| 1. |
- Ajeganova, Sofia, et al.
(författare)
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Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab
- 2017
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Ingår i: Arthritis Research & Therapy. - : BIOMED CENTRAL LTD. - 1478-6362. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: The causes and mechanisms of late-onset neutropenia (LON) following rituximab treatment in patients with rheumatic diseases are not known. In this study, we aimed to investigate the role of established Fc gamma receptor gene (FCGR) polymorphisms and B-cell-activating factor (BAFF) gene promoter polymorphisms for the development of LON and for the efficacy of rituximab in patients with rheumatic diseases. Methods: A single-center case-control retrospective study was nested in a cohort of 214 consecutive patients with rheumatic diseases treated with rituximab. Eleven patients presented with LON. Fifty non-LON control subjects were matched by diagnosis, age, sex, and treatments. Single-nucleotide polymorphisms of FCGR (FCGR2A 131H/R, FCGR2B 232I/T, FCGR3A 158V/F) and BAFF promoter polymorphism -871C/T were analyzed with polymerase chain reaction-based techniques, and serum immunoglobulin M (IgM) and BAFF levels were analyzed by enzyme-linked immunosorbent assay. Flare-free survival was related to LON occurrence and polymorphisms. Results: The FCGR3A V allele, but not other FCGR polymorphisms, correlated with the occurrence of LON; each V allele conferred a fourfold increased OR for LON (p = 0.017). FCGR3A 158V/V and presentation with LON were associated with a longer flare-free survival (p = 0.023 and p = 0.031, respectively). FCGR3A 158V/V was related to lower IgM levels (p = 0.016). Serum BAFF levels showed no relationship with LON and BAFF -871C/T promoter polymorphism. There was a tendency toward longer flare-free survival in patients with the BAFF -871T/T allotype compared with the C/T or C/C allotypes (p = 0.096). Conclusions: The results of the present study suggest that presentation with LON may be a result of the intrinsic efficacy of rituximab in patients with rheumatic diseases. LON could indicate a longer biological and therapeutic activity of rituximab modulated by a certain genotypic polymorphism: the high-affinity FCGR3A V allele. This genotype and the occurrence of LON are both related to longer flare-free survival, suggestive of common mechanisms for LON and duration of response to rituximab. The role of the BAFF -871C/T promoter polymorphism in LON occurrence is unclear.
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| 2. |
- Andersson, Emil, et al.
(författare)
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Low pericyte coverage of endometrial microvessels in heavy menstrual bleeding correlates with the microvessel expression of VEGF-A.
- 2015
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1791-244X .- 1107-3756. ; 35:2, s. 433-438
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Tidskriftsartikel (refereegranskat)abstract
- A prospective clinical study was carried out to investigate whether endometrial microvessels in patients with idiopathic heavy menstrual bleeding (HMB) of endometrial origin (HMB-E) are fragile due to low pericyte coverage. Idiopathic HMB-E is characterized by large endothelial cell gaps related to the microvascular overexpression of vascular endothelial growth factor (VEGF)-A and VEGF receptors 1-3. A total of 10 women with a normal menstrual cycle and a history of HMB of <5 years, and 17 healthy women with a normal menstrual cycle were recruited from the Karolinska University Hospital. Blood samples were obtained for hormone analysis and coagulation tests. Endometrial biopsies were collected in the proliferative or in the secretory phase. Pericyte coverage was assessed using immunohistochemical staining for smooth muscle actin-α (SMAα) and by image analysis (microvascular density) of endometrial biopsies from 10 patients with HMB-E and 17 healthy ovulating women (control subjects). Previously published data on endothelial cell gap size and the expression of VEGF receptors were used. Although microvascular density did not differ between the patients with HMB-E and the control subjects, the number of SMAα-positive microvessels in the proliferative phase was significantly (P=0.005) lower in the patients with HMB-E than in the control subjects. Moreover, the number of SMAα-positive microvessels in the control subjects was significantly fewer in the secretory (P=0.04) than in the proliferative phase, whereas this number did not differ among the patients with HMB-E regardless of phase. A significant negative correlation was observed between the number of VEGF-A-positive microvessels and microvessels with pericyte coverage (r=0.8; P=0.04). Finally, the endothelial cell layer was significantly thicker in the patients with HMB-E than in the control subjects. Thus, the upregulation of VEGF-A in idiopathic HMB-E is associated with a low pericyte coverage during the proliferative phase of intense angiogenesis, which may confer vessel fragility, possibly leading to excessive blood loss.
