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Objective: Acute alcohol exposure induces malformation and malfunction of placenta-yolk sac tissues in rodents, reducing the labyrinth zone in the placenta and altering the permeability and fluidity of the cell membrane. During normal mouse placentation the cells line up in an optimal way to form a hemotrichorial placenta where layers II and III are connected through gap junctions. These act as molecular sieves that limit the passage of large molecules. PlGF is a developmentally regulated protein that controls the passage of molecules in the vasculosyncytial membranes and media of large blood vessels in the placental villi. In addition to the chorioallontoic placenta, rodents also have another type of placenta that consists of Reichert's membrane within the trophoblast cell layer on the maternal side and the parietal endodermal cells on the embryonic site. This forms a separate materno-fetal transport system. We study here whether alcohol affects these two placental barriers, leading to placental malfunction that in turn diminishes the nutrient supply to the embryo. Study Design: CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals at 8.75 days post coitum (dpc). The placentas were collected on 9.5, 11.5 and 14.5 dpc and used for histopathological protein studies. Hemotrichorial cell layer structure interactions through connective tissue and gap junction were analyzed by electron microscopy. The permeability of the feto-maternal barrier was visualized with Evans Blue. Results: VEGF, a permeability inducer, was found to be up-regulated in the mouse placenta after acute alcohol exposure, and permeability was also affected by altered structures in the barriers that separate the feto-maternal blood circulation which destroyed the gap junctions in the hemotrichorial cell layer, reduced the thickness of Reichert's membrane and interfered with with Reichert's trophoblast/Reichert's parietal interaction. These defects together could have caused the permeability malfunction of the placenta-yolk sac tissues as visualized and quantified here by Evans Blue leakage. Conclusions: An altered PlGF/VEGF ratio together with barrier malformation may contribute to placental malfunction by altering the permeability of the feto-maternal barriers. Further studies are needed in order to show whether premature permeability is involved in the intrauterine growth restriction observed in human FAS embryos. [ABSTRACT FROM AUTHOR]

BACKGROUND: The genetic variance determining plasma lipid and lipoprotein concentrations may modify individual responsiveness to alterations in dietary fat and cholesterol content. OBJECTIVE: The aim was to examine the role of apolipoprotein (apo) B DNA polymorphisms in responsiveness of plasma lipids and lipoproteins to diet. DESIGN: A controlled dietary intervention study was conducted in 44 healthy, middle-aged subjects with a 3-mo baseline, a 1-mo fat-controlled, a 1-mo high-fat, and a 1-mo habitual diet period. We also conducted a meta-analysis of all published dietary trials, including our own. RESULTS: In our own dietary study, the apo B XbaI restriction-site polymorphism affected the responsiveness to diet of the plasma LDL-cholesterol concentration (P < 0.05, repeated-measures analysis of variance). Especially during the high-fat diet, homozygous absence of the XbaI restriction site (X(-)/X(-)) was associated with a greater increase in LDL cholesterol (44 +/- 5%) than was X(+)/X(+) (27 +/- 7%) or X(+)/X(-) (40 +/- 5%). The high-fat diet also induced a larger increase in plasma LDL cholesterol in subjects with the R(-)/R(-) genotype (homozygous absence of the EcoRI restriction site) (59 +/- 10%) than in those with the R(+)/R(-) (39 +/- 6%) or R(+)/R(+) (36 +/- 4%) genotype. The M(+)/M(+) genotype (homozygous presence of the MspI restriction site) was also more responsive (41 +/- 3% increase in LDL cholesterol) than the M(+)/M(-) genotype (27 +/- 10% increase). The meta-analysis supported the finding of the significant role of the EcoRI and MspI polymorphisms, but not that of the XbaI polymorphism. CONCLUSIONS: The present study indicated that the apo B EcoRI and MspI polymorphisms are associated with responsiveness to diet. Copyright © 2000 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Background/objectives: Digital health interventions are increasingly utilized as an adjunct to face-to-face counselling in the treatment of obesity. However, previous studies have shown inconsistent efficacy when digital interventions are used as stand-alone treatment. The purpose of this study was to investigate whether a mobile health behaviour change support system (mHBCSS) is effective in weight reduction and weight loss maintenance without additional counselling. Furthermore, changes in cardiometabolic risk factors were investigated., Methods: In this randomized controlled trial, a mHBCSS intervention was conducted for 200 volunteers with obesity (BMI 30-40 kg/m² and age 18-65 years). The study participants were randomly assigned into two groups: immediate access to mHBCSS intervention or wait-list control with access to mHBCSS after 6 months. Anthropometric and metabolic traits were also measured. The primary outcome was weight loss from the baseline to the 6-month visit., Results: Among 200 participants (88.5% women), mean BMI (SD) was 34.3 kg/m² (2.8) and age 46.5 years (9.5). The retention rate was 98.5% and 89.0% at the 6- and 12-month visits, respectively. At the 6-month visit, those with immediate access to mHBCSS had significantly greater weight loss (-2.5%, 95% CI -3.4 to -1.6, p < 0.001) compared with the wait-list control group (0.2%, 95% CI -0.4 to 0.9, p = 0.466; between groups p < 0.001). Weight loss was maintained until the 12-month time point in the mHBCSS group (-2.1%, 95% CI -3.3 to -0.9, p = 0.001). The usage of mHBCSS had no significant effect on metabolic traits., Conclusion: The mHBCSS as a stand-alone treatment of obesity results in weight reduction and weight loss maintenance with remarkable adherence rate. Further studies are needed to establish how to best implement the scalable and resource-efficient mHBCSS into the standard care of obesity to achieve optimal weight loss results., (© 2023. The Author(s).)

