Design, Methods, and Participation in Riksmaten Young Children-A Swedish National Dietary Survey.

Background: National dietary surveys provide essential data for risk benefit assessments of foods and nutrients, for management and policy development. Physical activity measurement and biomonitoring can provide important complementary data but are less commonly included. Objectives: This study aimed to describe the study design and methods of the cross-sectional Swedish national dietary survey Riksmaten Young Children (Riksmaten småbarn), of children aged 9 mo, 18 mo, and 4 y. Participation/dropout rates for the 2 older age groups are also presented. The impact of different recruitment strategies is discussed. Methods: Children (N = 16,655) were randomly selected from the population register; invitations to guardians were sent by post and where possible, followed up by telephone. Food intake was assessed by a 2-d food diary and/or questionnaire. Height and weight were reported after measurement. Physical activity (accelerometery, 7 d) and stool, blood, and urine samples were assessed in subgroups. Results: Food consumption data were collected in 1828 children (11% of the invited; 18 mo: n = 1078, and 4 y: n = 750). Of participants also in subgroups, 71% provided physical activity data (n = 1307), 60% stool samples (n = 630), and 51% blood and/or urine samples (n = 593). The study population represented all geographic regions and types of municipalities in Sweden, but participating households had both higher education level and higher income than the target population. Only minor differences were seen in participation rates between recruitment via post and telephone compared with those through post only (12% compared with 10%). Repeated contact attempts were needed for the majority of participants (65%). Despite the low-participation rate, 99% of the participants completed the study once started. Conclusions: Although it was a challenge to recruit participants, Riksmaten Young Children provides a substantial amount of information at national level, representative in terms of sex, geography, and family structure. The underrepresentation of households with lower socioeconomic position must be considered when generalizing results.

Cadmium, total mercury, and lead in blood and associations with diet, sociodemographic factors, and smoking in Swedish adolescents.

BACKGROUND: Despite their vulnerability to the toxic effects of certain metals, biomonitoring data on adolescents are limited. In the present study, we assessed blood concentrations of toxic metals (cadmium [Cd], total mercury [Hg], and lead [Pb] in a national representative sample of Swedish adolescents. We also examined the associations of Cd, total Hg and Pb with habitual intakes of major energy-providing food groups and other possible determinants such as age, sex, household education, Nordic or non-Nordic origin, and smoking. METHODS: We analysed blood concentrations of Cd, total Hg, and Pb in a sample of 1099 adolescents from the Riksmaten Adolescents 2016-17 study in three age groups (mean age of 12, 15, and 18 years) using inductively coupled plasma mass spectrometry. The participants completed web-based questionnaires on food consumption frequency, sociodemographic factors and health status. Dietary data from two web-based 24-h dietary recalls were used to estimate the habitual intake of 10 major food groups. RESULTS: Almost all participants had detectable concentrations of Cd, total Hg, and Pb in whole blood. The median blood concentrations were 0.12 µg/L for Cd, 0.72 µg/L for total Hg, and 7.1 µg/L for Pb. Higher blood concentrations of Cd were observed in girls than in boys, whereas concentrations of total Hg and Pb were higher in boys. We observed an inverse association between Cd and meat intake. Total Hg concentrations were positively associated with intakes of fish, eggs, meat, and vegetables, and Pb concentrations were inversely associated with intakes of dairy products. Furthermore, smokers had higher concentrations of Cd and Pb. CONCLUSIONS: We found that fish was a potentially important source of exposure to total Hg in Swedish adolescents. No other food group was identified to have a strong impact on the blood levels of Cd, total Hg and Pb. Thirteen per cent of the adolescents had blood Pb concentrations above 12 µg/L, the reference point used in the risk assessment of Pb by the European Food Safety Authority (EFSA).

Pharmacokinetics of Total and Unbound Paclitaxel After Administration of Paclitaxel Micellar or Nab-Paclitaxel: An Open, Randomized, Cross-Over, Explorative Study in Breast Cancer Patients.

