Changes in Kidney Fat upon Dietary-Induced Weight Loss.

As the metabolic role of kidney fat remains unclear, we investigated the effects of dietary weight loss on kidney fat content (KFC) and its connection to kidney function and metabolism. Overweight or obese participants (n = 137) of a dietary intervention trial were classified into quartiles of weight loss in a post hoc manner. Kidney sinus (KSF) and cortex fat (KCF) were measured by magnetic resonance imaging at baseline, week 12 and week 50. Weight loss effects on KFC were evaluated by linear mixed models. Repeated measures correlations between KFC, other body fat measures and metabolic biomarkers were obtained. KSF, but not KCF, decreased significantly across weight loss quartiles at week 12 (quartile 4: -21.3%; p = 0.02) and 50 (-22.0%, p = 0.001), which remained significant after adjusting for VAT. There were smaller improvements regarding creatinine (-2.5%, p = 0.02) at week 12, but not week 50. KSF, but not KCF, correlated with visceral (rrm = 0.38) and subcutaneous fat volumes (rrm = 0.31) and liver fat content (rrm = 0.32), as well as diastolic blood pressure and biomarkers of lipid, glucose and liver metabolism. Dietary weight loss is associated with decreases in KSF, but not KCF, which suggests that KSF may be the metabolically relevant ectopic fat depot of the kidney. KSF may be targeted for obesity-related disease prevention.

Calorie restriction improves metabolic state independently of gut microbiome composition: a randomized dietary intervention trial.

BACKGROUND: The gut microbiota has been suggested to play a significant role in the development of overweight and obesity. However, the effects of calorie restriction on gut microbiota of overweight and obese adults, especially over longer durations, are largely unexplored. METHODS: Here, we longitudinally analyzed the effects of intermittent calorie restriction (ICR) operationalized as the 5:2 diet versus continuous calorie restriction (CCR) on fecal microbiota of 147 overweight or obese adults in a 50-week parallel-arm randomized controlled trial, the HELENA Trial. The primary outcome of the trial was the differential effects of ICR versus CCR on gene expression in subcutaneous adipose tissue. Changes in the gut microbiome, which are the focus of this publication, were defined as exploratory endpoint of the trial. The trial comprised a 12-week intervention period, a 12-week maintenance period, and a final follow-up period of 26 weeks. RESULTS: Both diets resulted in ~5% weight loss. However, except for Lactobacillales being enriched after ICR, post-intervention microbiome composition did not significantly differ between groups. Overall weight loss was associated with significant metabolic improvements, but not with changes in the gut microbiome. Nonetheless, the abundance of the Dorea genus at baseline was moderately predictive of subsequent weight loss (AUROC of 0.74 for distinguishing the highest versus lowest weight loss quartiles). Despite the lack of consistent intervention effects on microbiome composition, significant study group-independent co-variation between gut bacterial families and metabolic biomarkers, anthropometric measures, and dietary composition was detectable. Our analysis in particular revealed associations between insulin sensitivity (HOMA-IR) and Akkermansiaceae, Christensenellaceae, and Tanerellaceae. It also suggests the possibility of a beneficial modulation of the latter two intestinal taxa by a diet high in vegetables and fiber, and low in processed meat. CONCLUSIONS: Overall, our results suggest that the gut microbiome remains stable and highly individual-specific under dietary calorie restriction. TRIAL REGISTRATION: The trial, including the present microbiome component, was prospectively registered at ClinicalTrials.gov NCT02449148 on May 20, 2015.

Adherence and Dietary Composition during Intermittent vs. Continuous Calorie Restriction: Follow-Up Data from a Randomized Controlled Trial in Adults with Overweight or Obesity.