We aimed to study levels of natural antibodies in plasma, and their associations to clinical and fecal biomarkers, before and 6 months after Roux-en-Y gastric bypass (RYGB) surgery. Thirty individuals with obesity [16 type 2 diabetic, 14 non-diabetic (ND)] had RYGB surgery. Total plasma IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts, Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44), and phosphocholine were measured using chemiluminescence immunoassay. Associations between plasma and fecal antibodies as well as clinical markers were analyzed. RYGB surgery reduced blood pressure, and the glycemic state was improved. A higher level of diastolic blood pressure was associated with lower plasma antibodies to oxLDL after surgery. Also, lower level of glucose markers associated with lower level of plasma antibodies to bacterial virulence factors. Antibodies to oxLDL decreased after surgery, and positive association between active serum lipopolysaccharide and specific oxLDL antibodies was detected. Total IgG levels decreased after surgery, but only in ND individuals. Reduced level of total plasma IgG, improved state of hypertension and hyperglycemia and their associations with decreased levels of specific antibodies in plasma, suggest an improved state of systemic inflammation after RYGB surgery., (© 2023 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Background: The Roux-en-Y gastric bypass (RYGB) is a common bariatric surgery to treat obesity. Its metabolic consequences are favourable and long-term clinical corollaries beneficial. However, detailed assessments of various affected metabolic pathways and their mediating physiological factors are scarce., Methods: We performed a clinical study with 30 RYGB patients in preoperative and 6-month postoperative visits. NMR metabolomics was applied to profiling of systemic metabolism via 80 molecular traits, representing core cardiometabolic pathways. Glucose, glycated haemoglobin (HbA1c), insulin, and apolipoprotein B-48 were measured with standard assays. Logistic regression models of the surgery effect were used for each metabolic measure and assessed individually for multiple mediating physiological factors., Results: Changes in insulin concentrations reflected those of BMI with robust decreases due to the surgery. Six months after the surgery, triglycerides, remnant cholesterol, and apolipoprotein B-100 were decreased -24%, -18%, and -14%, respectively. Lactate and glycoprotein acetyls, a systemic inflammation biomarker, decreased -16% and -9%, respectively. The concentrations of branched-chain (BCAA; leucine, isoleucine, and valine) and aromatic (phenylalanine and tyrosine) amino acids decreased after the surgery between -17% for tyrosine and -23% for leucine. Except for the most prominent metabolic changes observed for the BCAAs, all changes were almost completely mediated by weight change and insulin. Glucose and type 2 diabetes had clearly weaker effects on the metabolic changes., Conclusions: The comprehensive metabolic analyses indicate that weight loss and improved insulin sensitivity during the 6 months after the RYGB surgery are the key physiological outcomes mediating the short-term advantageous metabolic effects of RYGB. The clinical study was registered at ClinicalTrials.gov as NCT01330251., (© 2024. The Author(s).)

Success in long-term weight management depends partly on psychological and behavioral aspects. Understanding the links between psychological factors and eating behavior tendencies is needed to develop more effective weight management methods. This population-based cross-sectional study examined whether eating self-efficacy (ESE) is associated with cognitive restraint (CR), uncontrolled eating (UE), emotional eating (EE), and binge eating (BE). The hypothesis was that individuals with low ESE have more unfavorable eating behavior tendencies than individuals with high ESE. Participants were classified as low ESE and high ESE by the Weight-Related Self-Efficacy questionnaire (WEL) median cut-off point. Eating behavior tendencies were assessed with Three Factor Eating Questionnaire R-18 and Binge Eating Scale, and additionally, by the number of difficulties in weight management. The difficulties were low CR, high UE, high EE, and moderate or severe BE. Five hundred and thirty-two volunteers with overweight and obesity were included in the study. Participants with low ESE had lower CR (p < 0.03) and higher UE, EE, and BE (p < 0.001) than participants with high ESE. Thirty-nine percent of men with low ESE had at least two difficulties in successful weight control while this percentage was only 8% in men with high ESE. In women, the corresponding figures were 56% and 10%. The risk of low ESE was increased by high UE [OR 5.37 (95% CI 1.99-14.51)], high EE [OR 6.05 (95% CI 2.07-17.66)], or moderate or severe BE [OR 12.31 (95% CI 1.52-99.84)] in men, and by low CR [OR 5.19 (95% CI 2.22-12.18)], high UE [OR 7.20 (95% CI 2.41-19.22)], or high EE [OR 23.66 (95% CI 4.79-116.77)] in women. Low ESE was associated with unfavorable eating behavior tendencies and multiple concomitant difficulties in successful weight loss promotion. These eating behavior tendencies should be considered when counseling patients with overweight and obesity., (© 2023. The Author(s).)

