Hypothesis: vitamin E complements polyunsaturated fatty acids in essential fatty acid deficiency in cystic fibrosis

While several studies have demonstrated essential fatty acid (EFA) deficiency in plasma and tissue lipids of cystic fibrosis (CF) patients, the reasons for this deficiency are not well established. It is believed that reduced EFA intake, malabsorption of fat, altered desaturase/lipase activity and defective cystic fibrosis transmembrane conductance regulator (CFTR) altering utilisation of EFA in epithelial cells contribute to the development of EFA deficiency in CF. It is likely that increased metabolism of arachidonic acid to eicosanoids such as leukotrienes, thromboxane and prostaglandins may also be a contributing factor. Evidence is presented that elevated oxidative damage to EFA and impaired antioxidant defences, in particular vitamin E, may contribute to the development of EFA deficiency in CF. Furthermore, antioxidant supplementation in CF may improve EFA status.     

Serum phospholipid fatty acid profile and dietary intake in an adult Mediterranean population with cystic fibrosis

The relative importance of the usual diet in serum phospholipids in subjects with cystic fibrosis (CF) has been poorly studied. To compare the fatty acid profile in serum phospholipids from adult CF subjects with that of healthy subjects, and determine the role of the normal diet in this profile, we studied thirty-seven adult CF subjects with stable pulmonary disease and thirty-seven healthy controls matched for age, sex and nutritional status. A dietary questionnaire was obtained, anthropometric data were recorded, and the fatty acid profile measured by GLC. Compared with the controls, the percentages of myristic, palmitoleic and stearic acids and total MUFA were significantly higher in the CF group, and DHA, linoleic acid, total PUFA and n-6 fatty acids were significantly lower in the CF group. The CF subjects with worse pulmonary function and with pancreatic insufficiency had significantly lower levels of linoleic and n-6 fatty acids. The total energy intake was significantly higher in the CF subjects, although the energy distribution in the CF subjects and the controls was not different for the carbohydrates, lipids and proteins. No differences were detected in fat intake for MUFA (51 (SD 4) v. 52 (SD 4) %) or saturated fatty acids (33.5 (SD 5) v. 31.2 (SD 3.8) %), but the PUFA were slightly lower in the CF subjects (15.4 (SD 4.5) v. 17.4 (SD 4.2) %; P=0.02). The usual dietary intake of fatty acids by adult CF subjects does not appear to explain the difference in the fatty acid profile compared with controls. This suggests an abnormal fatty acid metabolism in CF subjects.     

Neutrophil unsaturated fatty acid release by GM-CSF is impaired in cystic fibrosis

Dysregulated inflammation in cystic fibrosis (CF) is attributed to an altered production of inflammatory mediators derived from polyunsaturated lipids. In comparison to the arachidonic acid (AA) cascade, little is known about the modulation of docosahexaenoic acid (DHA) membrane release. We compared data on neutrophil DHA- and AA- release from both control (CT) and patients with CF using [³H]AA or [¹⁴C]DHA as a markers for, respectively, AA and DHA- release. Granulocyte-macrophage-colony stimulating factor stimulated DHA release from CT, but not CF, neutrophils. Comparison showed that both [¹⁴C]DHA and [³H]AA liberated after stimulation was higher in CT than in CF neutrophils. Since bioactive mediators derived from DHA are resolving factors and those derived from AA are both pro- and anti- inflammatory, these results suggest that CF is associated with a reduction of the release of PUFA-precursors of lipooxygenated resolving mediators. This leads to the hypothesis that defects in the resolving factors production could contribute to the inflammatory dysregulated processes in CF. Furthermore, the methodology used may help to improve knowledge on the regulation and resolution of inflammation.     

Essential fatty acid status and fluidity of plasma phospholipids in cystic fibrosis infants

The fatty acid (FA) patterns of cord serum phospholipids (PLs) were examined in 4 cystic fibrosis (CF) newborns, 8 non-CF siblings, and 22 normal control subjects. Plasma from 27 newly diagnosed CF infants and 38 normal infants aged less than 2 y were studied for comparison. CF cord-blood PLs had patterns similar to those of CF siblings and to normal newborns, but the pattern for CF did not shift toward adult patterns during infancy as did patterns for normal infants. CF infants at diagnosis exhibited a deficiency pattern in which 18: 2 omega 6, 20:4 omega 6, 22:4 omega 6, an omega 3 polyunsaturated fatty acids (PUFAs) were significantly subnormal and 18:3 omega 6, total saturated fatty acids, and total monounsaturated fatty acids were significantly elevated compared with normal infants. In PLs in CF infants, although mean chain length of FAs was low, mean melting point was elevated 2.4 degrees C and double-bond index was low (both P less than 0.001), implying a significantly lessened fluidity. Nutritional supplements of both omega 6 and omega 3 PUFAs are cated.     

