHA (4-HDHA, OR 8.0; p = 0.015) at 14 weeks, or unesterified AA (OR 5.1; p = 0.038) at 24 weeks had higher risk of spontaneous preterm birth. The hypothesis that 5-lipoxygenase-derived oxylipins and unesterified AA could serve as mechanism-based biomarkers predicting spontaneous preterm birth should be evaluated in larger, adequately powered studies.
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http://dx.doi.org/10.1016/j.plefa.2019.102041DOI Listing
February 2020

Temperature and time-dependent effects of delayed blood processing on oxylipin concentrations in human plasma.

Prostaglandins Leukot Essent Fatty Acids 2019 11 5;150:31-37. Epub 2019 Sep 5.

University of Adelaide, Adelaide, SA, Australia.

Background: Oxidized derivatives of polyunsaturated fatty acids, collectively known as oxylipins, are labile bioactive mediators with diverse roles in human physiology and pathology. Oxylipins are increasingly being measured in plasma collected in clinical studies to investigate biological mechanisms and as pharmacodynamic biomarkers for nutrient-based and drug-based interventions. Whole blood is generally stored either on ice or at room temperature prior to processing. However, the potential impacts of delays in processing, and of temperature prior to processing, on oxylipin concentrations are incompletely understood.

Objective: To evaluate the effects of delayed processing of blood samples in a timeframe that is typical of a clinical laboratory setting, using typical storage temperatures, on concentrations of representative unesterified oxylipins measured by liquid chromatography-tandem mass spectrometry.

Design: Whole blood (drawn on three separate occasions from a single person) was collected into 5 mL purple-top potassium-EDTA tubes and stored for 0, 10, 20, 30, 60 or 120 min at room temperature or on wet ice, followed by centrifugation at 4 °C for 10 min with plasma collection. Each sample was run in duplicate, therefore there were six tubes and up to six data points at each time point for each oxylipin at each condition (ice/room temperature). Representative oxylipins derived from arachidonic acid, docosahexaenoic acid, and linoleic acid were quantified by liquid chromatography tandem mass spectrometry. Longitudinal models were used to estimate differences between temperature groups 2 h after blood draw.

Results: We found that most oxylipins measured in human plasma in traditional potassium-EDTA tubes are reasonably stable when stored on ice for up to 2 h prior to processing, with little evidence of auto-oxidation in either condition. By contrast, in whole blood stored at room temperature, substantial time-dependent increases in the 12-lipoxygenase-derived (12-HETE, 14-HDHA) and platelet-derived (thromboxane B2) oxylipins were observed.

Conclusion: These findings suggest that certain plasma oxylipins can be measured with reasonable accuracy despite delayed processing for up to 2 h when blood is stored on ice prior to centrifugation. 12-Lipoxygenase- and platelet-derived oxylipins may be particularly sensitive to post-collection artifact with delayed processing at room temperature. Future studies are needed to determine impacts of duration and temperature of centrifugation on oxylipin concentrations.
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http://dx.doi.org/10.1016/j.plefa.2019.09.001DOI Listing
November 2019

Effect of Adjunctive Estradiol on Schizophrenia Among Women of Childbearing Age: A Randomized Clinical Trial.

JAMA Psychiatry 2019 10;76(10):1009-1017

Department of Psychiatry, University of Illinois, Chicago.

Importance: Several lines of evidence suggest that estradiol influences the course of schizophrenia, and a previous randomized controlled trial demonstrated that transdermal estradiol improved symptoms in female patients of childbearing age. However, many initial positive findings in schizophrenia research are not later replicated.

Objective: To independently replicate the results of the effect of estradiol on schizophrenia in women of childbearing age.

Design, Setting, And Participants: An 8-week randomized, placebo-controlled trial performed in the Republic of Moldova between December 4, 2015, and July 29, 2016, among 200 premenopausal women aged 19 to 46 years with schizophrenia or schizoaffective disorder as defined by the DSM-5.

Intervention: Patients were randomized to receive a 200-μg estradiol patch or placebo patch changed twice a week added to their antipsychotic treatment.

Main Outcomes And Measures: The primary outcome was the positive subscale of the Positive and Negative Syndrome Scale (PANSS; lower scores indicated fewer symptoms and higher scores indicated more symptoms), analyzed with mixed models for repeated measures on an intention-to-treat basis.