Obesity is associated with low-grade inflammation and increased systemic oxidative stress. Roux-en-Y gastric bypass (RYGB) surgery is known to ameliorate the obesity-induced metabolic dysfunctions. We aimed to study the levels of natural antibodies in feces, before and 6 months after RYGB surgery in obese individuals with and without type 2 diabetes (T2D). Sixteen individuals with T2D and 14 non-diabetic (ND) individuals were operated. Total IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts (MAA adducts), Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44) and phosphocholine (PCho) were measured using chemiluminescence immunoassay. Total fecal IgA was elevated, while total IgM and IgG were not affected by the surgery. Fecal natural IgM specific to oxLDL decreased significantly in both T2D and ND individuals, while fecal IgM to Rgp44 and PCho decreased significantly in T2D individuals. A decrease in IgG to MAA-LDL, Rgp44 and PCho was detected. RYGB surgery increases the levels of total fecal IgA and decreases fecal natural IgG and IgM antibodies specific to oxLDL. Natural antibodies and IgA are important in maintaining the normal gut homeostasis and first-line defense against microbes, and their production is markedly altered with RYGB surgery., (© 2022 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Background & Aims: Intake assessment in multicenter trials is challenging, yet important for accurate outcome evaluation. The present study aimed to characterize a multicenter randomized controlled trial with a healthy Nordic diet (HND) compared to a Control diet (CD) by plasma and urine metabolic profiles and to associate them with cardiometabolic markers., Methods: During 18-24 weeks of intervention, 200 participants with metabolic syndrome were advised at six centres to eat either HND (e.g. whole-grain products, berries, rapeseed oil, fish and low-fat dairy) or CD while being weight stable. Of these 166/159 completers delivered blood/urine samples. Metabolic profiles of fasting plasma and 24 h pooled urine were analysed to identify characteristic diet-related patterns. Principal components analysis (PCA) scores (i.e. PC1 and PC2 scores) were used to test their combined effect on blood glucose response (primary endpoint), serum lipoproteins, triglycerides, and inflammatory markers., Results: The profiles distinguished HND and CD with AUC of 0.96 ± 0.03 and 0.93 ± 0.02 for plasma and urine, respectively, with limited heterogeneity between centers, reflecting markers of key foods. Markers of fish, whole grain and polyunsaturated lipids characterized HND, while CD was reflected by lipids containing palmitoleic acid. The PC1 scores of plasma metabolites characterizing the intervention is associated with HDL (β = 0.05; 95% CI: 0.02, 0.08; P = 0.001) and triglycerides (β = -0.06; 95% CI: -0.09, -0.03; P < 0.001). PC2 scores were related with glucose metabolism (2 h Glucose, β = 0.1; 95% CI: 0.05, 0.15; P < 0.001), LDL (β = 0.06; 95% CI: 0.01, 0.1; P = 0.02) and triglycerides (β = 0.11; 95% CI: 0.06, 0.15; P < 0.001). For urine, the scores were related with LDL cholesterol., Conclusions: Plasma and urine metabolite profiles from SYSDIET reflected good compliance with dietary recommendations across the region. The scores of metabolites characterizing the diets associated with outcomes related with cardio-metabolic risk. Our analysis therefore offers a novel way to approach a per protocol analysis with a balanced compliance assessment in larger multicentre dietary trials. The study was registered at clinicaltrials.gov with NCT00992641., Competing Interests: Conflict of interest The authors declare they have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved., Experimental Approach: We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis., Key Results: Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation., Conclusion and Implications: PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