Although intermittent calorie restriction (ICR) has become popular as an alternative weight loss strategy to continuous calorie restriction (CCR), there is insufficient evidence on diet quality during ICR and on its feasibility over longer time periods. Thus, we compared dietary composition and adherence between ICR and CCR in a follow-up analysis of a randomized trial. A total of 98 participants with overweight or obesity [BMI (kg/m2) 25-39.9, 35-65 years, 49% females] were randomly assigned to ICR, operationalized as a "5:2 diet" (energy intake: ~100% on five non-restricted (NR) days, ~25% on two restricted (R) days), or CCR (daily energy intake: ~80%). The trial included a 12-week (wk) intervention phase, and follow-up assessments at wk24, wk50 and wk102. Apart from a higher proportion of energy intake from protein with ICR vs. CCR during the intervention (wk2: p < 0.001; wk12: p = 0.002), there were no significant differences with respect to changes in dietary composition over time between the groups, while overall adherence to the interventions appeared to be good. No significant difference between ICR and CCR regarding weight change at wk102 was observed (p = 0.63). However, self-reported adherence was worse for ICR than CCR, with 71.1% vs. 32.5% of the participants reporting not to or only rarely have followed the regimen to which they were assigned between wk50 and wk102. These results indicate that within a weight management setting, ICR and CCR were equivalent in achieving modest weight loss over two years while affecting dietary composition in a comparable manner.

Changes in Bone Marrow Fat upon Dietary-Induced Weight Loss.

BACKGROUND: Bone marrow fat is implicated in metabolism, bone health and haematological diseases. Thus, this study aims to analyse the impact of moderate weight loss on bone marrow fat content (BMFC) in obese, healthy individuals. METHODS: Data of the HELENA-Trial (Healthy nutrition and energy restriction as cancer prevention strategies: a randomized controlled intervention trial), a randomized controlled trial (RCT) among 137 non-smoking, overweight or obese participants, were analysed to quantify the Magnetic Resonance Imaging (MRI)-derived BMFC at baseline, after a 12-week dietary intervention phase, and after a 50-week follow-up. The study cohort was classified into quartiles based on changes in body weight between baseline and week 12. Changes in BMFC in respect of weight loss were analysed by linear mixed models. Spearman's coefficients were used to assess correlations between anthropometric parameters, blood biochemical markers, blood cells and BMFC. RESULTS: Relative changes in BMFC from baseline to week 12 were 0.0 ± 0.2%, -3.2 ± 0.1%, -6.1 ± 0.2% and -11.5 ± 0.6% for Q1 to Q4. Across all four quartiles and for the two-group comparison, Q1 versus Q4, there was a significant difference (p < 0.05) for changes in BMFC. BMFC was not associated with blood cell counts and showed only weaker correlations (<0.3) with metabolic biomarkers. CONCLUSION: Weight loss is associated with a decrease of BMFC. However, BMFC showed no stronger associations with inflammatory and metabolic biomarkers.

Dietary Factors in Relation to Liver Fat Content: A Cross-sectional Study.

Non-alcoholic fatty liver disease (NAFLD) can lead to functional liver impairment and severe comorbidities. Beyond energy balance, several dietary factors may increase NAFLD risk, but human studies are lacking. The aim of this cross-sectional study was to investigate the associations between food consumption (47 food groups, derived Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diet quality scores) and liver fat content (continuous scale and NAFLD, i.e., >5% liver fat content). Liver fat content was measured by magnetic resonance imaging (MRI) in 136 individuals (BMI: 25-40 kg/m2, age: 35-65, 50.7% women) and food intake was recorded by food frequency questionnaires (FFQs). Associations between food items and liver fat were evaluated by multi-variable regression models. Intakes of cake and cookies as well legumes were inversely associated with liver fat content, while positive associations with intakes of high-fat dairy and cheese were observed. Only cake and cookie intake also showed an inverse association with NAFLD. This inverse association was unexpected, but not affected by adjustment for reporting bias. Both diet quality scores were inversely associated with liver fat content and NAFLD. Thus, as smaller previous intervention studies, our results suggest that higher diet quality is related to lower liver fat, but larger trials with iso-caloric interventions are needed to corroborate these findings.

Changes in Plasma Short-Chain Fatty Acid Levels after Dietary Weight Loss Among Overweight and Obese Adults over 50 Weeks.