Results: A total of 100 women (median age, 38 years; interquartile range, 34-42 years) were randomized to receive an estradiol patch and 100 women (median age, 38 years; interquartile range, 31-41 years) were randomized to receive a placebo patch; the median age at baseline for the entire group of 200 women was 38.0 years (range, 19.5-46.0 years). At baseline, the mean positive PANSS score was 19.6 for both groups combined; at week 8, the mean positive PANSS score was 14.4 in the placebo group and 13.4 in the estradiol group. Compared with placebo, participants receiving add-on estradiol patches had statistically significant improvements in the primary outcome measure, PANSS positive subscale points (-0.94; 95% CI, -1.64 to -0.24; P = .008; effect size = 0.38). Post hoc heterogeneity analyses found that this effect occurred almost entirely in 100 participants older than 38.0 years (46 in placebo group vs 54 in estradiol group; difference, -1.98 points on the PANSS positive subscale; 95% CI, -2.94 to -1.02; P < .001). Younger participants did not benefit from estradiol (difference, 0.08 points on the PANSS positive subscale; 95% CI, -0.91 to 1.07; P = .87). Breast tenderness was more common in the estradiol group (n = 15) than in the placebo group (n = 1) as was weight gain (14 in estradiol group vs 1 in placebo group).

Conclusions And Relevance: The results independently replicate the finding that transdermal estradiol is an effective add-on treatment for women of childbearing age with schizophrenia and extend it, finding improvements in negative symptoms and finding that the effect could be specific to those older than 38 years. The results should be viewed in the context of the differences in the natural course of schizophrenia between females and males.

Trial Registration: ClinicalTrials.gov identifier: NCT03848234.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.1842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669788PMC
October 2019

Should antipsychotic medications for schizophrenia be given for a lifetime? Replication of a naturalistic, long-term, follow-up study of antipsychotic treatment.

CNS Spectr 2019 10;24(5):557-563

College of Medicine, University of Illinois, Chicago, Illinois, USA.

Objective: Because ethically and practically a randomized control trial of antipsychotics will never be done, we recently conducted and reported a 8- to 50-year, naturalistic follow-up from an academic clinic of patients with chronic schizophrenia on antipsychotic medication. We found that better medication adherence was a statistically significant predictor of better long-term global outcome and life satisfaction. Because there were important limitations on our findings, we now in this communication, using similar methodology, detail outcomes for a very different sample-inner city patients with chronic schizophrenia with a long past history of antipsychotic treatment, who were enrolled in clinical trials for new medications for schizophrenia.

Methods: This is a retrospective, naturalistic, longitudinal 6- to 49-years antipsychotic treatment (mean average, 20) follow-up of a consecutive series of patients volunteering for screening for studies with schizophrenia. Lifetime data were collected on (1) their medication adherence, (2) long-term global outcome, and (3) life satisfaction. Outcomes were rated by 2 different clinicians, 1 with information on medication adherence (nonblind rater) and 1 without (blind rater). We used linear regression models adjusted for age, family support, substance use disorder, race, marital status, and number of years in treatment to estimate the association between adherence and each outcome.

Results: A total of 34 patients were assessed. Medication adherence was positively associated with the blind clinician's rating of global outcome (P value=0.03) and the global assessment of functioning (P value=0.05). In the nonblinded clinician rating, medication adherence was unrelated to global outcome (P value=0.26) and to patients' report of life satisfaction (P value=0.54).

Conclusion: This replication study, like our previous study, is not inconsistent with the recommendation for continuous, long-term treatment for chronic schizophrenia unless medically contraindicated.
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http://dx.doi.org/10.1017/S109285291800144XDOI Listing
October 2019

The effect of minocycline on symptoms in schizophrenia: Results from a randomized controlled trial.

Schizophr Res 2019 04 16;206:325-332. Epub 2018 Nov 16.

Department of Psychiatry, University of Illinois, Chicago, IL 60607, USA.

Background: Studies have hypothesized that immunological abnormalities might contribute to schizophrenia, and basic science studies, as well as several clinical trials suggest that minocycline could be efficacious in ameliorating both positive and negative symptoms of schizophrenia. In this study we examined the effect of minocycline on schizophrenia in a large randomized controlled trial.

Methods: We performed a 16-week, multi-center, double-blind, randomized, placebo-controlled study on 200 subjects with schizophrenia or schizoaffective disorder randomized to receive either minocycline (200 mg/day, n = 100), or placebo (n = 100) as an add-on to anti-psychotic treatment. The primary outcome measure was the PANSS total score.