HDL particles can be structurally modified in atherosclerotic disorders associated with low HDL cholesterol level (HDL-C). We studied whether the lipidome of the main phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelin (SM) species of HDL2 and HDL3 subfractions is associated with premature coronary heart disease (CHD) or metabolic syndrome (MetS) in families where common low HDL-C predisposes to premature CHD. The lipidome was analyzed by LC-MS. Lysophosphatidylcholines were depleted of linoleic acid relative to more saturated and shorter-chained acids containing species in MetS compared with non-affected subjects: the ratio of palmitic to linoleic acid was elevated by more than 30%. A minor PC (16:0/16:1) was elevated (28-40%) in MetS. The contents of oleic acid containing PCs were elevated relative to linoleic acid containing PCs in MetS; the ratio of PC (16:0/18:1) to PC (16:0/18:2) was elevated by 11-16%. Certain PC and SM ratios, e.g., PC (18:0/20:3) to PC (16:0/18:2) and a minor SM 36:2 to an abundant SM 34:1, were higher (11-36%) in MetS and CHD. The fatty acid composition of certain LPCs and PCs displayed a characteristic pattern in MetS, enriched with palmitic, palmitoleic or oleic acids relative to linoleic acid. Certain PC and SM ratios related consistently to CHD and MetS.

Background: Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for obesity, which improves cardiovascular health and reduces the risk of premature mortality. However, some reports have suggested that RYGB may predispose patients to adverse health outcomes, such as inflammatory bowel disease (IBD) and colorectal cancer., Objectives: The present prospective study aimed to evaluate the impact of RYGB surgery on cardiovascular risk factors and gastrointestinal inflammation in individuals with and without type 2 diabetes (T2D)., Setting: University hospital setting in Finland., Methods: Blood and fecal samples were collected at baseline and 6 months after surgery from 30 individuals, of which 16 had T2D and 14 were nondiabetics. There were also single study visits for 6 healthy reference patients. Changes in cardiovascular risk factors, serum cholesterol, and triglycerides were investigated before and after surgery. Fecal samples were analyzed for calprotectin, anti-Saccharomyces cerevisiae immunoglobulin A antibodies (ASCA), active lipopolysaccharide (LPS) concentration, short-chain fatty acids (SCFAs), intestinal alkaline phosphatase activity, and methylglyoxal-hydro-imidazolone (MG-H1) protein adducts formation., Results: After RYGB, weight decreased on average -21.6% (-27.2 ± 7.8 kg), excess weight loss averaged 51%, and there were improvements in cardiovascular risk factors. Fecal calprotectin levels (P < .001), active LPS concentration (P < .002), ASCA (P < .02), and MG-H1 (P < .02) values increased significantly, whereas fecal SCFAs, especially acetate (P < .002) and butyrate (P < .03) levels, were significantly lowered., Conclusion: The intestinal homeostasis is altered after RYGB, with several fecal markers suggesting increased inflammation; however, clinical significance of the detected changes is currently uncertain. As chronic inflammation may predispose patients to adverse health effects, our findings may have relevance for the suggested association between RYGB and increased risks of incident IBD and colorectal cancer., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Gaucher disease (GD) is a rare inherited multiorgan disorder, yet a diagnosis can be significantly delayed due to a broad spectrum of symptoms and lack of disease awareness. Recently, the prototype of a GD point-scoring system (PSS) was established by the Gaucher Earlier Diagnosis Consensus (GED-C) initiative, and more recently, validated in Gaucher patients in UK. In our study, the original GED-C PSS was tested in Finnish GD patients. Furthermore, the feasibility of point scoring large electronic health record (EHR) data set by data mining to identify potential undiagnosed GD cases was evaluated., Methods: This biobank study was conducted in collaboration with two Finnish biobanks. Five previously diagnosed Finnish GD patients and ~ 170,000 adult biobank subjects were included in the study. The original PSS was locally adjusted due to data availability issues and applied to the Finnish EHR data representing special health care recordings., Results: All GD patients had high levels of the biomarker lyso-Gb1 and deleterious GBA mutations. One patient was a compound heterozygote with a novel variant, potentially pathogenic mutation. Finnish EHR data allowed the retrospective assessment of 27-30 of the 32 original GED-C signs/co-variables. Total point scores of GD patients were high but variable, 6-18.5 points per patient (based on the available data on 28-29 signs/co-variables per patient). All GD patients had been recorded with anaemia while only three patients had a record of splenomegaly. 0.72% of biobank subjects were assigned at least 6 points but none of these potential "GD suspects" had a point score as high as 18.5. Splenomegaly had been recorded for 0.25% of biobank subjects and was associated with variable point score distribution and co-occurring ICD-10 diagnoses., Discussion: This study provides an indicative GED-C PSS score range for confirmed GD patients, also representing potential mild cases, and demonstrates the feasibility of scoring Finnish EHR data by data mining in order to screen for undiagnosed GD patients. Further prioritisation of the "GD suspects" with more developed algorithms and data-mining approaches is needed., Funding: This study was funded by Shire (now part of Takeda)., Competing Interests: CVF and KE are employed by Takeda (Stockholm, Sweden and Helsinki, Finland, respectively). AK and SR are employed by Auria Biobank and Biobank Borealis, respectively, which received reimbursement from Shire (now part of Takeda), for the work done at Auria/Borealis. IT, KU, and MIL are employed by Medaffcon Oy (Espoo, Finland) which received funding from Shire (now part of Takeda), for conducting the study. MJS reports personal consultancy fees and travel grants from Shire (now part of Takeda) during the study, as well as grant support, paid to his institution, from several foundations for research outside the submitted work., (© 2021 The Authors.)