The essential fatty acid deficient chicken as a model for cystic fibrosis

The essential fatty acid deficient (EFAD) chicken was evaluated as a model for cystic fibrosis (CF). Three semipurified diets--(I) 1% hydrogenated coconut oil (HCO), (II) 10% soybean oil + 1% HCO, and (III) 11% HCO--were fed to chickens from hatching to 5, 8, or 11 wk. Groups I and III exhibited poor weight gain and abnormal serum fatty acid patterns characteristic of EFAD. Production of prostaglandin F2 alpha, thromboxane B2, 6-keto-prostaglandin F1 alpha, and prostaglandin E in lung was significantly reduced at 5, 8, and 11 wk in both EFAD groups. Histopathologic examination revealed increased peribronchiolitis in group I compared with II. Incidence of pulmonary lesions in group III was intermediate. These data support the theory that essential fatty acids are necessary to maintain proper lung function. In this respect, the chicken is a good model for studying the relationship between EFAD and pulmonary disease in CF patients.     

Paradoxical effects of essential fatty acid supplementation on lipid profiles and sweat electrolytes in cystic fibrosis

Supplements of evening primrose oil (Oenothera biennis), which contains at least 72% linoleic (18:2n-6) and 7% gamma-linolenic (18:3 n-6) acids (expressed as % fatty acid methyl esters) were given to sixteen cystic fibrosis patients for a period of 12 months. Clinical observations showed no significant changes in patients' weights or respiratory function throughout. Linoleic acid levels in plasma and erythrocyte membranes increased significantly during the first 6 months but this increase was not sustained at its initial level. After supplementation was discontinued reversion to baseline (low) levels occurred within 4 months. Levels of plasma prostaglandins (PG) and urinary PG metabolites varied among individuals over a wide range, and urinary PGF2 alpha metabolites fell during the supplementation. There was a significant fall in sweat sodium concentrations after 6 weeks of supplementation, but sweat chloride was unchanged. It is not known whether the effect of essential fatty acids on sweat Na+ reflects changes in cell membrane conformation or if there is a direct effect on Na+ pump activity.     

Prenatal screening for cystic fibrosis: an economic analysis

Cystic fibrosis (CF) is the most common life-shortening genetically transmitted disease in Denmark with a birth prevalence of 1 in 4700, resulting in 12-15 new cases of cystic fibroses annually.The aim of this study is to disclose the societal resource implications of introducing a population wide prenatal screening programme for cystic fibrosis in Denmark. The present analysis is limited to the monetary consequences of introducing a screening programme, where costs of screening are compared to the potential benefits measured in cost savings involved if births of CF patients are avoided.Screening costs in a Danish setting were estimated at DKK 2 771 262 ( pound sterlings 231 438) per aborted affected fetus in the first screening round, stabilising at DKK 1 864 594 ( pound sterlings 155 383) per aborted affected fetus at subsequent screening rounds. Comparing this figure with the estimated benefits of avoiding a CF case (DKK 2.1-4.4 million; pound sterlings 175 000-366 667) suggests that introducing a screening programme for cystic fibrosis will be net cost saving irrespective of the perspective of the analysis, assumptions on replacement children and method of estimating long-term production gains/losses.     

Increased plasma fatty acid concentrations after respiratory exacerbations are associated with elevated oxidative stress in cystic fibrosis patients