Results: Mixed models for repeated measures showed no significant difference between minocycline and placebo for total PANSS (p = 0.862), PANSS subscales, CGI or BACS.

Conclusions: Minocycline did not improve symptoms or cognition in schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2018.10.023DOI Listing
April 2019

Effects of diets enriched in linoleic acid and its peroxidation products on brain fatty acids, oxylipins, and aldehydes in mice.

Biochim Biophys Acta Mol Cell Biol Lipids 2018 10 25;1863(10):1206-1213. Epub 2018 Jul 25.

Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, Davis, CA, USA.

Background: Linoleic acid (LA) is abundant in modern industrialized diets. Oxidized LA metabolites (OXLAMs) and reactive aldehydes, such as 4-hydroxy-2-nonenal (4-HNE), are present in heated vegetable oils and can be endogenously synthesized following consumption of dietary LA. OXLAMs have been implicated in cerebellar degeneration in chicks; 4-HNE is linked to neurodegenerative conditions in mammals. It unknown whether increasing dietary LA or OXLAMs alters the levels of oxidized fatty acids (oxylipins), precursor fatty acids, or 4-HNE in mammalian brain.

Objectives: To determine the effects of increases in dietary OXLAMs and dietary LA, on levels of fatty acids, oxylipins, and 4-HNE in mouse brain tissues.

Methods: Mice (n = 8 per group) were fed one of three controlled diets for 8 weeks: (1) a low LA diet, (2) a high LA diet, or (3) the low LA diet with added OXLAMs. Brain fatty acids, oxylipins, and 4-HNE were quantified in mouse cerebellum and cerebral cortex by gas chromatography-flame ionization detection, liquid chromatography-tandem mass spectrometry, and immunoblot, respectively.

Results: Increasing dietary LA significantly increased omega-6 fatty acids, decreased omega-3 fatty acids, and increased OXLAMs in brain. Dietary OXLAMs had minimal effect on oxidized lipids but did decrease both omega-6 and omega-3 fatty acids. Neither dietary LA nor OXLAMs altered 4-HNE levels.

Conclusion: Brain fatty acids are modulated by both dietary LA and OXLAMs, while brain OXLAMs are regulated by endogenous synthesis from LA, rather than incorporation of preformed OXLAMs.
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http://dx.doi.org/10.1016/j.bbalip.2018.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180905PMC
October 2018

A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch.

Sci Signal 2017 Aug 22;10(493). Epub 2017 Aug 22.

Department of Perioperative Medicine, Clinical Center, NIH, Bethesda, MD 20814, USA.

Chronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy- or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives. All of these mediators were confirmed to be abundant in rat and human skin by mass spectrometry. However, only the two 11-hydroxy-epoxy-octadecenoates sensitized rat dorsal root ganglion neurons to release more calcitonin gene-related peptide (CGRP), which is involved in pain transmission, in response to low pH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy--pentenyl--epoxide moiety, thus suggesting that this substructure could mediate nociceptor sensitization. In rats, intradermal hind paw injection of 11-hydroxy-12,13--epoxy-(9)-octadecenoate elicited C-fiber-mediated sensitivity to thermal pain. In a randomized trial testing adjunctive strategies to manage refractory chronic headaches, reducing the dietary intake of linoleic acid was associated with decreases in plasma 11-hydroxy-12,13--epoxy-(9)-octadecenoate, which correlated with clinical pain reduction. Human psoriatic skin had 30-fold higher 9-keto-12,13--epoxy-(10)-octadecenoate compared to control skin, and intradermal injection of this compound induced itch-related scratching behavior in mice. Collectively, these findings define a family of endogenous mediators with potential roles in pain and itch.
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http://dx.doi.org/10.1126/scisignal.aal5241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805383PMC
August 2017

A randomized, double-blind, placebo- and risperidone-controlled study on valnoctamide for acute mania.

Bipolar Disord 2017 06 12;19(4):285-294. Epub 2017 Jun 12.

Department of Psychiatry, University of Illinois, Chicago, IL, USA.

Objectives: Mood stabilizers administered for bipolar disorder during pregnancy, such as valproic acid, can increase the risk of congenital anomalies in offspring. Valnoctamide is a valproic acid derivative associated with a decreased risk for congenital abnormalities in animals. The present study evaluated the efficacy and safety of valnoctamide monotherapy, compared to placebo, in the treatment of patients in an acute manic episode.