Background: People face varying obstacles when interacting with health information in their everyday lives., Objectives: This study aims to examine the applicability of a multidimensional Everyday Health Information Literacy (EHIL) screening tool in detecting people with challenges in accessing, understanding, evaluating and using health information in everyday situations., Methods: Previously collected EHIL screening tool data from Finnish upper secondary school students (n = 217), Finnish young men (n = 1450), Finnish adults with an increased risk for metabolic syndrome (n = 559) and Namibian university students (n = 271) were reanalysed to examine the factorial structure of the tool and to compare the groups. Statistical analyses included exploratory factor analyses, calculation of mean factor scores and one-way analysis of variance., Results: A three factor structure ('awareness', 'access', 'assessment') for the screening tool was supported based on the Finnish samples. However, the Namibian data did not follow a similar structure. Significant differences in groupwise factor scores were discovered., Discussion: The findings suggest that the multidimensional EHIL screening tool can be used in pointing out areas where individuals or groups may need support., Conclusion: The tool may be useful to health information and library services workers when counselling or educating the public., (© 2020 The Authors Health Information and Libraries Journal published by John Wiley & Sons Ltd on behalf of Health Libraries Group.)

Objectives: The aim was to investigate whether lifestyle changes produced by persuasive Information and Communication Technology (ICT) counselling can lower the prevalence of metabolic syndrome (MetS)., Methods: A total of 532 participants (20-60 years, body mass index 27-35 kg/m 2 ) were randomly assigned to six arms according to counselling type (no, short-term, or intensive) with or without ICT intervention. In this report the prevalence of MetS and its components were compared between no-ICT group and ICT group. Moreover, the frequency of the web information system usage was analysed for the number of logins, responses to weekly messages, and other record variables., Results: The ICT group had significantly lower proportion of MetS (33.7% vs. 45.3%, p  = .022) than the no-ICT group at 2-year follow-up. In mixed model, the ICT group had lower prevalence of MetS than no-ICT group (OR 0.50, 95%CI 0.27-0.90) after intervention. The tertile with the highest utilization had 71% lower prevalence of MetS compared with the lowest utilization tertile or the no-ICT group., Conclusions: Web-based ICT is able to reduce the prevalence of MetS. In addition, higher utilization of the web information system is associated with a greater decrease in the prevalence of MetS. Key messages Our internet health behaviour change support system based on persuasive design and cognitive behaviour therapy markedly reduces metabolic syndrome in overweight/obese subjects. As a stand-alone tool it may save healthcare personnel resources as it is suitable at a low cost for both obese/overweight patients and the public at large.

Activation of pregnane X receptor (PXR) elevates circulating 4 β -hydroxycholesterol (4βHC), an agonist of liver X receptor (LXR). PXR may also regulate 25-hydroxycholesterol and 27-hydroxycholesterol. Our aim was to elucidate the roles of PXR and oxysterols in the regulation of cholesterol transporters. We measured oxysterols in serum of volunteers dosed with PXR agonist rifampicin 600 mg/day versus placebo for a week and analyzed the expression of cholesterol transporters in mononuclear cells. The effect of 4 β HC on the transport of cholesterol and the expression of cholesterol transporters was studied in human primary monocyte-derived macrophages and foam cells in vitro . The expression of cholesterol transporters was measured also in rat tissues after dosing with a PXR agonist. The levels of 4 β HC were elevated, while 25-hydroxycholesterol and 27-hydroxycholesterol remained unchanged in volunteers dosed with rifampicin. The expression of ATP binding cassette transporter A1 (ABCA1) was induced in human mononuclear cells in vivo . The influx of cholesterol was repressed by 4 β HC, as was the expression of influx transporter lectin-like oxidized LDL receptor-1 in vitro . The cholesterol efflux and the expression of efflux transporters ABCA1 and ABCG1 were induced. The expression of inducible degrader of the LDL receptor was induced. In rats, PXR agonist increased circulating 4 β HC and expression of LXR targets in peripheral tissues, especially ABCA1 and ABCG1 in heart. In conclusion, PXR activation-elevated 4 β HC is a signaling molecule that represses cholesterol influx and induces efflux. The PXR-4 β HC-LXR pathway could link the hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues., (Copyright © 2020 Salonurmi, Nabil, Ronkainen, Hyötyläinen, Hautajärvi, Savolainen, Tolonen, Orešič, Känsäkoski, Rysä, Hakkola and Hukkanen.)