BACKGROUND: Oxidative stress and depleted antioxidant defenses occur in stable cystic fibrosis patients. During acute infection, the balance between oxidants and antioxidants may be further disturbed. OBJECTIVE: We examined the oxidative stress during acute infection in cystic fibrosis patients by measuring 8-iso-prostaglandin F(2 alpha) (8-iso-PGF(2 alpha)) and antioxidant defenses in relation to dietary intake, fatty acid status, immune function, and clinical status. DESIGN: Plasma concentrations of total 8-iso-PGF(2 alpha), vitamins E and C, beta-carotene, zinc, selenium, and copper; plasma fatty acid compositions; erythrocyte glutathione concentrations; glutathione peroxidase and superoxide dismutase activity; sputum glutathione and 8-iso-PGF(2 alpha) concentrations; lung function; clinical symptoms; and dietary intake were measured in 15 cystic fibrosis patients before and after 10-14 d of intravenous antibiotic treatment for a pulmonary exacerbation. RESULTS: After treatment, respiratory status improved (percentage of forced expiratory volume in 1 s: 60 +/- 6% at baseline compared with 74 +/- 7% after treatment, P = 0.01), quality of well-being improved (P = 0.001), and total plasma 8-iso-PGF(2 alpha) concentrations increased from 469 nmol/L at baseline (interquartile range: 373-554 nmol/L) to 565 nmol/L after treatment (interquartile range: 429-689 nmol/L; P = 0.008). Total energy, fat, carbohydrate, and protein intakes per kilogram body weight also increased; however, dietary antioxidant intake was unchanged. Plasma fatty acid concentrations increased after treatment, strongly correlating with plasma 8-iso-PGF(2 alpha) concentrations (r = 0.768, P = 0.001). There were no significant changes in white cell counts or plasma concentrations of vitamins E and C or beta-carotene. Erythrocyte glutathione peroxidase activity was reduced after treatment, whereas there was no significant change in superoxide dismutase activity. CONCLUSIONS: Oxidative stress increased after treatment for pulmonary exacerbations and was strongly linked to increased concentrations of plasma fatty acids. Although intravenous antibiotic therapy and physiotherapy improved lung function within 10-14 d of treatment, the biochemical effects of oxidation continued further. Thus, antioxidant intervention during treatment for and recovery from acute infection in cystic fibrosis should be considered.     

Scaling up health promotion interventions: an emerging concept in implementation science

As the chronic disease burden grows, government is increasingly investing in prevention. However, policy makers frequently report a scarcity of effective programs suitable for population‐level implementation. Policy makers also seek information to aid decisions about whether programs found to be effective in small‐scale studies can be implemented at the population level. To date, investigation of optimal ways to expand programs has not received adequate attention, and there is an urgent need for studies assessing mechanisms by which widespread intervention adoption and reach can be achieved.     

Nutritional status of an adult cystic fibrosis population

Nutritional management and dietary recommendations in patients with cystic fibrosis (CF) have changed considerably over the past 10-15 y. The nutritional status of adult CF patients was assessed in a clinical survey before these changes in nutritional management. The aim of the study was to assess the current nutritional status of the CF population and compare the results with those of the previous study. Forty-three (24 male, 19 female) subjects participated in this study. Subjects' height, weight, mid-upper-arm circumference, and skinfolds at four sites were measured. Nutritional intake was measured by using a 7-d food intake diary including documentation of supplements taken. Compared with the 1983 study, the incidence of malnutrition, as indicated by a body mass index of less than 20, has decreased from 62% to 9%. Furthermore, there have been significant improvements in the weight, height, and body mass index of both males (P < 0.001) and females (P < 0.04). Individuals with CF are no longer subject to growth arrest, as their mean height is now comparable to the Australian average. Mid-upper-arm circumference (P < 0.0001), triceps skinfold (P < 0.0001), and percentage of body fat (P < 0.05) of males and females have also significantly increased. The fat intake (P < 0.02) of females and males and energy intake (P < 0.03) of females have increased significantly, and the mean energy intake of subjects has exceeded the recommended 120% of the recommended daily intake. A significant number of patients in the present study receive dietary oral and/or enteral supplements. Multiple linear regression analysis indicated that nutritional management was principally responsible for improvements in nutritional status. The findings suggest that there has been a significant improvement in the nutritional status of the adult CF population, which may be due primarily to changes in nutritional management.     

The deltaF508 mutation in the cystic fibrosis transmembrane conductance regulator alters control of essential fatty acid utilization in epithelial cells