Methods: A 3-week, double-blind, randomized, placebo- and risperidone-controlled, parallel group trial was conducted on 173 patients in an acute manic episode. Patients were randomized to receive valnoctamide 1500 mg/d (n=71), risperidone 6 mg/d (n=32), or matching placebo (n=70). The primary outcome measure was the change in Young Mania Rating Scale (YMRS) scores.

Results: Valnoctamide did not differ significantly from placebo on any of the study endpoints (YMRS, Positive and Negative Syndrome Scale, and the Clinical Global Impression Scale for Bipolar Disorder [CGI-BP] scales; all P>.60). Mixed models for repeated measures showed that risperidone produced significantly more improvement than placebo in the overall bipolar disorder CGI-BP severity scale (P=.036), and the CGI-BP severity scale for mania (P=.021). The Kaplan-Meier survival curve revealed higher all-cause discontinuation rates (mainly due to lack of efficacy) in the valnoctamide group compared to the other study groups (P=.026). Patients with higher valnoctamide plasma levels had a numerically higher YMRS response, but this was not statistically significant.

Conclusions: Valnoctamide was well tolerated at 1500 mg/d but lacked efficacy in the treatment of symptoms in patients with acute mania. Possible differences between the biological mechanisms of action of valproic acid and valnoctamide are discussed.
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http://dx.doi.org/10.1111/bdi.12506DOI Listing
June 2017

Raloxifene Plus Antipsychotics Versus Placebo Plus Antipsychotics in Severely Ill Decompensated Postmenopausal Women With Schizophrenia or Schizoaffective Disorder: A Randomized Controlled Trial.

J Clin Psychiatry 2017 Jul;78(7):e758-e765

Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.

Objective: Several single-center studies have found raloxifene, an estrogen agonist, to be effective in ameliorating symptoms of schizophrenia in stable patients as augmentation of antipsychotics. This multicenter study assessed whether raloxifene plus antipsychotic treatment, in comparison to placebo plus antipsychotics, improves symptoms or cognition in severely ill decompensated schizophrenia patients.

Methods: In this 16-week, double-blind, randomized, placebo-controlled study, 200 severely ill, decompensated postmenopausal women who met DSM-IV-TR criteria for schizophrenia or schizoaffective disorder were recruited from January 2011 to December 2012 and were randomized to receive either raloxifene 120 mg/d plus antipsychotics or placebo plus antipsychotics. The primary outcome measure was Positive and Negative Syndrome Scale (PANSS) total score at the end of the trial.

Results: The placebo plus antipsychotics group experienced statistically significant improvement in PANSS total score (P < .001) compared to the raloxifene plus antipsychotics group, using mixed models for repeated measures, with results favoring placebo by 4.5 points (95% CI, 2.3-6.7). These results were clearly outside the 95% confidence interval. This negative effect was more pronounced in patients who had more frequent relapses and in those with baseline PANSS scores of 100 or higher. There were no differences between groups in Clinical Global Impression Scale-Severity scores or Composite Brief Assessment of Cognition in Schizophrenia scores at 16 weeks (P > .3). Baseline follicle-stimulating hormone and estradiol levels did not alter the drug-placebo differences.

Conclusions: Individuals in the active treatment arm showed worse outcome than those in the placebo arm, most likely as a result of chance variation, but the results unequivocally show no benefit of antipsychotics plus raloxifene versus antipsychotics plus placebo in this large randomized, double-blind, placebo-controlled trial in postmenopausal women. These data do not support the use of raloxifene in severely decompensated schizophrenia patients until reliable research identifies what subgroup of patients or domain of outcome is benefited.

Trial Registration: ClinicalTrials.gov identifier: NCT01280305.
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http://dx.doi.org/10.4088/JCP.15m10498DOI Listing
July 2017

Should Antipsychotic Medications for Schizophrenia Be Given for a Lifetime?: A Naturalistic, Long-Term Follow-Up Study.

J Clin Psychopharmacol 2017 Apr;37(2):125-130

From the *Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA; †College of Medicine, University of Illinois, Chicago, IL; ‡Department of Psychiatry, University of North Carolina, Chapel Hill, NC; and §School of Medicine, University of Florida, Gainesville, FL.

Background: Schizophrenia remains a major health problem despite antipsychotic medications that, for most patients, can decrease acute symptoms, decrease relapses, and contribute to partial and sometimes strong positive response in patients with chronic symptoms. What has not been clear-because a double-blind, randomized, placebo-controlled trial is not feasible or ethical-is how many years after the initial episode, or onset of antipsychotic treatment, should medication be continued to achieve the best global outcome. We designed a small, clinical study to retrospectively perform a detailed follow-up to examine antipsychotic medication because it relates to both global outcome and life satisfaction.