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| 3. |
- Eriksdotter, Maria, et al.
(författare)
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Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer's Disease Patients During Oral Omega-3 Fatty Acid Supplementation : The OmegAD Study
- 2015
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 48:3, s. 805-812
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: ω3 fatty acids (ω3 FAs) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer's disease (AD). However, the relationship between changes of plasma ω3 FA levels and cognitive performance, as well as effects of gender, are poorly known.OBJECTIVE: To study the effect of 6-month administration of DHA-rich ω3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender. This investigation is part of the OmegAD Study.METHODS: 174 AD patients (74 ± 9 years) were randomized to a daily intake of 2.3 g ω3 FA or placebo for 6 months; subsequently all received the ω3 FA preparation for the next 6 months. Baseline as well as changes in plasma levels of the main ω3 FAs in 165 patients, while receiving ω3 FA supplementation for 6 months, were analyzed for association to cognitive performance (assessed by ADAS-cog and MMSE scores) as well as to gender.RESULTS: Preservation of cognitive functioning, assessed by ADAS-cog or its sub-items (but not MMSE) scores, was significantly associated to increasing plasma ω3 FA levels over time. Thus, the higher ω3 FA plasma levels rose, the lower was the rate of cognitive deterioration. This effect was not related to gender; since although females displayed higher ω3 FA plasma levels than did males after 6 months of supplementation, this difference disappeared when adjusted for body weight.CONCLUSIONS: Since our study suggests dose-response relationships between plasma levels of ω3 FA and preservation of cognition, future ω3 FA trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of ω3 FA.
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| 4. |
- Faxen-Irving, Gerd, et al.
(författare)
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Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies?
- 2018
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 61:2, s. 515-519
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Tidskriftsartikel (refereegranskat)abstract
- Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.
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| 5. |
- Faxén-Irving, Gerd, et al.
(författare)
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Effects on transthyretin in plasma and cerebrospinal fluid by DHA-rich n - 3 fatty acid supplementation in patients with Alzheimer's disease : the OmegAD study
- 2013
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 36:1, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Transthyretin (TTR) binds amyloid-β (Aβ) and may reduce brain Aβ, a pathological feature in Alzheimer's disease (AD). N - 3 fatty acids (FA), docosahexaenoic (DHA), and eicosapentaenoic acid (EPA) may increase TTR transcription in rat hippocampus. We studied effects of n - 3 FA supplementation on TTR-levels in patients with AD. Outpatients were randomized to receive 1.7 g DHA and 0.6 g EPA (n - 3/n - 3 group) or placebo (placebo/n - 3 group) during 6 months. After 6 months, all patients received n - 3 FA for another 6 months. TTR and FA were measured in plasma in all subjects, whereas TTR in cerebrospinal fluid (CSF) was measured in a subgroup. The study was completed by 89 patients in the n - 3/n - 3 group (75 y, 57% w) and 85 in the placebo/n - 3 group (75 y, 46% w). Baseline plasma-TTR was within normal range in both groups. After 6 months, plasma-TTR decreased in the placebo/n - 3 group (p < 0.001 within and p < 0.015 between the groups). No changes were observed in CSF TTR. From 6 to 12 months when both groups were supplemented, plasma-TTR increased significantly in both groups. Repeated measures ANOVA indicated an increase in TTR over time (p = 0.04) in those receiving n - 3 FA for 12 months. By linear regression analyses, n - 3 FA treatment was independently associated with increased plasma-TTR at 6 months (β = -0.172, p = 0.028). Thus, n - 3 FA treatment appeared to increase plasma-TTR in patients with AD. Since TTR may influence Aβ deposition in the brain, the results warrant further exploration.
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| 6. |
- Freund-Levi, Yvonne, 1956-, et al.