Gut microbial-derived short-chain fatty acids (SCFAs) may regulate energy homeostasis and exert anti-carcinogenic, immunomodulatory and anti-inflammatory effects. Smaller trials indicate that dietary weight loss may lead to decreased SCFA production, but findings have been inconclusive. SCFA concentrations were measured by HPLC-MS/MS in plasma samples of 150 overweight or obese adults in a trial initially designed to evaluate the metabolic effects of intermittent (ICR) versus continuous (CCR) calorie restriction (NCT02449148). For the present post hoc analyses, participants were classified by quartiles of weight loss, irrespective of the dietary intervention. Linear mixed models were used to analyze weight-loss-induced changes in SCFA concentrations after 12, 24 and 50 weeks. There were no differential changes in SCFA levels across the initial study arms (ICR versus CCR versus control) after 12 weeks, but acetate concentrations significantly decreased with overall weight loss (mean log-relative change of -0.7 ± 1.8 in the lowest quartile versus. -7.6 ± 2 in the highest, p = 0.026). Concentrations of propionate, butyrate and other SCFAs did not change throughout the study. Our results show that weight-loss, achieved through calorie restriction, may lead to smaller initial decreases in plasma acetate, while plasma SCFAs generally remain remarkably stable over time.

Generalizability of a Diabetes-Associated Country-Specific Exploratory Dietary Pattern Is Feasible Across European Populations.

BACKGROUND: Population-specificity of exploratory dietary patterns limits their generalizability in investigations with type 2 diabetes incidence. OBJECTIVE: The aim of this study was to derive country-specific exploratory dietary patterns, investigate their association with type 2 diabetes incidence, and replicate diabetes-associated dietary patterns in other countries. METHODS: Dietary intake data were used, assessed by country-specific questionnaires at baseline of 11,183 incident diabetes cases and 14,694 subcohort members (mean age 52.9 y) from 8 countries, nested within the European Prospective Investigation into Cancer and Nutrition study (mean follow-up time 6.9 y). Exploratory dietary patterns were derived by principal component analysis. HRs for incident type 2 diabetes were calculated by Prentice-weighted Cox proportional hazard regression models. Diabetes-associated dietary patterns were simplified or replicated to be applicable in other countries. A meta-analysis across all countries evaluated the generalizability of the diabetes-association. RESULTS: Two dietary patterns per country/UK-center, of which overall 3 dietary patterns were diabetes-associated, were identified. A risk-lowering French dietary pattern was not confirmed across other countries: pooled HRFrance per 1 SD: 1.00; 95% CI: 0.90, 1.10. Risk-increasing dietary patterns, derived in Spain and UK-Norfolk, were confirmed, but only the latter statistically significantly: HRSpain: 1.09; 95% CI: 0.97, 1.22 and HRUK-Norfolk: 1.12; 95% CI: 1.04, 1.20. Respectively, this dietary pattern was characterized by relatively high intakes of potatoes, processed meat, vegetable oils, sugar, cake and cookies, and tea. CONCLUSIONS: Only few country/center-specific dietary patterns (3 of 18) were statistically significantly associated with diabetes incidence in this multicountry European study population. One pattern, whose association with diabetes was confirmed across other countries, showed overlaps in the food groups potatoes and processed meat with identified diabetes-associated dietary patterns from other studies. The study demonstrates that replication of associations of exploratory patterns with health outcomes is feasible and a necessary step to overcome population-specificity in associations from such analyses.

Effects of Weight-Loss Interventions on Short-Chain Fatty Acid Concentrations in Blood and Feces of Adults: A Systematic Review.

Short-chain fatty acids (SCFAs, mainly acetate, propionate, and butyrate), which are primarily derived from the gut microbiome, may exert anti-inflammatory and immunomodulatory effects, and regulate energy homeostasis. It has been suggested that weight loss may affect SCFA metabolism, but a systematic review of intervention studies is lacking. We aimed to systematically assess the effects of dietary, physical activity-based, and surgical weight-loss interventions among overweight [body mass index (BMI) 25-29.9 kg/m2)] or obese (BMI ≥30 kg/m2) adults (≥18 y) on concentrations of acetate, propionate, butyrate, and total SCFAs in blood, urine, or feces. We conducted a systematic literature search in PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to April 30, 2018 for randomized and nonrandomized weight-loss trials among overweight or obese adults, in which the concentrations of individual and total SCFAs were assessed. A total of 9 studies consisting of 2 randomized parallel-arm trials, 4 crossover trials, and 3 nonrandomized clinical or surgical trials were included. In the majority of studies, changes in fecal SCFA concentrations were assessed, whereas changes in serum SCFAs were reported from 1 trial. Individual and total SCFA concentrations either remained unchanged or decreased significantly following weight loss. Three of the dietary interventions that resulted in decreased SCFA concentrations were low (≤5% of energy) in total carbohydrates. Most of the studies had a high risk of bias. Decreases in SCFA concentrations may accompany weight loss induced by bariatric surgery or dietary restriction among overweight or obese adults, particularly when carbohydrate intake is reduced. However, findings were inconsistent and based on studies with high to unclear risk of bias, and small sample sizes. Because measurements of fecal SCFAs may not be ideal due to limited sample standardization, well-powered trials with repeated blood measurements of SCFAs are required. This review was registered at PROSPERO as CRD42018088716.