Essential fatty acid (EFA) incorporation into phospholipid is influenced by chloride channels, suggesting that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) may regulate aspects of EFA metabolism. The objective of this study was to determine whether the DeltaF508 mutation in the CFTR lowers 18:2(n-6) levels in phospholipid. Control cells, CF cells and CF cells transfected with the "normal" CFTR gene or the DeltaF508 CFTR gene were cultured for 3-5 d and used to determine [1-(14)C]18:2(n-6) incorporation into cell lipids. CF cells exhibited low 18:2(n-6) levels in phospholipid, reduced [1-(14)C]18:2(n-6) incorporation into phospholipid (50% of control) and greater [1-(14)C]18:2(n-6) incorporation into the triacylglycerol fraction (400% of control; P: < 0.05). Kinetic modeling of time course data for [1-(14)C]18:2(n-6) incorporation revealed a loss of metabolic control over the intracellular partitioning of 18:2(n-6) between phospholipid and triacylglycerol pools in CF cells. Expression of the normal CFTR gene in transfected CF cells increased chloride efflux and the incorporation of [1-(14)C]18:2(n-6) into phospholipid and triacylglycerol fractions. The increased incorporation of [1-(14)C]18:2(n-6) into phospholipid was attributed to significantly increased incorporation of [1-(14)C]18:2(n-6) into phosphatidylcholine and phosphatidylinositol. In CF cells expressing the defective DeltaF508 CFTR gene, conversion of [1-(14)C]18:2(n-6) to 20:4(n-6) by desaturation-chain elongation was 1.8-fold greater (P: < 0.05) than observed for CF cells transfected with the normal gene. The observations suggest that CF results in a defect in the utilization of 18:2(n-6), which is attributed in part to the defective CFTR.     

Dietary n-3 polyunsaturated fatty acids: modification of rat cardiac lipids and fatty acid composition

The effects of 5, 10 and 20% dietary menhaden oil (MO) on the composition of heart lipid classes and fatty acids were studied. Male Sprague-Dawley rats were fed ad libitum 0, 5, 10 and 20% MO for 3 wk. The heart phosphoglyceride content and composition and cholesterol were unchanged by dietary MO. A nonlinear dose-response relationship was observed between dietary MO levels and fatty acid compositional changes. Cardiolipin, choline (PC), ethanolamine (PE) and serine/inositol (PS/PI) phosphoglycerides showed an incorporation of n-3 fatty acids, eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3), between the control and 5% MO group, a plateau between the 5 and 10% MO groups and a further increase at the 20% MO level. The initial reduction in 20:4n-6 content remained unchanged as dietary MO increased except in PE where a further reduction was found at the 20% MO level. Dietary MO did not significantly change the 20:4n-6 content in neutral lipids. Linoleic acid content was most resistant to dietary MO removal. The level of 18:2n-6 was significantly lowered in heart PC when rats were fed 10% MO. No significant differences were found in PS/PI. In PE and NL significant differences occurred only when rats were fed 20% MO. The significant fatty acid modifications of heart lipid and PL found between the control and lowest level of dietary MO (5%) suggest that dietary fish oil supplementation in human diets may not be required for this effect.     

Improved antioxidant and fatty acid status of patients with cystic fibrosis after antioxidant supplementation is linked to improved lung function

BACKGROUND: Oxidative stress, as measured by 8-iso-prostaglandin F(2)(alpha) (8-iso-PGF(2)(alpha)), and depleted antioxidant defenses were shown in stable cystic fibrosis (CF) patients. The plasma fatty acid status of CF patients was linked to oxidative stress after respiratory exacerbations. OBJECTIVE: We examined changes in plasma 8-iso-PGF(2)(alpha), antioxidant defenses, plasma fatty acid status, and clinical markers resulting from short-term antioxidant supplementation. DESIGN: Forty-six CF patients were randomly assigned to either group A [low dose of supplement (10 mg vitamin E and 500 micro g vitamin A)] or group B [high dose of supplement (200 mg vitamin E, 300 mg vitamin C, 25 mg beta-carotene, 90 micro g Se, and 500 micro g vitamin A)]. Plasma concentrations of 8-iso-PGF(2)(alpha), vitamins E and C, beta-carotene, zinc, selenium, and copper; plasma fatty acid composition; erythrocyte glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities; lung function; and dietary intake were measured before and after 8 wk of supplementation. RESULTS: Antioxidant defenses in group B improved, whereas those in group A did not: in groups B and A, the mean (+/- SEM) changes (Delta) in vitamin E were 10.6 +/- 1.5 and -1.9 +/- 0.9 micro mol/L, respectively (P < 0.001), (Delta)beta-carotene were 0.1 +/- 0.04 and -0.01 +/- 0.02 micro mol/L, respectively (P = 0.007), (Delta)selenium were 0.51 +/- 0.10 and -0.09 +/- 0.04 micro mol/L, respectively (P < 0.001), and (Delta)glutathione peroxidase activity were 1.3 +/- 0.3 and -0.3 +/- 0.6 U/g hemoglobin, respectively (P = 0.016). There were no significant differences between the groups in Delta8-iso-PGF(2)(alpha), (Delta)vitamin C, (Delta)fatty acid composition, (Delta)superoxide dismutase activity, (Delta)lung function, or (Delta)white cell count. Within group B, (Delta)beta-carotene correlated with (Delta)percentage of forced vital capacity (r = 0.586, P = 0.005), (Delta)selenium correlated with (Delta)percentage of forced expiratory volume in 1 s (r = 0.440, P = 0.046), and (Delta)plasma fatty acid concentrations correlated with (Delta)percentage of forced expiratory volume in 1 s (r = 0.583, P = 0.006) and Delta8-iso-PGF(2)(alpha) (r = 0.538, P = 0.010). CONCLUSIONS: Whereas increased beta-carotene, selenium, and fatty acid concentrations are linked to improved lung function, increased plasma fatty acid concentrations are linked to oxidative stress. If oxidative stress is deemed to be important to the clinical outcome of CF patients, means of reducing oxidative stress while maintaining a high-fat, high-energy diet must be investigated.     