(författare)
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Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer's disease : the OmegAD study
- 2009
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger. - 1420-8008 .- 1421-9824. ; 27:5, s. 481-490
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: omega-3 fatty acids (omega-3 FAs) found in dietary fish or fish oils are anti-inflammatory agents that may influence Alzheimer's disease (AD).OBJECTIVE: To study the effects of dietary omega-3 FA supplementation on inflammatory markers in cerebrospinal fluid (CSF) and plasma from patients with mild to moderate AD.METHODS: Thirty-five patients (70.3 +/- 8.2 years) were randomized to a daily intake of 2.3 g omega-3 FAs or placebo for 6 months. The inflammatory markers interleukin (IL)-6, tumour necrosis factor-alpha and soluble interleukin-1 receptor type II (sIL-1RII) were analysed in CSF and plasma at baseline and at 6 months. The AD markers tau-protein, hyperphosphorylated tau-protein and beta-amyloid (Abeta(1-42)) were assessed in CSF. High-sensitivity C-reactive protein was assessed in plasma. A possible relation to the APOE genotype was investigated.RESULTS: There was no significant treatment effect of omega-3 FAs on inflammatory and AD biomarkers in CSF or on inflammatory markers in plasma, nor was there any relation with APOE. A significant correlation was observed at baseline between sIL-1RII and Abeta(1-42) levels in CSF.CONCLUSIONS: Treatment of AD patients with omega-3 FAs for 6 months did not influence inflammatory or biomarkers in CSF or plasma. The correlation between sIL-1RII and Abeta(1-42) may reflect the reciprocal interactions between IL-1 and Abeta peptides.
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| 7. |
- Freund-Levi, Yvonne, 1956-, et al.
(författare)
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Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer's disease : the OmegAD study
- 2014
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 42:3, s. 823-831
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Omega-3 fatty acids (ω-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation.OBJECTIVE: The objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary ω-3 FA.METHODS: Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for 6 months. Urinary samples were collected before and after supplementation. The levels of the major F2-isoprostane, 8-iso-PGF2α, a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF2α, a major metabolite of PGF2α and biomarker of inflammatory response, were measured.RESULTS: F2-isoprostane in urine increased in the placebo group after 6 months, but there was no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F2-isoprostanes and 15-keto-dihydro-PGF2α. At baseline, the levels of 15-keto-dihydro-PGF2α showed negative correlative relationships to ω-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF2α correlated negatively to the ω-6 FA arachidonic acid.CONCLUSION: The findings indicate that supplementation of ω-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F2-isoprostane or cyclooxygenase-mediated formation of prostaglandin F2α. The correlative relationships to FAs indicate a potential role of FAs in immunoregulation.
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| 8. |
- Freund-Levi, Yvonne, 1956-, et al.
(författare)
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Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease : OmegAD study - A randomized double-blind trial
- 2006
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Ingår i: Archives of Neurology. - : American Medical Association (AMA). - 0003-9942 .- 1538-3687. ; 63:10, s. 1402-1408
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epidemiologic and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids, for example, docosahexaenoic acid and eicosapentaenoic acid, may prevent Alzheimer disease (AD). Objective: To determine effects of dietary omega-3 fatty acid supplementation on cognitive functions in patients with mild to moderate AD. Design: Randomized, double-blind, placebo-controlled clinical trial. Participants: Two hundred four patients with AD (age range [mean +/- SD], 74 +/- 9 years) whose conditions were stable while receiving acetylcholine esterase inhibitor treatment and who had a Mini-Mental State Examination (MMSE) score of 15 points or more were randomized to daily intake of 1.7 g of docosahexaenoic acid and 0.6 g of eicosapentaenoic acid (omega-3 fatty acid-treated group) or placebo for 6 months, after which all received omega-3 fatty acid supplementation for 6 months more. Main Outcome Measures: The primary outcome was cognition measured with the MMSE and the cognitive portion of the Alzheimer Disease Assessment Scale. The secondary outcome was global function as assessed with the Clinical Dementia Rating Scale; safety and tolerability of omega-3 fatty acid supplementation; and blood pressure determinations. Results: One hundred seventy-four patients fulfilled the trial. At baseline, mean values for the Clinical Dementia Rating Scale, MMSE, and cognitive portion of the Alzheimer Disease Assessment Scale in the 2 randomized groups were similar. At 6 months, the decline in cognitive functions as assessed by the latter 2 scales did not differ between the groups. However, in a subgroup (n=32) with very mild cognitive dysfunction (MMSE > 27 points), a significant (P <.05) reduction in MMSE decline rate was observed in the omega-3 fatty acid-treated group compared with the placebo group. A similar arrest in decline rate was observed between 6 and 12 months in this placebo subgroup when receiving omega-3 fatty acid supplementation. The omega-3 fatty acid treatment was safe and well tolerated. Conclusions: Administration of omega-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale. However, positive effects were observed in a small group of patients with very mild AD (MMSE > 27 points).