Changes in Pancreatic Fat Content Following Diet-Induced Weight Loss.

BACKGROUND: Obesity can lead to ectopic pancreatic fat accumulation and increase the risk for type 2 diabetes. Smaller intervention trials have shown a decrease in pancreatic fat content (PFC) with weight loss, and we intended to investigate the effects of weight loss on PFC in a larger trial. METHODS: Data from the HELENA-Trial, a randomized controlled trial (RCT) among 137 non-diabetic obese adults were used. The study cohort was classified into 4 quartiles based on weight change between baseline and 12 weeks post-intervention. Changes in PFC (baseline, 12 weeks and 50 weeks post-intervention) upon weight loss were analyzed by linear mixed models. Spearman's coefficients were used to obtain correlations between anthropometric parameters, blood biochemical markers, and PFC. RESULTS: At baseline, PFC only showed a significant correlation with visceral adipose tissue (VAT) (r = 0.41). Relative changes in PFC were significantly (p = 0.01) greater in Q4 (-30.8 ± 5.7%) than in Q1 (1.3 ± 6.7%). These differences remained similar after one year. However, when adjusting the statistical analyses for changes in VAT, the differences in PFC between Q1 and Q4 were no longer statistically significant. CONCLUSION: Weight loss is associated with a decrease in PFC. However, the reduction of PFC is not independent from reductions in VAT. Unlike VAT, PFC was not associated with metabolic biomarkers.

Similar Weight Loss Induces Greater Improvements in Insulin Sensitivity and Liver Function among Individuals with NAFLD Compared to Individuals without NAFLD.

BACKGROUND: Preliminary evidence suggests that weight loss among obese has differential metabolic effects depending on the presence of non-alcoholic fatty liver disease (NAFLD). We assessed whether NAFLD predisposes to differential changes in liver fat content, liver function, and metabolic parameters upon diet-induced weight loss in a 50-week intervention trial. METHODS: 143 overweight and obese non-smokers underwent a 12-week dietary intervention and a 38-week follow-up. Diet-induced changes in anthropometric measures, circulating biomarkers, and magnetic resonance (MR)-derived liver fat content and adipose tissue volumes were evaluated by mixed linear models stratifying by NAFLD at baseline. RESULTS: The prevalence of NAFLD at baseline was 52%. Diet-induced weight loss after 12 (NAFLD: 4.8 ± 0.5%, No NAFLD: 5.1 ± 0.5%) and 50 weeks (NAFLD: 3.5 ± 0.7%, No NAFLD: 3.5 ± 0.9%) was similar in both groups, while the decrease in liver fat was significantly greater in the NAFLD group (week 12: 32.9 ± 9.5% vs. 6.3 ± 4.0%; week 50: 23.3 ± 4.4% vs. 5.0 ± 4.2%). Decreases in biomarkers of liver dysfunction (GGT, ALT, AST) and HOMA IR were also significantly greater in the NAFLD group. Other metabolic parameters showed no significant differences. CONCLUSION: Our data suggest that individuals with NAFLD show greater improvements of liver function and insulin sensitivity after moderate diet-induced weight loss than individuals without NAFLD.

Key Genes of Lipid Metabolism and WNT-Signaling Are Downregulated in Subcutaneous Adipose Tissue with Moderate Weight Loss.