INTRODUCTION: Paclitaxel micellar is a novel formulation of paclitaxel in which retinoic acid derivates solubilize paclitaxel. The aim of the present study was to compare the unbound and total plasma pharmacokinetics of the new formulation with those of nanoparticle albumin-bound (nab)-paclitaxel and to further assess its safety. METHODS: In this open, randomized, cross-over study, 28 female patients with breast cancer were given paclitaxel micellar and nab-paclitaxel as a 1-h intravenous infusion at a dose of 260 mg/m2. Plasma samples were collected during 10 h, which were projected to cover at least 80% of the area to infinite time, AUCinf. Unbound paclitaxel was measured in ultrafiltrate of plasma. Total paclitaxel in plasma was measured after protein precipitation with acetonitrile. Both assays used ultra-performance liquid chromatography (UPLC) followed by MS/MS for drug quantification. The unbound fraction, fu, was calculated as the ratio between the unbound and the total concentration. RESULTS: No difference in fu of paclitaxel between the two formulations was observed. Statistical comparison of AUC0-10h and Cmax of unbound paclitaxel demonstrated that the two formulations met the criteria for bioequivalence. Regarding total paclitaxel levels, Cmax but not AUC0-10h met the criteria. This study supports a safe administration of paclitaxel micellar. CONCLUSION: The two formulations, paclitaxel micellar and nab-paclitaxel, behaved similarly following infusion. Probably, both formulations dissociate immediately in the blood, whereupon released paclitaxel rapidly distributes into tissue. Judged from the bioequivalence demonstrated for unbound paclitaxel, the two formulations are considered clinically equivalent. TRIAL REGISTRATION: EudraCT no.: 2010-019838-27. FUNDING: Oasmia Pharmaceutical AB.

Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours: A Dose-Escalation Study.

INTRODUCTION: A water-soluble Cremophor EL-free formulation of paclitaxel, in which retinoic acid derivates solubilize paclitaxel by forming micelles (paclitaxel micellar), was studied for the first time in man to establish the maximum tolerated dose (MTD) and to characterize the pharmacokinetics (PK). METHODS: This was an open-label, one-arm, dose-escalating study in patients with advanced solid malignant tumours, for which no standard therapy was available or had failed. Paclitaxel micellar was given as 1-h intravenous infusion every 21 days for 3 cycles, mainly without premedication. Plasma samples were collected during 24 h at the first cycle and paclitaxel concentrations were assayed by high-performance liquid chromatography. PK was evaluated using a two-compartment model. RESULTS: Thirty-four patients received paclitaxel micellar at doses ranging between 90 and 275 mg/m2. MTD was established as 250 mg/m2. Fatigue and neuropathy were the most frequent dose-limiting toxicities. No hypersensitivity reactions were observed. PK of paclitaxel was evaluated in 25 data sets. Paclitaxel micellar had a rapid initial distribution phase, mean half-life 0.55 h, estimated to be completed 3 h after dosing and a mean terminal half-life of 8.8 h. Mean clearance was 13.4 L/h/m2 with fivefold interindividual variability. The residual areas after 10 h and 24 h were 15.7 ± 8.6% and 5.7 ± 3.9% of the area under the plasma concentration-time curve to infinite time (AUCinf), respectively. CONCLUSION: No new side effects unknown for paclitaxel were observed. Maximum plasma concentration (Cmax) and AUCinf showed a tendency to increase linearly with dose within the 150-275 mg/m2 dose range. The possibility to administer paclitaxel micellar without steroid premedication makes it an attractive candidate for further studies in combination with immunotherapy. TRIAL REGISTRATION: EudraCT no: 2004-001821-54. FUNDING: Oasmia Pharmaceutical AB.

Fatty acid composition in serum cholesterol esters and phospholipids is linked to visceral and subcutaneous adipose tissue content in elderly individuals: a cross-sectional study.