Methods: This is a naturalistic study of 35 patients with chronic schizophrenia examining antipsychotic medication adherence from 8 to 50 years (average, 21 y) after onset of antipsychotic treatment. The sample was derived from all patients treated for many years in 1 physician's academic clinic. Most were treated by community physicians before referral to the academic clinic. Information was gathered on (1) medication adherence, (2) long-term global outcomes (based on both the patient ratings and a blind clinician's assessment [blind to medication data] on both the Global Outcome Scale and the Global Assessment of Functioning Scale), and (3) a patient-rated Satisfaction With Life Scale. Spearman rank order correlations were used to relate medication adherence to global outcomes and life satisfaction, as were linear regression models adjusted for demographic and clinical characteristics.

Results: A total of 35 patients (mean age, 45 y; mean years of possible medication since onset of treatment, 21 y) were assessed. Medication adherence was a statistically significant predictor of better long-term global outcomes and life satisfaction, both in Spearman rank order correlations and in covariate-adjusted linear regressions (all P values <0.01). Poor medication adherence was associated with poor outcomes, often disastrous, with low life satisfaction. Other variables such as presence of substance use disorders or family support did not explain the difference between those who adhered and those who did not.

Conclusions: In this naturalistic study, patients who adhered to antipsychotic medication had better long-term global outcomes than those who had poor adherence. Study limitations include the potential for residual confounding. This sample provides data consistent with the recommendation, in the absence of clinically important unwanted drug effects like tardive dyskinesia or large weight gain, for continuous, long-term antipsychotic treatment for chronic schizophrenia.
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http://dx.doi.org/10.1097/JCP.0000000000000680DOI Listing
April 2017

Lipidomic Analysis of Oxidized Fatty Acids in Plant and Algae Oils.

J Agric Food Chem 2017 Mar 28;65(9):1941-1951. Epub 2017 Feb 28.

Department of Psychiatry, University of North Carolina-Chapel Hill , North Carolina 27516, United States.

Linoleic acid (LA) and α-linolenic acid (ALA) in plant or algae oils are precursors to oxidized fatty acid metabolites known as oxylipins. Liquid chromatography tandem mass spectrometry was used to quantify oxylipins in soybean, corn, olive, canola, and four high-oleic acid algae oils at room temperature or after heating for 10 min at 100 °C. Flaxseed oil oxylipin concentrations were determined in a follow-up experiment that compared it to soybean, canola, corn, and olive oil. Published consumption data for soybean, canola, corn, and olive oil were used to estimate daily oxylipin intake. The LA and ALA fatty acid composition of the oils was generally related to their respective oxylipin metabolites, except for olive and flaxseed oil, which had higher LA derived monohydroxy and ketone oxylipins than other oils, despite their low LA content. Algae oils had the least amount of oxylipins. The change in oxylipin concentrations was not significantly different among the oils after short-term heating. The estimated oxylipin intake from nonheated soybean, canola, corn, and olive oil was 1.1 mg per person per day. These findings suggest that oils represent a dietary source of LA and ALA derived oxylipins and that the response of oils to short-term heating does not differ among the various oils.
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http://dx.doi.org/10.1021/acs.jafc.6b05559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581005PMC
March 2017

Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid.

Prostaglandins Leukot Essent Fatty Acids 2018 11 11;138:71-80. Epub 2016 May 11.

Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA; Department of Physical Medicine and Rehabilitation, University of North Carolina-Chapel Hill, NC, USA.

Linoleic acid (LA, 18:2n-6) is the most abundant polyunsaturated fatty acid in the North American diet and is a precursor to circulating bioactive fatty acid metabolites implicated in brain disorders. This exploratory study tested the effects of increasing dietary LA on plasma and cerebral cortex metabolites derived from LA, its elongation-desaturation products dihomo-gamma linolenic (DGLA, 20:3n-6) acid and arachidonic acid (AA, 20:4n-6), as well as omega-3 alpha-linolenic (α-LNA, 18:3n-3), eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Plasma and cortex were obtained from rats fed a 0.4%, 5.2% or 10.5% energy LA diet for 15 weeks and subjected to liquid chromatography tandem mass spectrometry analysis. Total oxylipin concentrations, representing the esterified and unesterified pool, and unesterified oxylipins derived from LA and AA were significantly increased and EPA metabolites decreased in plasma at 5.2% or 10.5% energy LA compared to 0.4% energy LA. Unesterified plasma DHA metabolites also decreased at 10.5% energy LA. In cortex, total and unesterified LA and AA metabolites increased and unesterified EPA metabolites decreased at 5.2% or 10.5% LA. DGLA and α-LNA metabolites did not significantly change in plasma or cortex. Dietary LA lowering represents a feasible approach for targeting plasma and brain LA, AA, EPA or DHA-derived metabolite concentrations.
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http://dx.doi.org/10.1016/j.plefa.2016.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5106341PMC
November 2018

Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73).