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| 9. |
- Freund-Levi, Yvonne, 1956-, et al.
(författare)
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Omega-3 supplementation in mild to moderate Alzheimer's disease : effects on neuropsychiatric symptoms
- 2008
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Ingår i: International Journal of Geriatric Psychiatry. - : Wiley. - 0885-6230 .- 1099-1166. ; 23:2, s. 161-169
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epidemiological and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids (ω3), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may have effects in psychiatric and behavioral symptoms in Alzheimer's disease (AD). An association with APOEω4 carriers and neuropsychiatric symptoms in AD has also been suggested. Objective: To determine effects of dietary ω3 supplementation to AD patients with mild to moderate disease on psychiatric and behavioral symptoms, daily functions and a possible relation to APOEgenotype. Methods: Randomized, double-blind, placebo-controlled clinical trial where 204 AD patients (74 ± 9 years) with acetylcholine esterase inhibitor treatment and a MMSE >15 points were randomized to daily intake of 1.7 g DHA and 0.6 g EPA (ω3 group) or placebo for 6 months. Then, all received the ω3 supplementation for 6 more months. Neuropsychiatric symptoms were measured with Neuropsychiatric Inventory (NPI) and Montgomery Åsberg Depression Scale (MADRS). Caregivers burden and activities of daily living (Disability Assessment for Dementia, DAD) were also assessed. Results: One hundred and seventy-four patients fulfilled the trial. 72% were APOEω4 carriers. No significant overall treatment effects on neuropsychiatric symptoms, on activities of daily living or on caregiver's burden were found. However, significant positive treatment effects on the scores in the NPI agitation domain in APOEω4 carriers (p = 0.006) and in MADRS scores in non-APOEω4 carriers (p = 0.005) were found. Conclusions: Supplementation with ω3 in patients with mild to moderate AD did not result in marked effects on neuropsychiatric symptoms except for possible positive effects on depressive symptoms (assessed by MADRS) in non-APOEω4 carriers and agitation symptoms (assessed by NPI) in APOEω4 carriers. ClinicalTrials.gov identifier: NCT00211159.
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| 10. |
- Hjorth, Erik, et al.
(författare)
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Omega-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-β42 by human microglia and decrease inflammatory markers
- 2013
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 35:4, s. 697-713
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Tidskriftsartikel (refereegranskat)abstract
- The use of supplements with omega-3 (ω3) fatty acids (FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is widespread due to proposed beneficial effects on the nervous and cardiovascular systems. Many effects of ω3 FAs are believed to be caused by down-regulation and resolution of inflammation. Alzheimer's disease (AD) is associated with inflammation mediated by microglia and astrocytes, and ω3 FAs have been proposed as potential treatments for AD. The focus of the present study is on the effects of DHA and EPA on microglial phagocytosis of the AD pathogen amyloid-β (Aβ), on secreted and cellular markers of immune activity, and on production of brain-derived neurotrophic factor (BDNF). Human CHME3 microglial cells were exposed to DHA or EPA, with or without the presence of Aβ42. Phagocytosis of Aβ42 was analyzed by flow cytometry in conjunction with immunocytochemistry using antibodies to cellular proteins. Secreted proteins were analyzed by ELISA. Both DHA and EPA were found to stimulate microglial phagocytosis of Aβ42. Phagocytosis of Aβ42 was performed by microglia with a predominance of M2 markers. EPA increased the levels of BDNF in the culture medium. The levels of TNF-α were decreased by DHA. Both DHA and EPA decreased the pro-inflammatory M1 markers CD40 and CD86, and DHA had a stimulatory effect on the anti-inflammatory M2 marker CD206. DHA and EPA can be beneficial in AD by enhancing removal of Aβ42, increasing neurotrophin production, decreasing pro-inflammatory cytokine production, and by inducing a shift in phenotype away from pro-inflammatory M1 activation.