A healthy dietary pattern is associated with a lower risk of metabolic syndrome (MetS) and reduced inflammation. To explore this at the molecular level, we investigated the effect of a Nordic diet (ND) on changes in the gene expression profiles of inflammatory and lipid-related genes in peripheral blood mononuclear cells (PBMCs) of individuals with MetS. We hypothesized that the intake of an ND compared to a control diet (CD) would alter the expression of inflammatory genes and genes involved in lipid metabolism. The individuals with MetS underwent an 18/24-week randomized intervention to compare a ND with a CD. Eighty-eight participants (66% women) were included in this sub-study of the larger SYSDIET study. Fasting PBMCs were collected before and after the intervention and changes in gene expression levels were measured using TaqMan Array Micro Fluidic Cards. Forty-eight pre-determined inflammatory and lipid related gene transcripts were analyzed. The expression level of the gene tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) was down-regulated ( p = 0.004), whereas the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) subunit, RELA proto-oncogene , was up-regulated ( p = 0.016) in the ND group compared to the CD group. In conclusion, intake of an ND in individuals with the MetS may affect immune function.

Background: Recently, a group of betainized compounds have been suggested to play a role in health effects in relation to a whole-grain-rich diet., Objectives: The aims of this study were to develop a quantitative mass spectrometric method for selected betainized compounds in human plasma, and to investigate their association with nutrient intake and measures of metabolic health in participants of the SYSDIET study., Methods: The SYSDIET study was a controlled randomized intervention including individuals with metabolic syndrome, where the healthy Nordic diet (HND) group increased intakes of whole grains, canola oil, berries, and fish, whereas the control diet (CD) group consumed low-fiber cereal products, milk fat, and restricted amounts of fish and berries. A quantitative LC combined with triple quadrupole MS method for betainized compounds was developed and applied to fasting plasma samples from baseline (week 0) and the end of the intervention (week 18 or 24). Concentrations of betainized compounds were correlated with intakes of selected nutrients and fiber and measures of metabolic health., Results: Pipecolic acid betaine (PAB) concentrations were significantly higher in the HND group than in the CD group (P = 0.00032) at the end of the intervention and correlated directly (P < 0.0001) with intakes of dietary fiber (r = 0.376) and a biomarker related to whole-grain rye intake, namely the ratio of alkylresorcinol C17:0 to C21:0 (r = 0.442). PAB was associated inversely with fasting plasma insulin consistently at the beginning and at the end of the intervention (P < 0.001, r = -0.300; P < 0.01, r = -0.250, respectively), as well as IL-1 receptor antagonist (P < 0.01, r = -0.232 at the beginning; P < 0.01, r = -0.236 at the end) and serum LDL/HDL cholesterol (P < 0.01, r = -0.239 at the beginning; P < 0.01, r = -0.241 at the end)., Conclusions: Among adults with the metabolic syndrome, PAB plasma concentrations were associated with fasting insulin, inflammation, and lipids and were significantly increased with adoption of the HND. Further studies are needed to clarify the biological functions of betainized compounds. This trial was registered at clinicaltrials.gov as NCT00992641., (Copyright © American Society for Nutrition 2019.)