BACKGROUND: Visceral adipose tissue (VAT) and truncal fat predict cardiometabolic disease. Intervention trials suggest that saturated fatty acids (SFA), e.g. palmitic acid, promote abdominal and liver fat storage whereas polyunsaturated fatty acids (PUFA), e.g. linoleic acid, prevent fat accumulation. Such findings require investigation in population-based studies of older individuals. We aimed to investigate the relationships of serum biomarkers of PUFA intake as well as serum levels of palmitic acid, with abdominal and total adipose tissue content. METHODS: In a population-based sample of 287 elderly subjects in the PIVUS cohort, we assessed fatty acid composition in serum cholesterol esters (CE) and phospholipids (PL) by gas chromatography and the amount of VAT and abdominal subcutaneous (SAT) adipose tissue by magnetic resonance imaging (MRI), liver fat by MR spectroscopy (MRS), and total body fat, trunk fat and leg fat by dual-energy X-ray absorptiometry (DXA). Insulin resistance was estimated by HOMA-IR. RESULTS: VAT and trunk fat showed the strongest correlation with insulin resistance (r = 0.49, P < 0.001). Linoleic acid in both CE and PL was inversely related to all body fat depots (r = -0.24 to -0.33, P < 0.001) including liver fat measured in a sub-group (r = -0.26, P < 0.05, n = 73), whereas n-3 PUFA showed weak inverse (18:3n-3) or positive (20:5n-3) associations. Palmitic acid in CE, but not in PL, was directly correlated with VAT (r = 0.19, P < 0.001) and trunk fat (r = 0.18, P = 0.003). Overall, the significant associations remained after adjusting for energy intake, height, alcohol, sex, smoking, education and physical activity. The inverse correlation between linoleic acid and VAT remained significant after further adjustment for total body fat. CONCLUSIONS: Serum linoleic acid is inversely related to body fat storage including VAT and trunk fat whereas palmitic acid was less consistently but directly associated, in line with recent feeding studies. Considering the close link between VAT and insulin resistance, a potential preventive role of plant-based PUFA in VAT accumulation warrants further study.

Serum levels of brominated flame retardants (BFRs: PBDE, HBCD) and influence of dietary factors in a population-based study on Swedish adults.

The aim of this study was to investigate associations between serum concentrations of brominated flame retardants and personal characteristics, including diet, in adults participating in a population-based study in Sweden 2010-11. Moreover, observed concentrations were used in a health risk assessment, using published health-based reference values. Serum samples of 170 adult individuals of both sexes were analyzed for 10 PBDE congeners and HBCD by GC-MS. When including concentrations between LOD and LOQ, highest median serum concentration was observed for BDE-153 (1.2 ng/g serum lipid), followed by BDE-209 (0.95 ng/g lipid), BDE-47 (0.49 ng/g lipid) and BDE-100 (0.21 ng/g lipid). Median concentration of HBCD was 0.10 ng/g lipid. A few markedly elevated concentrations of BDE-209, HBCD (77-78 ng/g lipid) and BDE-47 (44 ng/g lipid) were observed. The only statistical significant findings were higher BDE-153 concentrations in men than in women, and positive associations between serum BDE-153 concentrations and consumption of fish (total), beef, mutton and poultry. PBDE concentrations were in accordance with concentrations reported in other European countries but generally lower than those found in North America. Median PBDE serum concentrations observed in adults from Sweden suggest sufficient health protection, when compared with published health-based reference values, although some outliers with high serum concentrations had lower safety margins.

The educational gradient of obesity increases among Swedish pregnant women: a register-based study.

BACKGROUND: Overweight or obesity is detrimental during pregnancy. We studied time trends in the educational gradient of overweight and obesity among pregnant women. Differences in overweight and obesity by area of residence and country of birth were also examined. METHODS: The study was based on the Swedish Medical Birth Register between 1992 and 2010 and included 1,569,173 singleton pregnancies. Weight and height were registered during the first visit at the antenatal-care clinic. Data on education, country of birth, and area of residence were derived from registers with national coverage. RESULTS: In 2008-2010, 32% of Swedish nulliparous pregnant women were overweight or obese. The relative risk of obesity among lower educated women compared to women with higher education increased from 1.91 (95% confidence interval: 1.85-1.97) in 1992-1995 to 2.09 (95% confidence interval: 2.05-2.14) in 2008-2010. There was an inverse linear relationship between risks of overweight or obesity, and population density and type of residence municipality. An excessive gestational weight gain according to the American Institute of Medicine was observed among 57-63% of the overweight or obese women, but there were small differences by education. Pregnant women born in Africa, Middle East or Latin America had higher risks of being overweight or obese compared to women born in Sweden. CONCLUSIONS: The prevalence of obesity as well as the social inequalities in obesity during pregnancy increased in Sweden between 1992 and 2010. Further understanding of social inequalities and geographical differentials in health behaviours of pregnant women is needed when planning public health interventions.