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| 11. |
- Irving, Gerd Faxén, et al.
(författare)
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Omega-3 fatty acid supplementation effects on weight and appetite in patients with Alzheimer's disease : the omega-3 Alzheimer's disease study
- 2009
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Ingår i: Journal of The American Geriatrics Society. - : Wiley. - 0002-8614 .- 1532-5415. ; 57:1, s. 11-17
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To study the effects of omega (Omega)-3 fatty acid (FA) supplements on weight and appetite in patients with mild to moderate Alzheimer's disease (AD) in relation to inflammatory biomarkers and apolipoprotein E epsilon4 (APOEepsilon4). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Specialist memory clinics in the Stockholm catchment area. PARTICIPANTS: Two hundred four patients (aged 73+/-9, 52% women) with mild to moderate AD. INTERVENTION: Patients with AD received 1.7 g of docosahexaenoic acid (DHA) and 0.6 g of eicosapentaenoic acid (EPA) (Omega-3/Omega-3 group; n=89, aged 73+/-9, 57% women) or placebo 0.6 g of linoleic acid per day (placebo/Omega-3 group; n=85, aged 73+/-9, 46% women) for 6 months. After 6 months, all patients received DHA and EPA for another 6 months. MEASUREMENTS: Anthropometry, biochemical nutritional and inflammatory markers, and appetite assessed by caregiver. RESULTS: Mean weight and body mass index (kg/m(2)) at baseline were 70.0+/-11.8 kg and 24.3+/-3.0 kg/m(2), respectively. At 6- and 12-month follow-up, weight had increased 0.7+/-2.5 kg (P=.02) and 1.4+/-2.9 kg (P<.001) in the Omega-3/Omega-3 group. In the placebo group, weight was unchanged at 6 months but had increased (P=.01) at 12 months follow-up after Omega-3 supplementation was initiated. Appetite improved in the Omega-3/Omega-3 group over the treatment period (P=.01). In logistic regression analyses, not carrying the APOEepsilon4 allele and high plasma DHA concentrations were independently related to weight gain in the combined group of patients at 6 months follow-up. CONCLUSION: A DHA-enriched Omega-3 FA supplement may positively affect weight and appetite in patients with mild to moderate AD. Not carrying the APOEepsilon4 allele and high DHA were independently associated with weight gain.
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| 12. |
- Karimi, Mohsen, et al.
(författare)
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DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes : the OmegAD study
- 2017
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Ingår i: American Journal of Clinical Nutrition. - : HighWire Press. - 0002-9165 .- 1938-3207. ; 106:4, s. 1157-1165
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dietary fish oils, rich in long-chain n-3 (ω-3) fatty acids (FAs) [e.g., docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3)], modulate inflammatory reactions through various mechanisms, including gene expression, which is measured as messenger RNA concentration. However, the effects of long-term treatment of humans with DHA and EPA on various epigenetic factors-such as DNA methylation, which controls messenger RNA generation-are poorly described.Objective: We wanted to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global DNA methylation of peripheral blood leukocytes (PBLs) and the relation to plasma EPA and DHA concentrations in Alzheimer disease (AD) patients.Design: In the present study, DNA methylation in four 5'-cytosine-phosphate-guanine-3' (CpG) sites of long interspersed nuclear element-1 repetitive sequences was assessed in a group of 63 patients (30 given the n-3 FA preparation and 33 given placebo) as an estimation of the global DNA methylation in blood cells. Patients originated from the randomized, double-blind, placebo-controlled OmegAD study, in which 174 AD patients received either 1.7 g DHA and 0.6 g EPA (the n-3 FA group) or placebo daily for 6 mo.Results: At 6 mo, the n-3 FA group displayed marked increases in DHA and EPA plasma concentrations (2.6- and 3.5-fold), as well as decreased methylation in 2 out of 4 CpG sites (P < 0.05 for all), respectively. This hypomethylation in CpG2 and CpG4 sites showed a reverse correlation to changes in plasma EPA concentration (r = -0.25, P = 0.045; and r = -0.26, P = 0.041, respectively), but not to changes in plasma DHA concentration, and were not related to apolipoprotein E-4 allele frequency.Conclusion: Supplementation with n-3 FA for 6 mo was associated with global DNA hypomethylation in PBLs. Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients with AD and in other patients taking n-3 FA supplements. This trial was registered at clinicaltrials.gov as NCT00211159.