Smaller cross-sectional studies and bariatric surgery trials suggest that weight loss may change the expression of genes in adipose tissue that have been implicated in the development of metabolic diseases, but well-powered intervention trials are lacking. In post hoc analyses of data from a 12-week dietary intervention trial initially designed to compare metabolic effects of intermittent vs. continuous calorie restriction, we analyzed the effects of overall weight loss on the subcutaneous adipose tissue (SAT) transcriptome. Changes in the transcriptome were measured by microarray using SAT samples of 138 overweight or obese individuals (age range: 35⁻65 years, BMI range: 25⁻40, non-smokers, non-diabetics). Participants were grouped post hoc according to the degree of their weight loss by quartiles (average weight loss in quartiles 1 to 4: 0%, -3.2%, -5.9%, and -10.7%). Candidate genes showing differential expression with weight loss according to microarray analyses were validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR), and fold changes (FCs) were calculated to quantify differences in gene expression. A comparison of individuals in the highest vs. the lowest weight loss quartile revealed 681 genes to be differentially expressed (corrected p < 0.05), with 40 showing FCs of at least 0.4. Out of these, expression changes in secreted frizzled-related protein 2 (SFRP2, FC = 0.65, p = 0.006), stearoyl-CoA desaturase (SCD, FC = -1.00, p < 0.001), and hypoxia inducible lipid droplet-associated (HILPDA, FC = -0.45, p = 0.001) with weight loss were confirmed by RT-qPCR. Dietary weight loss induces significant changes in the expression of genes implicated in lipid metabolism (SCD and HILPDA) and WNT-signaling (SFRP2) in SAT.

Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial.

Background: Although preliminary evidence suggests that intermittent calorie restriction (ICR) exerts stronger effects on metabolic parameters, which may link obesity and major chronic diseases, compared with continuous calorie restriction (CCR), there is a lack of well-powered intervention studies. Objective: We conducted a randomized controlled trial to test whether ICR, operationalized as the "5:2 diet," has stronger effects on adipose tissue gene expression, anthropometric and body composition measures, and circulating metabolic biomarkers than CCR and a control regimen. Design: One hundred and fifty overweight and obese nonsmokers [body mass index (kg/m2) ≥25 to <40, 50% women], aged 35-65 y, were randomly assigned to an ICR group (5 d without energy restriction and 2 d with 75% energy deficit, net weekly energy deficit ∼20%), a CCR group (daily energy deficit ∼20%), or a control group (no advice to restrict energy) and participated in a 12-wk intervention phase, a 12-wk maintenance phase, and a 26-wk follow-up phase. Results: Loge relative weight change over the intervention phase was -7.1% ± 0.7% (mean ± SEM) with ICR, -5.2% ± 0.6% with CCR, and -3.3% ± 0.6% with the control regimen (Poverall < 0.001, PICR vs. CCR = 0.053). Despite slightly greater weight loss with ICR than with CCR, there were no significant differences between the groups in the expression of 82 preselected genes in adipose tissue implicated in pathways linking obesity to chronic diseases. At the final follow-up assessment (week 50), weight loss was -5.2% ± 1.2% with ICR, -4.9% ± 1.1% with CCR, and -1.7% ± 0.8% with the control regimen (Poverall = 0.01, PICR vs. CCR = 0.89). These effects were paralleled by proportional changes in visceral and subcutaneous adipose tissue volumes. There were no significant differences between ICR and CCR regarding various circulating metabolic biomarkers. Conclusion: Our results on the effects of the "5:2 diet" indicate that ICR may be equivalent but not superior to CCR for weight reduction and prevention of metabolic diseases. This trial was registered at clinicaltrials.gov as NCT02449148.

Anthropometric and blood parameters for the prediction of NAFLD among overweight and obese adults.