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Scope: To explore the effect of a healthy Nordic diet on the global transcriptome profile in peripheral blood mononuclear cells (PBMCs) of subjects with metabolic syndrome., Methods and Results: Subjects with metabolic syndrome undergo a 18/24 week randomized intervention study comparing an isocaloric healthy Nordic diet with an average habitual Nordic diet served as control (SYSDIET study). Altogether, 68 participants are included. PBMCs are obtained before and after intervention and total RNA is subjected to global transcriptome analysis. 1302 probe sets are differentially expressed between the diet groups (p-value < 0.05). Twenty-five of these are significantly regulated (FDR q-value < 0.25) and are mainly involved in mitochondrial function, cell growth, and cell adhesion. The list of 1302 regulated probe sets is subjected to functional analyses. Pathways and processes involved in the mitochondrial electron transport chain, immune response, and cell cycle are downregulated in the healthy Nordic diet group. In addition, gene transcripts with common motifs for 42 transcription factors, including NFR1, NFR2, and NF-κB, are downregulated in the healthy Nordic diet group., Conclusion: These results suggest that benefits of a healthy diet may be mediated by improved mitochondrial function and reduced inflammation., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Krill powder is rich in bioactive ingredients such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), phospholipids, protein and astaxanthin. Containing dominantly EPA, it is considered to be effective in lowering lipids, foremost serum triglycerides and LDL cholesterol. Krill-derived protein hydrolysates/peptides may have positive effect on blood pressure and astaxanthin has anti-oxidative and anti-inflammatory properties. Thus, krill powder has a lot of potential in improving lipid and metabolic profile and reinforcing the activity of the antioxidant system. However, randomized clinical trials on krill powder are scarce and systematic data of krill meal on human safety is limited. Some of the earlier studies have reported several, non-serious adverse events, mostly related to gastrointestinal tract, but systematic sufficiently powered study on safety is lacking. The aim of this study was to collect data on safety and tolerability of krill powder in humans and simultaneously gain efficacy data by measuring the risk factors for cardiovascular disease., Methods: The study was a randomised, double-blinded, placebo-controlled intervention study with 35 overweight subjects with mildly or moderately elevated blood pressure, who took 4 g krill oil powder or 4 g of placebo during an 8-week follow-up period. The study consisted of a pre-screening, screening, day 0 baseline (randomization visit) and three follow-up visits on days 14, 28 and 56. The reported adverse events in the groups were compared as primary endpoint and haematological safety parameters and changes in systolic and diastolic pressure and blood total and lipoprotein lipids were measured as secondary end points., Results: There were in total 80 reported adverse events during the follow-up; 50 in placebo and 30 in krill powder group. Gastrointestinal symptoms (flatulence, heartburn and diarrhea) were the most commonly reported among those probably related to the test products. No serious adverse events were reported. The mean value of all measured hematology variables remained within the reference values in all study subject and no significant changes were observed in blood pressure or lipid values., Conclusions: The results seem to indicate that using krill powder as a source for EPA and DHA is safe in therapeutic dose and the risk of adverse events, let alone serious ones, is low., Trial Registration: ClinicalTrials.gov, NCT03112083 , retrospectively registered.

Background: Weight loss can prevent and treat obesity-related diseases. However, lost weight is usually regained, returning to the initial or even higher levels in the long term. New counselling methods for maintaining lifestyle changes are urgently needed., Objectives: An information and communication technology-based health behaviour change support system (HBCSS) that utilizes persuasive design and methods of cognitive behavioural therapy (CBT) was developed with the aim of helping individuals to maintain body weight. The purpose of this study was to assess whether CBT-based group counselling combined with HBCSS or HBCSS alone helps to maintain improved lifestyle changes needed for weight loss compared to self-help guidance or usual care., Methods: A randomized lifestyle intervention for overweight or obese persons (BMI 27-35 kg m -2 and age 20-60 years), recruited from the population registry in the city of Oulu, Finland, was conducted. This study comprised six randomly assigned study arms: CBT-based group counselling (eight sessions led by a nutritionist), self-help guidance-based group counselling (SHG; two sessions led by a nurse) and control, each with or without HCBSS, for 52 weeks. Subjects visited the study centre for anthropometric measurements, blood sample collection and to complete questionnaires at baseline, 12 and 24 months. The main outcome was weight change from baseline to 12 months and from baseline to 24 months., Results: Of the 1065 volunteers screened for the study, 532 subjects (51% men) met the inclusion criteria and were enrolled. The retention rate was 80% at 12 months and 70% at 24 months. CBT-based counselling with HBCSS produced the largest weight reduction without any significant weight gain during follow-up. The mean weight change in this arm was 4.1% [95% confidence interval (CI), -5.4 to -2.8, P < 0.001) at 12 months and 3.4% (95% CI, -4.8 to -2.0, P < 0.001) at 24 months. HBCSS even without any group counselling reduced the mean weight by 1.6% (95% CI, -2.9 to -0.3, P = 0.015) at 24 months., Conclusion: The combination of CBT-based group counselling and HBCSS-based weight management is feasible for overweight or obese individuals. Moreover, HBCSS alone could be disseminated to the population at large as an effective means of treating obesity., (© 2018 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