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| 13. |
- Vedin, Inger, et al.
(författare)
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Effects of DHA-rich n-3 fatty acid supplementation on gene expression in blood mononuclear leukocytes : the OmegAD study
- 2012
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dietary fish oil, rich in n-3 fatty acids (n-3 FAs), e.g. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), regulate inflammatory reactions by various mechanisms, e.g. gene activation. However, the effects of long-term treatment with DHA and EPA in humans, using genome wide techniques, are poorly described. Hence, our aim was to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global gene expression in peripheral blood mononuclear cells.METHODS AND FINDINGS: In the present study, blood samples were obtained from a subgroup of 16 patients originating from the randomized double-blind, placebo-controlled OmegAD study, where 174 Alzheimer disease (AD) patients received daily either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months. In blood samples obtained from 11 patients receiving n-3 FA and five placebo, expressions of approximately 8000 genes were assessed by gene array. Significant changes were confirmed by real-time PCR. At 6 months, the n-3 FAs group displayed significant rises of DHA and EPA plasma concentrations, as well as up- and down-regulation of nine and ten genes, respectively, was noticed. Many of these genes are involved in inflammation regulation and neurodegeneration, e.g. CD63, MAN2A1, CASP4, LOC399491, NAIP, and SORL1 and in ubiqutination processes, e.g. ANAPC5 and UBE2V1. Down-regulations of ANAPC5 and RHOB correlated to increases of plasma DHA and EPA levels.CONCLUSIONS: We suggest that 6 months of dietary n-3 FA supplementation affected expression of genes that might influence inflammatory processes and could be of significance for AD.TRIAL REGISTRATION: ClinicalTrials.gov NCT00211159.
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| 14. |
- Vedin, Inger, et al.
(författare)
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Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes : the OmegAD study
- 2008
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Ingår i: American Journal of Clinical Nutrition. - : HighWire Press. - 0002-9165 .- 1938-3207. ; 87:6, s. 1616-1622
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dietary fish or fish oil rich in n-3 fatty acids (n-3 FAs), eg, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms. Whereas most studies have explored the effects of predominantly EPA-based n-3 FAs preparations, few have addressed the effects of n-3 FAs preparations with DHA as the main FA.OBJECTIVE: The objective was to determine the effects of 6 mo of dietary supplementation with an n-3 FAs preparation rich in DHA on release of cytokines and growth factors from peripheral blood mononuclear cells (PBMCs).DESIGN: In a randomized, double-blind, placebo-controlled trial, 174 Alzheimer disease (AD) patients received daily either 1.7 g DHA and 0.6 g EPA (n-3 FAs group) or placebo for 6 mo. In the present study blood samples were obtained from the 23 first randomized patients, and PBMCs were isolated before and after 6 mo of treatment.RESULTS: Plasma concentrations of DHA and EPA were significantly increased at 6 mo in the n-3 FAs group. This group also showed significant decreases of interleukin (IL)-6, IL-1beta, and granulocyte colony-stimulating factor secretion after stimulation of PBMCs with lipopolysaccharide. Changes in the DHA and EPA concentrations were negatively associated with changes in IL-1beta and IL-6 release for all subjects. Reductions of IL-1beta and IL-6 were also significantly correlated with each other. In contrast, this n-3 FA treatment for 6 mo did not decrease tumor necrosis factor-alpha, IotaL-8, IL-10, and granulocyte-macrophage colony-stimulating factor secretion.CONCLUSION: AD patients treated with DHA-rich n-3 FAs supplementation increased their plasma concentrations of DHA (and EPA), which were associated with reduced release of IL-1beta, IL-6, and granulocyte colony-stimulating factor from PBMCs. This trial was registered at clinicaltrials.gov as NCT00211159.