BACKROUND: Non-alcoholic fatty liver disease (NAFLD) comprises non-progressive steatosis and non-alcoholic steatohepatitis (NASH), the latter of which may cause cirrhosis and hepatocellular carcinoma (HCC). As NAFLD detection is imperative for the prevention of its complications, we evaluated whether a combination of blood-based biomarkers and anthropometric parameters can be used to predict NAFLD among overweight and obese adults. METHODS: 143 overweight or obese non-smokers free of diabetes (50% women, age: 35-65 years) were recruited. Anthropometric indices and routine biomarkers of metabolism and liver function were measured to predict magnetic resonance (MR) - derived NAFLD by multivariable logistic regression models. In addition, we evaluated to which degree the use of more novel biomarkers (adiponectin, leptin, resistin, C-reactive protein, TNF-α, IL-6, IL-8 and interferon-γ) could improve prediction models. RESULTS: NAFLD was best predicted by a combination of age, sex, waist circumference, ALT, HbA1c, and HOMA-IR at an area under the receiver operating characteristic curve (AUROC) of 0.87 (95% CI: 0.81, 0.93) before and 0.85 (95% CI: 0.78, 0.91) after internal bootstrap validation. The use of additional biomarkers of inflammation and metabolism did not improve NAFLD prediction. Previously published indices predicted NAFLD at AUROCs between 0.71 and 0.82. CONCLUSIONS: The AUROC of > 0.8 obtained by our regression model suggests the feasibility of a non-invasive detection of NAFLD by anthropometry and circulating biomarkers, even though further increments in the capacity of prediction models may be needed before NAFLD indices can be applied in routine clinical practice.

Pre-diagnostic plasma concentrations of Fibrinogen, sGPIIb/IIIa, sP-selectin, sThrombomodulin, Thrombopoietin in relation to cancer risk: Findings from a large prospective study.

While enhanced platelet activation may drive cancer progression and metastases, less is known about its role in early cancer development. Thus, we evaluated whether pre-diagnostic biomarkers of platelet activation and coagulation are related to the risks of common cancers in the prospective EPIC-Heidelberg Study using a case-cohort design. Levels of fibrinogen, soluble glycoprotein (sGP) IIb/IIIa, soluble P-selectin (sP-selectin), soluble thrombomodulin (sTM), and thrombopoietin (TPO) were measured in baseline plasma samples of a random subcohort (n = 2,480) and incident cases of breast (n = 605), prostate (n = 543), and colorectal cancer (n = 249). Multivariable Cox regression models revealed no statistically significant associations between biomarker concentrations and any of the cancer endpoints. Subgroup analyses showed a significant inverse relationship between TPO and colorectal cancer among men, with a hazard ratio (HR, highest vs. lowest quartile) of 0.60 (95% confidence interval: 0.37,0.95), whereas no significant association was observed among women. With regard to fibrinogen levels and breast cancer risk, there was a significant positive association among nulliparous women (HR: 2.53 [95% CI: 1.21, 5.30]), but not among parous women. Overall, our data suggest that enhanced platelet activation and a pro-coagulative state may not be related to increased risks of common cancers, although studies on other potential biomarkers of platelet activation and further cancer types are needed. Findings from our subgroup analyses require further investigation, as potential underlying mechanisms are not known.

Inflammatory potential of the diet and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Background: Chronic inflammation plays a critical role in the pathogenesis of the 2 major types of gastric cancer. Several foods, nutrients, and nonnutrient food components seem to be involved in the regulation of chronic inflammation. Objective: We assessed the association between the inflammatory potential of the diet and the risk of gastric carcinoma, overall and for the 2 major subsites: cardia cancers and noncardia cancers. Design: A total of 476,160 subjects (30% men, 70% women) from the European Investigation into Cancer and Nutrition (EPIC) study were followed for 14 y, during which 913 incident cases of gastric carcinoma were identified, including 236 located in the cardia, 341 in the distal part of the stomach (noncardia), and 336 with overlapping or unknown tumor site. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated with the use of 28 dietary components and their corresponding inflammatory scores. The association between the ISD and gastric cancer risk was estimated by HRs and 95% CIs calculated by multivariate Cox regression models adjusted for confounders. Results: The inflammatory potential of the diet was associated with an increased risk of gastric cancer. The HR (95% CI) for each increase in 1 SD of the ISD were 1.25 (1.12, 1.39) for all gastric cancers, 1.30 (1.06, 1.59) for cardia cancers, and 1.07 (0.89, 1.28) for noncardia cancers. The corresponding values for the highest compared with the lowest quartiles of the ISD were 1.66 (1.26, 2.20), 1.94 (1.14, 3.30), and 1.07 (0.70, 1.70), respectively. Conclusions: Our results suggest that low-grade chronic inflammation induced by the diet may be associated with gastric cancer risk. This pattern seems to be more consistent for gastric carcinomas located in the cardia than for those located in the distal stomach. This study is listed on the ISRCTN registry as ISRCTN12136108.