Serum phospholipid fatty acid pattern is associated with bone mineral density in children, but not adults, with cystic fibrosis

Essential fatty acids (EFA) have proved to be important for normal bone mineral density (BMD) and bone growth in animal studies. Patients with cystic fibrosis often have low serum EFA levels, and low BMD has also been reported in patients with normal anthropometry. The aim of the present study was to analyse if BMD during a 2-year period was related to fatty acid status in patients with cystic fibrosis. Fifty-four patients, aged 6-33 years, were studied prospectively. BMD was measured with dual X-ray absorptiometry, and fatty acid concentrations in serum phospholipids were determined with capillary GLC. The cystic fibrosis patients showed low linoleic acid concentration and a high arachidonic acid (AA):DHA ratio in serum. The high eicosatrienoic acid:AA ratio, an indicator of EFA deficiency, increased further over 2 years, as did the total concentration of saturated fatty acids. In the adults there were no significant changes in fatty acids during the study. In the children, positive correlations were found between palmitic acid and bone mineral content in the lumbar spine and femoral neck. The lumbar spine BMD Z score correlated negatively with the AA:DHA ratio. No correlation was seen in adults except for a positive correlation between EFA deficiency index and the areas of lumbar spine and femoral neck. The present results imply that fatty-acid status influenced BMD in cystic fibrosis children, but not in adults, indicating that fatty-acid status would be important for bone growth.     

Resilience beyond reductionism: ethical and social dimensions of an emerging concept in the neurosciences

Medicine, Health Care and Philosophy - Since a number of years, popular and scientific interest in resilience is rapidly increasing. More recently, also neuroscientific research in resilience and...     

Omega-3 fatty acid deficiency selectively up-regulates delta6-desaturase expression and activity indices in rat liver: prevention by normalization of omega-3 fatty acid status

This study investigated the effects of perinatal dietary omega-3 (n-3) fatty acid depletion and subsequent repletion on the expression of genes that regulate long-chain (LC) polyunsaturated fatty acid biosynthesis in rat liver and brain. It was hypothesized that chronic n-3 fatty acid deficiency would increase liver Fads1 and Fads2 messenger RNA (mRNA) expression/activity and that n-3 fatty acid repletion would normalize this response. Adult rats fed the n-3-free diet during perinatal development exhibited significantly lower erythrocyte, liver, and frontal cortex LCn-3 fatty acid composition and reciprocal elevations in LC omega-6 (n-6) fatty acid composition compared with controls (CONs) and repleted rats. Liver Fads2, but not Fads1, Elovl2, or Elovl5, mRNA expression was significantly greater in n-3-deficient (DEF) rats compared with CONs and was partially normalized in repleted rats. The liver 18:3n-6/18:2n-6 ratio, an index of delta6-desturase activity, was significantly greater in DEF rats compared with CON and repleted rats and was positively correlated with Fads2 mRNA expression among all rats. The liver 18:3n-6/18:2n-6 ratio, but not Fads2 mRNA expression, was also positively correlated with erythrocyte and frontal cortex LCn-6 fatty acid compositions. Neither Fads1 or Fads2 mRNA expression was altered in brain cortex of DEF rats. These results confirm previous findings that liver, but not brain, delta6-desaturase expression and activity indices are negatively regulated by dietary n-3 fatty acids.