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| 15. |
- Vedin, Inger
(författare)
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Inflammation modulating effects of prostaglandins and omega-3 fatty acids
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Omega-(omega6) and omega-3 fatty acids (FA) and their metabolites (eikosanoids, such as prostaglandins, PG) are important modulators of immune and inflammatory responses in various ways. The aim of this thesis was to assess some in vitro and ex vivo effects of these lipids on blood leukocytes. In the first part of this thesis (studies I and II), we examined the in vitro effects on peripheral blood lymphocytes and monocytes by various PGs. We found that the natural killer (NK) activity of lymphocytes was decreased by PGD2 and PGE2. PGD2 also decreased surface expression of the CD8 antigen (on cytotoxic/suppressor T cells), as well as of Fc receptors for IgG on T cells. In peripheral blood mononuclear cells (PBMC), the proliferative response to phytohemagglutinin (PHA) was reduced in the presence of PGD2, PGA2 and PGE2, in falling order of potency. In lipopolysaccharide (LPS) stimulated purified monocytes we found that, although PGD2 did not influence TNF-alpha release, its metabolites PGJ2, delta12-PGJ2 and 15-deoxy delta12, delta14 -PGJ2 (15d-PGJ2) enhanced the TNF-alpha release. The monocyte NADPH oxidase activity was not affected by PGB2, PGD2 or PGE2. In the second part of the thesis (III-V), we assessed various ex vivo effects on PBMC of a dietary treatment for 6 months with a DHA enriched fish oil preparation (1.7 g of docosahexaenoic acid (DHA) and 0.6 g of eicosapentaenoic acid (EPA) per day; omega-3 FA group) or an isocaloric placebo oil in patients with Alzheimer disease (AD; the OmegAD trial). The omega-3 FA-treated group displayed significant increases of DHA and EPA plasma levels whereas the placebo group did not. The release of PGF2alpha (a stable metabolite of PGE2) was significantly diminished from LPS (but not from PHA) stimulated PBMC in the omega-3 FAs group, while no change was noted for the placebo group (III). The omega-3 group showed significant decreases of IL-1beta, IL-6, and G-CSF release after LPS stimulation of PBMC (IV). PGF2alpha, IL-1beta and IL-6 changes correlated inversely with changes in DHA and EPA plasma levels. Furthermore, reductions of IL-1beta and IL-6 were significantly correlated with each other, and decreased IL-1beta and IL-6 levels correlated with decreased PGF2alpha levels. In paper V, we studied gene expressions in the PBMC, using a genome wide technique with approx. 8000 genes. At 6 months, a significant up-regulation of nine, and a down-regulation of 10 genes were noted in the omega-3 group. Many of these genes are involved in inflammation and neurodegeneration, e.g. CD63, RHOB, CASP4, NAIP, VCP and SORL1. The up-regulation of CD63 and SUPT4H1 genes and the down-regulation of RHOB, LOC 399491, ZNF24 and ANAPC5 genes were significant in the omega-3 group compared to placebo group. The downregulated ANAPC5 and RHOB genes correlated to increased DHA and EPA levels. In conclusion, cyclooxygenase products of arachidonic acid, i.e. prostaglandin of the E and D series, influence various immune and inflammatory responses of lymphocytes and monocytes in vitro in a complex way, depending on the specific eikosanoid, the dose and studied functions. Dietary intake of DHA rich fish oil reduces the release of PGE2, pro- inflammatory cytokines and the myeloid growth factor G-CSF ex vivo in PBMCs. Moreover, the DHA rich fish oil affected several genes, which might be of significance for inflammation or Alzheimer's disease. Although these responses point to a down-regulation of inflammatory reactions, it remains to be seen whether the DHA rich fish oil also affects the inflammatory process in the AD brain.
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| 16. |
- Vedin, Inger, et al.