Iron status in relation to cancer risk and mortality: Findings from a population-based prospective study.

While experimental evidence suggests potential carcinogenic effects of increased iron load, there is a lack of data on iron status and cancer risk from epidemiological studies. Here, we evaluated prediagnostic serum concentrations of ferritin, iron and transferrin as well as transferrin saturation (TSAT) in relation to cancer risk and mortality in a prospective study by multivariable Cox regression analyses. A case-cohort sample of the population-based EPIC-Heidelberg Study including a random subcohort (n = 2738) and incident cases of breast cancer (n = 627), prostate cancer (n = 554), lung cancer (n = 195), colorectal cancer (n = 256) and cancer death (n = 759) was used. Ferritin levels were inversely associated with breast cancer risk in the multivariable Cox regression model, with a hazard ratio (HR) of 0.67 [95% confidence interval: 0.49, 0.92] for women in the highest quartile compared to those in the lowest quartile. Neither ferritin nor the other markers of iron status were significantly associated with colorectal, prostate or lung cancer risk. An inverse association was observed between ferritin and total cancer mortality (HR: 0.70 [0.53, 0.92]). There were no significant overall associations between serum iron, transferrin or TSAT and cancer mortality. The present findings do not support the notion of increased iron load constituting a cancer risk factor in the general population. By contrast, our analyses revealed inverse associations between ferritin levels and breast cancer risk as well as cancer mortality.

Red meat consumption and risk of cardiovascular diseases-is increased iron load a possible link?

Background: High iron load and red meat consumption could increase the risk of cardiovascular diseases (CVDs). As red meat is the main source of heme iron, which is in turn a major determinant of increased iron load, adverse cardiometabolic effects of meat consumption could be mediated by increased iron load. Objective: The object of the study was to assess whether associations between red meat consumption and CVD risk are mediated by iron load in a population-based human study. Design: We evaluated relations between red meat consumption, iron load (plasma ferritin), and risk of CVD in the prospective EPIC-Heidelberg Study using a case-cohort sample including a random subcohort (n = 2738) and incident cases of myocardial infarction (MI, n = 555), stroke (n = 513), and CVD mortality (n = 381). Following a 4-step mediation analysis, associations between red meat consumption and iron load, red meat consumption and CVD risk, and iron load and CVD risk were assessed by multivariable regression models before finally testing to which degree associations between red meat consumption and CVD risk were attenuated by adjustment for iron status. Results: Red meat consumption was significantly positively associated with ferritin concentrations and MI risk [HR per 50 g daily intake: 1.18 (95% CI: 1.05, 1.33)], but no significant associations with stroke risk and CVD mortality were observed. While direct associations between ferritin concentrations and MI risk as well as CVD mortality were significant in age- and sex-adjusted Cox regression models, these associations were substantially attenuated and no longer significant after multivariable adjustment for classical CVD risk factors. Strikingly, ferritin concentrations were positively associated with a majority of classical CVD risk factors (age, male sex, alcohol intake, obesity, inflammation, and lower education). Conclusion: Increased ferritin concentrations may be a marker of an overall unfavorable risk factor profile rather than a mediator of greater CVD risk due to meat consumption.

Albumin, bilirubin, uric acid and cancer risk: results from a prospective population-based study.