BMJ 2016 Apr 12;353:i1246. Epub 2016 Apr 12.

Section on Nutritional Neurosciences, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Objective: To examine the traditional diet-heart hypothesis through recovery and analysis of previously unpublished data from the Minnesota Coronary Experiment (MCE) and to put findings in the context of existing diet-heart randomized controlled trials through a systematic review and meta-analysis.

Design: The MCE (1968-73) is a double blind randomized controlled trial designed to test whether replacement of saturated fat with vegetable oil rich in linoleic acid reduces coronary heart disease and death by lowering serum cholesterol. Recovered MCE unpublished documents and raw data were analyzed according to hypotheses prespecified by original investigators. Further, a systematic review and meta-analyses of randomized controlled trials that lowered serum cholesterol by providing vegetable oil rich in linoleic acid in place of saturated fat without confounding by concomitant interventions was conducted.

Setting: One nursing home and six state mental hospitals in Minnesota, United States.

Participants: Unpublished documents with completed analyses for the randomized cohort of 9423 women and men aged 20-97; longitudinal data on serum cholesterol for the 2355 participants exposed to the study diets for a year or more; 149 completed autopsy files.

Interventions: Serum cholesterol lowering diet that replaced saturated fat with linoleic acid (from corn oil and corn oil polyunsaturated margarine). Control diet was high in saturated fat from animal fats, common margarines, and shortenings.

Main Outcome Measures: Death from all causes; association between changes in serum cholesterol and death; and coronary atherosclerosis and myocardial infarcts detected at autopsy.

Results: The intervention group had significant reduction in serum cholesterol compared with controls (mean change from baseline -13.8%v-1.0%; P<0.001). Kaplan Meier graphs showed no mortality benefit for the intervention group in the full randomized cohort or for any prespecified subgroup. There was a 22% higher risk of death for each 30 mg/dL (0.78 mmol/L) reduction in serum cholesterol in covariate adjusted Cox regression models (hazard ratio 1.22, 95% confidence interval 1.14 to 1.32; P<0.001). There was no evidence of benefit in the intervention group for coronary atherosclerosis or myocardial infarcts. Systematic review identified five randomized controlled trials for inclusion (n=10,808). In meta-analyses, these cholesterol lowering interventions showed no evidence of benefit on mortality from coronary heart disease (1.13, 0.83 to 1.54) or all cause mortality (1.07, 0.90 to 1.27).

Conclusions: Available evidence from randomized controlled trials shows that replacement of saturated fat in the diet with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes. Findings from the Minnesota Coronary Experiment add to growing evidence that incomplete publication has contributed to overestimation of the benefits of replacing saturated fat with vegetable oils rich in linoleic acid.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836695PMC
http://dx.doi.org/10.1136/bmj.i1246DOI Listing
April 2016

Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids: Implications for idiopathic pain syndromes?

Mol Pain 2016 10;12. Epub 2016 Mar 10.

National Institute on Aging, Bethesda, MD, USA Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California-Davis, Davis, CA, USA.

Background: Chronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes.

Results: Increasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues.

Conclusions: The present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes.
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http://dx.doi.org/10.1177/1744806916636386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955998PMC
December 2016

Diet-induced changes in n-3- and n-6-derived endocannabinoids and reductions in headache pain and psychological distress.

J Pain 2015 Aug 7;16(8):707-16. Epub 2015 May 7.

Section on Nutritional Neurosciences, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.