The formation of healthy habits is considered to play a fundamental role in health behavior change. A variety of studies on Health Behavior Change Support Systems (HBCSS) have been conducted recently, in which individuals use such systems to influence their own attitudes or behaviors to achieve their personal goals. However, comparatively much less research has been devoted to studying how the users of these systems form habits with the help of HBCSS, or to understanding how to design these systems to support habit formation., Objective: The objective of this article is to study HBCSS user experiences regarding habit formation through an intervention study targeted at establishing a healthier lifestyle. This study also aims to map habit formation stages, as suggested by Lally and Gardner, with the Persuasive System Design (PSD) model. The application domain is the prevention of metabolic syndrome, in which 5% weight loss can significantly reduce the prevalence of the syndrome., Methods: This study employs a web-based HBCSS named Onnikka, a lifestyle intervention designed for the prevention of metabolic syndrome for participants who are at risk of developing a metabolic syndrome or are already suffering from it. The system under investigation was designed according to the principles of the PSD model and Behavior Change Support System framework. Lally and Gardner's research on the stages of habit formation were used to study the extent to which the Onnikka system was able to enhance the development of new habits. A total of 43 Onnikka users were interviewed for this study during and after a 52-week intervention period. The research approach employed here was hermeneutics, which leans ontologically toward the social construction of reality, gained through language, consciousness, and shared meaning. In addition, the system's login data and participants' weight measurements were utilized to build an interpretation of the results., Results: The findings of this study suggest that IT habits appear to have a strong linkage with use adherence, whereas lifestyle habits did not seem to be directly related to the 5% weight loss among study participants. Moreover, habit formation stages provide a possible explanation for why self-monitoring, reminders, and tunneling were perceived as especially valuable features in this study., Conclusions: For sustainable weight management, holistic e-health interventions are required, and the PSD model offers a practical approach for designing and developing them. Recognizing the stages of habit formation provides additional valuable guidance for designing systems that help shape an individual's habits., (Copyright © 2018. Published by Elsevier Inc.)

Aims: Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization., Methods and Results: We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture., Conclusion: Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

Aims/hypothesis: Ceramide lipids have a role in the development of insulin resistance, diabetes and risk of cardiovascular disease. Here we investigated four ceramides and their ratios to find the best predictors of incident diabetes., Methods: A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes., Results: Analysis in FINRISK 2002 showed that the Cer(d18:1/18:0)/Cer(d18:1/16:0) ceramide ratio was predictive of incident diabetes (HR per SD 2.23, 95% CI 2.05, 2.42), and remained significant after adjustment for several risk factors, including BMI, fasting glucose and HbA 1c (HR 1.34, 95% CI 1.14, 1.57). The finding was validated in the WECAC study (unadjusted HR 1.81, 95% CI 1.53, 2.14; adjusted HR 1.39, 95% CI 1.16, 1.66). In the intervention trial, the ceramide ratio and diabetes risk scores significantly decreased in individuals who had 5% or more weight loss., Conclusions/interpretation: The Cer(d18:1/18:0)/Cer(d18:1/16:0) ratio is an independent predictive biomarker for incident diabetes, and may be modulated by lifestyle intervention.

Objective: The potential of high-density lipoproteins (HDL) to facilitate cholesterol removal from arterial foam cells is a key function of HDL. We studied whether cholesterol efflux to serum and HDL subfractions is impaired in subjects with early coronary heart disease (CHD) or metabolic syndrome (MetS) in families where a low HDL-cholesterol level (HDL-C) predisposes to early CHD., Methods: HDL subfractions were isolated from plasma by sequential ultracentrifugation. THP-1 macrophages loaded with acetyl-LDL were used in the assay of cholesterol efflux to total HDL, HDL2, HDL3 or serum., Results: While cholesterol efflux to serum, total HDL and HDL3 was unchanged, the efflux to HDL2 was 14% lower in subjects with MetS than in subjects without MetS (p<0.001). The efflux to HDL2 was associated with components of MetS such as plasma HDL-C (r = 0.76 in men and r = 0.56 in women, p<0.001 for both). The efflux to HDL2 was reduced in men with early CHD (p<0.01) only in conjunction with their low HDL-C. The phospholipid content of HDL2 particles was a major correlate with the efflux to HDL2 (r = 0.70, p<0.001). A low ratio of HDL2 to total HDL was associated with MetS (p<0.001)., Conclusion: Our results indicate that impaired efflux to HDL2 is a functional feature of the low HDL-C state and MetS in families where these risk factors predispose to early CHD. The efflux to HDL2 related to the phospholipid content of HDL2 particles but the phospholipid content did not account for the impaired efflux in cardiometabolic disease, where a combination of low level and poor quality of HDL2 was observed.

Genetic variants in the fat mass- and obesity-associated gene Fto are linked to the onset of obesity in humans. The causal role of the FTO protein in obesity is supported by evidence obtained from transgenic mice; however, the underlying molecular pathways pertaining to the role of FTO in obesity have yet to be established. In this study, we investigate the Fto gene in mouse brown adipose tissue and in the browning process of white adipose tissue. We analyze distinct structural and molecular factors in brown and white fat depots of Fto -deficient mice under normal and obesogenic conditions. We report significant alterations in the morphology of adipose tissue depots and the expression of mRNA and microRNA related to brown adipogenesis and metabolism in Fto -deficient mice. Furthermore, we show that high-fat feeding does not attenuate the browning process of Fto -deficient white adipose tissue as observed in wild-type tissue, suggesting a triggering effect of the FTO pathways by the dietary environment., Competing Interests: The authors declare no conflict of interest.