BACKGROUND: It has long been proposed that albumin, bilirubin and uric acid may inhibit cancer development due to their anti-oxidative properties. However, there is a lack of population-based studies on blood levels of these molecules and cancer risk. METHODS: Associations between pre-diagnostic serum albumin, bilirubin and uric acid and the risks of common cancers as well as cancer death in the EPIC-Heidelberg cohort were evaluated by multivariable Cox regression analyses. A case-cohort sample including a random subcohort (n=2739) and all incident cases of breast (n=627), prostate (n=554), colorectal (n=256), and lung cancer (n=195) as well as cancer death (n=761) that occurred between baseline (1994-1998) and 2009 was used. RESULTS: Albumin levels were inversely associated with breast cancer risk (hazard ratioQuartile 4 vs Quartile 1 (95% CI): 0.71 (0.51, 0.99), Plinear trend=0.004) and overall cancer mortality (HRQ4 vs Q1 (95% CI): 0.64 (0.48, 0.86), Plinear trend<0.001) after multivariable adjustment. Uric acid levels were also inversely associated with breast cancer risk (HRQ4 vs Q1 (95% CI): 0.72 (0.53, 0.99), Plinear trend=0.043) and cancer mortality (HRQ4 vs Q1 (95% CI): 0.75 (0.58, 0.98), Plinear trend=0.09). There were no significant associations between albumin or uric acid and prostate, lung and colorectal cancer. Serum bilirubin was not associated with any cancer end point. CONCLUSIONS: The present findings indicate that higher levels of albumin and uric acid are related to lower risks of breast cancer and cancer mortality. Further studies are needed to assess whether the observed associations are causal.

Identification of Urinary Polyphenol Metabolite Patterns Associated with Polyphenol-Rich Food Intake in Adults from Four European Countries.

We identified urinary polyphenol metabolite patterns by a novel algorithm that combines dimension reduction and variable selection methods to explain polyphenol-rich food intake, and compared their respective performance with that of single biomarkers in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The study included 475 adults from four European countries (Germany, France, Italy, and Greece). Dietary intakes were assessed with 24-h dietary recalls (24-HDR) and dietary questionnaires (DQ). Thirty-four polyphenols were measured by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS-MS) in 24-h urine. Reduced rank regression-based variable importance in projection (RRR-VIP) and least absolute shrinkage and selection operator (LASSO) methods were used to select polyphenol metabolites. Reduced rank regression (RRR) was then used to identify patterns in these metabolites, maximizing the explained variability in intake of pre-selected polyphenol-rich foods. The performance of RRR models was evaluated using internal cross-validation to control for over-optimistic findings from over-fitting. High performance was observed for explaining recent intake (24-HDR) of red wine (r = 0.65; AUC = 89.1%), coffee (r = 0.51; AUC = 89.1%), and olives (r = 0.35; AUC = 82.2%). These metabolite patterns performed better or equally well compared to single polyphenol biomarkers. Neither metabolite patterns nor single biomarkers performed well in explaining habitual intake (as reported in the DQ) of polyphenol-rich foods. This proposed strategy of biomarker pattern identification has the potential of expanding the currently still limited list of available dietary intake biomarkers.

Biological reproducibility of circulating P-Selectin, Thrombopoietin, GPIIb/IIIa and Thrombomodulin over one year.

BACKGROUND: Enhanced platelet activation has been implicated in several pathophysiological processes. Here, we evaluated the biological reproducibility of circulating P-Selectin, Thrombomodulin (TM), Thrombopoietin (TPO), and Glycoprotein IIb/IIIa (GPIIb/IIIa) to assess whether these analytes can be used as reliable biomarkers of platelet activation in epidemiological studies. METHODS: We measured circulating P-Selectin, TM, TPO and GPIIb/IIIa by immunoassays in two blood samples of 78 participants of the EPIC Heidelberg study (47-80years, 50% female) that were collected one year apart. Biological reproducibility of biomarker levels over time and associations with routine biochemistry parameters were assessed by Spearman's correlation coefficients. RESULTS: Statistical analyses revealed good reproducibility over one year for two of the analyzed markers, with Spearman coefficients of ρ=0.80 (P-Selectin) and ρ=0.73 (TPO) and reasonable reproducibility for TM (ρ=0.63) and GPIIb/IIIa (ρ=0.51). Levels of P-Selectin, TM, TPO and GPIIb/IIIa were not significantly associated with routine biochemistry parameters, such as glucose, HbA1c, LDL, HDL, Triglycerides and CRP. CONCLUSIONS: Our findings suggest that a single assessment of P-Selectin, TM, TPO and GPIIb/IIIa at baseline in prospective epidemiological studies is appropriate to investigate associations between platelet activation and risks of chronic diseases.