Unlabelled: Omega-3 and omega-6 fatty acids are biosynthetic precursors of endocannabinoids with antinociceptive, anxiolytic, and neurogenic properties. We recently reported that targeted dietary manipulation-increasing omega-3 fatty acids while reducing omega-6 linoleic acid (the H3-L6 intervention)-reduced headache pain and psychological distress among chronic headache patients. It is not yet known whether these clinical improvements were due to changes in endocannabinoids and related mediators derived from omega-3 and omega-6 fatty acids. We therefore used data from this trial (N = 55) to investigate 1) whether the H3-L6 intervention altered omega-3- and omega-6-derived endocannabinoids in plasma and 2) whether diet-induced changes in these bioactive lipids were associated with clinical improvements. The H3-L6 intervention significantly increased the omega-3 docosahexaenoic acid derivatives 2-docosahexaenoylglycerol (+65%, P < .001) and docosahexaenoylethanolamine (+99%, P < .001) and reduced the omega-6 arachidonic acid derivative 2-arachidonoylglycerol (-25%, P = .001). Diet-induced changes in these endocannabinoid derivatives of omega-3 docosahexaenoic acid, but not omega-6 arachidonic acid, correlated with reductions in physical pain and psychological distress. These findings demonstrate that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids in humans and suggest that 2-docosahexaenoylglycerol and docosahexaenoylethanolamine could have physical and/or psychological pain modulating properties.

Trial Registration: ClinicalTrials.gov (NCT01157208) PERSPECTIVE: This article demonstrates that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids and that these changes are related to reductions in headache pain and psychological distress. These findings suggest that dietary interventions could provide an effective, complementary approach for managing chronic pain and related conditions.
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http://dx.doi.org/10.1016/j.jpain.2015.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522350PMC
August 2015

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.

Pain 2015 Apr;156(4):587-596

Section on Nutritional Neurosciences, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA Department of Physical Medicine and Rehabilitation, Program on Integrative Medicine, University of North Carolina, Chapel Hill, NC, USA Division of Gastroenterology and Hepatology, Center for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, NC, USA Nutrition Research and Metabolism Core, North Carolina Translational Clinical Sciences Institute, University of North Carolina, Chapel Hill, NC, USA Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA Department of Neurology, University of North Carolina, Chapel Hill, NC, USA.

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.
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http://dx.doi.org/10.1097/01.j.pain.0000460348.84965.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020375PMC
April 2015

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

Pain 2013 Nov 22;154(11):2441-2451. Epub 2013 Jul 22.

Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA Department of Physical Medicine and Rehabilitation, Program on Integrative Medicine, University of North Carolina-Chapel Hill, NC, USA Department of Biostatistics, School of Public Health, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA Nutrition Research and Metabolism Core, North Carolina Translational Clinical Sciences Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA Department of Pediatric Gastroenterology, Hepatology and Nutrition, University of California, San Diego, San Diego, CA, USA School of Medicine and Pharmacology, Royal Perth Hospital, The University of Western Australia, Perth, Australia Division of Gastroenterology and Hepatology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA School of Dentistry, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA Department of Neurology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.

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.
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http://dx.doi.org/10.1016/j.pain.2013.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850757PMC
November 2013

Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis.

BMJ 2013 Feb 4;346:e8707. Epub 2013 Feb 4.

Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.

Objective: To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death.

Design: Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data.

Setting: Ambulatory, coronary care clinic in Sydney, Australia.

Participants: 458 men aged 30-59 years with a recent coronary event.

Interventions: Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups.

Outcome Measures: All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group.

Results: The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07).

Conclusions: Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats.

Trial Registration: Clinical trials NCT01621087.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688426PMC
http://dx.doi.org/10.1136/bmj.e8707DOI Listing
February 2013

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

Br J Nutr 2013 Aug 18;110(3):559-68. Epub 2013 Jan 18.

Nutrition Research and Metabolism Core, North Carolina Translational Clinical Sciences Institute, 101 Manning Drive, CB#7600, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

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; $1·5 en%) and EPA þ DHA ($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.
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http://dx.doi.org/10.1017/S0007114512005181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091836PMC
August 2013

Intakes of long-chain omega-3 (n-3) PUFAs and fish in relation to incidence of asthma among American young adults: the CARDIA study.

Am J Clin Nutr 2013 Jan 28;97(1):173-8. Epub 2012 Nov 28.

Departments of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Although long-chain ω-3 (n-3) PUFAs (LCω3PUFAs) have been linked to the prevention of some inflammatory disorders, little is known about the association between these fatty acids and incidence of asthma.

Objective: The objective was to prospectively investigate the association between LCω3PUFAs and fish intake and incidence of asthma among American young adults.