Serum concentrations of perfluorinated alkyl acids and their associations with diet and personal characteristics among Swedish adults.

SCOPE: In this study, food is suggested as a major source of human exposure to perfluorinated alkyl acids (PFAA). We investigated relations between serum levels of PFAA in adults and diet/lifestyle factors nationwide in Sweden. METHODS AND RESULTS: In 2010-2011, adults (18-80 years, N = 270) recorded their diet for 4 days and answered a food frequency questionnaire. PFAA were measured in blood serum as well as v-3 fatty acids in plasma phospholipids as a biomarker for fish consumption. Higher levels of PFAA were associated with male sex, increased age, and higher education. Women reporting full breastfeeding for ≥12 months had 32-44% lower levels of perfluorooctane sulfonate, perfluorooctanoic acid, and perfluorohexane sulfonate than women who never nursed their infants full-time. Serum perfluorooctane sulfonate, perfluorononanoic acid, perfluorodecanoic acid, and perfluoroundecanoic acid were positively related to n-3 fatty acids in plasma (partial r = 0.19-0.34, p ≤ 0.05). CONCLUSION: The relatively strong correlations between biomarkers of fish consumption and certain PFAA suggest that PFAA exposure should be taken into account in health risk and benefit assessment of fish consumption. Breastfeeding appears to be a major source of elimination of certain PFAA among women, and consequently PFAA exposure of nursed infants could be significant.

Lead, mercury, and cadmium in blood and their relation to diet among Swedish adults.

The aim of the present study was to examine the body burden of lead (Pb), mercury (Hg), and cadmium (Cd) in blood among Swedish adults and the association between blood levels, diet and other lifestyle factors. The study was based on a subgroup (n=273) of the national survey Riksmaten 2010-2011 (4-day food records and questionnaire). Lead, Hg, and Cd were measured in whole blood, and Cd additionally in urine, by mass or fluorescence spectrometry methods. The median values (5-95th percentiles) of the metals in blood were as follows; Pb: 13.4 (5.8-28.6) µg/L, Hg: 1.13 (0.31-3.45) µg/L, and Cd: 0.19 (0.09-1.08) µg/L. All three metals increased with increasing age. Lead levels in blood were positively associated with intakes of game and alcohol, Hg was related to fish intake, and blood Cd related to smoking and low iron stores and to a low meat intake. Body burdens of the studied metals were generally below health based reference values, but several individuals had blood Pb levels above the reference point for possible nephrotoxic and developmental neurotoxic effects. As health effects cannot be excluded, individuals with high Pb exposure should aim at decreasing their body burden, both from food and from other exposure routes.

Fish intake and breastfeeding time are associated with serum concentrations of organochlorines in a Swedish population.

Persistent organic pollutants (POPs) exert harmful effects on cognitive, endocrine and immune functions and bioaccumulate in the environment and human tissues. The aim of this study was to investigate the body burden of several POPs in the adult population (n=246) and their association to diet and other lifestyle factors in a Swedish national survey. Serum concentrations of several polychlorinated biphenyls (PCBs), and the pesticides hexachlorobenzene (HCB), ß-hexachlorocyclohexane (ß-HCH), chlordane compounds and dichlorodiphenyldichloroethylene (DDE) were determined by liquid-liquid extraction, silica column cleanup and gas chromatography high resolution mass spectrometry. Diet was assessed using 4-day food records and complementary dietary and lifestyle factors by questionnaire. Fish intake was additionally assessed by plasma fatty acid composition. Clustering of the compounds revealed that PCBs were separated into two clusters, one including low-chlorinated PCB 28 and 52, and the other high-chlorinated mono- and di-ortho PCBs, suggesting similarities and dissimilarities in exposure sources and possibly also toxicokinetics. Men had 24% and 32% higher levels of PCB 138-180 and chlordane compounds, respectively, compared with women. This may partly be explained by elimination of the POPs among women reporting a history of breastfeeding. The proportion of very long-chain n-3 fatty acids in plasma were positively correlated with the pollutants: r=0.24 (PCB 28), r=0.33 (PCB 118), r=0.35 (PCB 138-180), r=0.29 (HCB), r=0.18 (ß-HCH), r=0.34 (chlordane compounds), r=0.34 (p,p'-DDE), p≤0.005. Individuals consuming fatty Baltic fish≥1 time per months had 45% higher serum levels of PCB 118 compared with non-consumers. Levels of PCB 28 were associated with the age of the residential building. To conclude, the population-distributed approach of surveying dietary habits, lifestyle factors and POP body burdens, made it possible to identify personal characteristics associated with the POP body burdens in Sweden.

Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial.

BACKGROUND: Replacing SFAs with vegetable PUFAs has cardiometabolic benefits, but the effects on liver fat are unknown. Increased dietary n-6 PUFAs have, however, also been proposed to promote inflammation-a yet unproven theory. OBJECTIVE: We investigated the effects of PUFAs on liver fat, systemic inflammation, and metabolic disorders. DESIGN: We randomly assigned 67 abdominally obese subjects (15% had type 2 diabetes) to a 10-wk isocaloric diet high in vegetable n-6 PUFA (PUFA diet) or SFA mainly from butter (SFA diet), without altering the macronutrient intake. Liver fat was assessed by MRI and magnetic resonance proton (1H) spectroscopy (MRS). Proprotein convertase subtilisin/kexin type-9 (PCSK9, a hepatic LDL-receptor regulator), inflammation, and adipose tissue expression of inflammatory and lipogenic genes were determined. RESULTS: A total of 61 subjects completed the study. Body weight modestly increased but was not different between groups. Liver fat was lower during the PUFA diet than during the SFA diet [between-group difference in relative change from baseline; 16% (MRI; P < 0.001), 34% (MRS; P = 0.02)]. PCSK9 (P = 0.001), TNF receptor-2 (P < 0.01), and IL-1 receptor antagonist (P = 0.02) concentrations were lower during the PUFA diet, whereas insulin (P = 0.06) tended to be higher during the SFA diet. In compliant subjects (defined as change in serum linoleic acid), insulin, total/HDL-cholesterol ratio, LDL cholesterol, and triglycerides were lower during the PUFA diet than during the SFA diet (P < 0.05). Adipose tissue gene expression was unchanged. CONCLUSIONS: Compared with SFA intake, n-6 PUFAs reduce liver fat and modestly improve metabolic status, without weight loss. A high n-6 PUFA intake does not cause any signs of inflammation or oxidative stress. Downregulation of PCSK9 could be a novel mechanism behind the cholesterol-lowering effects of PUFAs. This trial was registered at clinicaltrials.gov as NCT01038102.

Role of hepatic desaturases in obesity-related metabolic disorders.

PURPOSE OF REVIEW: This review aims to address the latest research on hepatic desaturases and metabolic disorders, with focus on stearoyl-CoA desaturase-1 (SCD-1) indices in observational studies. RECENT FINDINGS: In animal studies, SCD-1 inhibition protects against features of the metabolic syndrome and is associated with improved hepatic insulin resistance and decreased steatosis. In human observational studies, higher estimated hepatic SCD-1 and Δ6-desaturase activities predict the metabolic syndrome, insulin resistance and mortality whereas Δ5-desaturase index is often inversely related. However, because the desaturase activities in the liver and adipose tissue may not be regulated in parallel, it is important to define used lipid fractions when comparing studies. It is also important to take the background diets of the populations into account when comparing studies. Moreover, there may be a divergence in desaturase regulation depending on glycaemic control among individuals. SUMMARY: Increased SCD-1 indices reflecting liver desaturase activity have been associated with insulin resistance, fatty liver, the metabolic syndrome and mortality. However, it remains to be determined if high hepatic SCD-1 activity plays a direct role in the development of metabolic disorders or rather is a marker for an unfavourable diet or hepatic insulin resistance.