(författare)
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Reduced prostaglandin F-2 alpha release from blood mononuclear leukocytes after oral supplementation of omega 3 fatty acids : the OmegAD study
- 2010
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Ingår i: Journal of Lipid Research. - : American Society for Biochemistry and Molecular Biology. - 0022-2275 .- 1539-7262. ; 51:5, s. 1179-1185
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Tidskriftsartikel (refereegranskat)abstract
- Omega-3 fatty acids, e. g., dokosahexaenoic acid (DHA) and eikosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms, but the role of prostaglandins remains unclear. Our aim was to determine if dietary supplementation with a DHA-rich fish oil influenced the release of PGF(2 alpha) from peripheral blood mononuclear cells (PBMC). In the OmegAD study, 174 Alzheimer disease patients received either 1.7 g DHA plus 0.6 g EPA or a placebo daily for six months. PBMCs from the 21 ( 9 on fish oil and 12 on placebo) first-randomized patients were stimulated with either lipopolysaccharide (LPS) or phytohemagglutinin (PHA) before and after 6 months. Our results showed that plasma concentrations of DHA and EPA increased significantly at 6 months in the omega-3 group. PGF(2 alpha) release from LPS- ( but not from PHA-) stimulated PBMC was significantly diminished in this group; no change was noted in the placebo group. PGF(2 alpha) changes correlated inversely with changes in plasma DHA and EPA. Decreased IL-6 and IL-1(beta) levels correlated with decreased PGF(2 alpha) levels. The stimulus-specific PGF(2 alpha) release from PBMC after 6 months of oral supplementation with the DHA-rich fish oil might be one event related to reduced inflammatory reactions associated with omega-3 fatty acid intake.
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| 17. |
- Wang, Xiuzhe, et al.
(författare)
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Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells : the OmegAD study
- 2015
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Ingår i: Journal of Lipid Research. - : American Society for Biochemistry and Molecular Biology. - 0022-2275 .- 1539-7262. ; 56:3, s. 674-681
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Tidskriftsartikel (refereegranskat)abstract
- Specialized proresolving mediators (SPMs) induce resolution of inflammation. SPMs are derivatives of n-3 and n-6 PUFAs and may mediate their beneficial effects. It is unknown whether supplementation with PUFAs influences the production of SPMs. Alzheimer's disease (AD) is associated with brain inflammation and reduced levels of SPMs. The OmegAD study is a randomized, double-blind, and placebo-controlled clinical trial on AD patients, in which placebo or a supplement of 1.7 g DHA and 0.6 g EPA was taken daily for 6 months. Plasma levels of arachidonic acid decreased, and DHA and EPA levels increased after 6 months of n-3 FA treatment. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial. Analysis of the culture medium of PBMCs incubated with amyloid-β 1-40 showed unchanged levels of the SPMs lipoxin A4 and resolvin D1 in the group supplemented with n-3 FAs, whereas a decrease was seen in the placebo group. The changes in SPMs showed correspondence to cognitive changes. Changes in the levels of SPMs were positively correlated to changes in transthyretin. We conclude that supplementation with n-3 PUFAs for 6 months prevented a reduction in SPMs released from PBMCs of AD patients, which was associated with changes in cognitive function.
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| 18. |
- Åström, Maria, 1959-, et al.
(författare)
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X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis : comparisons with primary myelofibrosis
- 2015
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 90:3, s. E44-E48
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Tidskriftsartikel (refereegranskat)abstract
- X-linked thrombocytopenia with thalassemia (XLTT) is caused by the mutation 216R > Q in exon 4 of the GATA1 gene. Male hemizygous patients display macrothrombocytopenia, splenomegaly, and a β-thalassemia trait. We describe two XLTT families where three males were initially misdiagnosed as having primary myelofibrosis (PMF) and all five investigated males showed mild-moderate bone marrow (BM) reticulin fibrosis. Comparative investigations were performed on blood samples and BM biopsies from males with XLTT, PMF patients and healthy controls. Like PMF, XLTT presented with high BM microvessel density, low GATA1 protein levels in megakaryocytes, and elevated blood CD34+ cell counts. But unlike PMF, the BM microvessel pericyte coverage was low in XLTT, and no collagen fibrosis was found. Further, as evaluated by immunohistochemistry, expressions of the growth factors VEGF, AGGF1, and CTGF were low in XLTT megakaryocytes and microvessels but high in PMF. Thus, although the reticulin fibrosis in XLTT might simulate PMF, opposing stromal and megakaryocyte features may facilitate differential diagnosis. Additional comparisons between these disorders may increase the understanding of mechanisms behind BM fibrosis in relation to pathological megakaryopoiesis.
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