Design: A 20-y follow-up longitudinal analysis was conducted in a biracial cohort of 4162 Americans, aged 18-30 y, with a history of asthma at baseline in 1985. Diet was assessed by a validated interviewer-administered quantitative food-frequency questionnaire at the examinations in 1985, 1992, and 2005. Incident self-reported asthma was defined as having a physician diagnosis of asthma and/or the use of asthma medications between 1985 and 2005.

Results: During the 20-y follow-up, 446 incident cases of asthma were identified. LCω3PUFA intake was significantly inversely associated with incidence of asthma after adjustment for sociodemographic, major lifestyle, and dietary confounders. The multivariable-adjusted HR for the highest quintile of LCω3PUFA intake as compared with the lowest quintile was 0.46 (95% CI: 0.33, 0.64; P-trend < 0.01). However, a higher frequency of nonfried fish consumption was not significantly associated with the risk of asthma. DHA showed a greater inverse association than did EPA. The association between LCω3PUFAs and incident asthma was not appreciably modified by sex, race, BMI, smoking status, or atopic status.

Conclusion: This study showed that intakes of LCω3PUFAs are inversely longitudinally associated with the incidence of asthma in American young adults.
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http://dx.doi.org/10.3945/ajcn.112.041145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522136PMC
January 2013

Low-carbohydrate diet scores and risk of type 2 diabetes in men.

Am J Clin Nutr 2011 Aug;94(2):611; author reply 611-2

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http://dx.doi.org/10.3945/ajcn.111.017053DOI Listing
August 2011

Are the 2005 Dietary Guidelines for Americans Associated With reduced risk of type 2 diabetes and cardiometabolic risk factors? Twenty-year findings from the CARDIA study.

Diabetes Care 2011 May 8;34(5):1183-5. Epub 2011 Apr 8.

Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Objective: To examine the prospective association between accordance with the 2005 Dietary Guidelines for Americans (DGA) and subsequent diabetes incidence and changes in cardiometabolic risk factors.

Research Design And Methods: The sample consisted of 4,381 black and white young adults examined repeatedly from 1985 to 2005. We used the 2005 Diet Quality Index (DQI) to rate participants' diets based on meeting key dietary recommendations conveyed by the 2005 DGA.

Results: Overall, we found no association between DQI score and diabetes risk using Cox models adjusted for potential confounders. Higher DQI scores were associated with favorable changes in HDL cholesterol and blood pressure overall (P for trend < 0.05), but with increased insulin resistance among blacks (P for trend < 0.01).

Conclusions: Our findings highlight the need for evaluation of the DGA's effectiveness, particularly among ethnic minority populations. Clinicians should be aware that following the DGA might not lower diabetes risk.
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http://dx.doi.org/10.2337/dc10-2041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114488PMC
May 2011

Diet quality and weight gain among black and white young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study (1985-2005).

Am J Clin Nutr 2010 Oct 4;92(4):784-93. Epub 2010 Aug 4.

Carolina Population Center and Department of Nutrition, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, NC 27516-3997, USA.

Background: Little is known about the long-term health consequences of following the 2005 Dietary Guidelines for Americans (DGA; Washington, DC: US Government Printing Office, 2005).

Objective: The objective was to examine the longitudinal association between diets consistent with the 2005 DGA and subsequent weight gain.

Design: We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a cohort of black and white men and women aged 18-30 y at baseline who attended ≤7 examinations from 1985-1986 to 2005-2006 (n = 4913). We created a 100-point Diet Quality Index (2005 DQI) to rate participants' diets based on meeting the 2005 DGA key recommendations. Longitudinal models of weight gain were adjusted for physical activity, smoking, energy intake, age, education, sex, and initial body mass index (BMI) and included interaction terms of DQI by race and initial BMI (if statistically significant).

Results: We found effect modification by race (likelihood ratio test, P < 0.03 in all models). The mean adjusted 20-y weight change was +19.4 kg for blacks and +11.2 kg for whites with high diet quality (DQI >70) and +17.8 for blacks and +13.9 for whites with a DQI <50 (P < 0.05). In race-specific Cox models (with interaction terms for DQI × initial BMI, P < 0.05), a 10-point increase in DQI score was associated with a 10% lower risk of gaining 10 kg in whites with an initial BMI (in kg/m(2)) <25 but with a 15% higher risk in blacks with baseline obesity (P < 0.001).

Conclusions: Our findings do not support the hypothesis that a diet consistent with the 2005 DGA benefits long-term weight maintenance in American young adults. Greater need for attention to obesity prevention in future DGAs is warranted.
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http://dx.doi.org/10.3945/ajcn.2010.29161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937583PMC
October 2010
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