Background: The Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project is a multiagency and multicountry collaboration that was formed to improve micronutrient assessment and to better characterize anemia.Objectives: The aims of the project were to 1) identify factors associated with inflammation, 2) assess the relations between inflammation, malaria infection, and biomarkers of iron and vitamin A status and compare adjustment approaches, and 3) assess risk factors for anemia in preschool children (PSC) and women of reproductive age (WRA).Design: The BRINDA database inclusion criteria included surveys that 1) were conducted after 2004, 2) had target groups of PSC, WRA, or both, and 3) used a similar laboratory methodology for the measurement of ≥1 biomarker of iron [ferritin or soluble transferrin receptor or vitamin A status (retinol-binding protein or retinol)] and ≥1 biomarker of inflammation (α-1-acid glycoprotein or C-reactive protein). Individual data sets were standardized and merged into a BRINDA database comprising 16 nationally and regionally representative surveys from 14 countries. Collectively, the database covered all 6 WHO geographic regions and contained ∼30,000 PSC and 27,000 WRA. Data were analyzed individually and combined with the use of a meta-analysis.Results: The methods that were used to standardize the BRINDA database and the analytic approaches used to address the project's research questions are presented in this article. Three approaches to adjust micronutrient biomarker concentrations in the presence of inflammation and malaria infection are presented, along with an anemia conceptual framework that guided the BRINDA project's anemia analyses.Conclusions: The BRINDA project refines approaches to interpret iron and vitamin A biomarker values in settings of inflammation and malaria infection and suggests the use of a new regression approach as well as proposes an anemia framework to which real-world data can be applied. Findings can inform guidelines and strategies to prevent and control micronutrient deficiencies and anemia globally.
Vitamin A deficiency (VAD) is an important contributor to child morbidity and mortality. The prevalence of VAD, measured by retinol-binding protein (RBP) or retinol, is overestimated in populations with a high prevalence of inflammation. We aimed to quantify and adjust for the effect of inflammation on VAD prevalence in a nationally representative survey of Liberian children 6 to 35months of age. We compared five approaches to adjust RBP for inflammation and estimate VAD prevalence (defined as RBP<0.7μmol/L): (1) ignoring inflammation; (2) excluding individuals with inflammation (C-reactive protein (CRP) >5mg/L or alpha1-acid glycoprotein (AGP) >1g/)L; (3) multiplying each individual's RBP by an internal correction factor; (4) by an external correction factor; and (5) using regression (corrected RBP=exp(InRBP - β1(lnCRPobs-lnCRPref) - β2(lnAGPobs-lnAGPref)). Corrected RBP was based on a regression model where reference lnCRP and lnAGP were set to the maximum of the lowest decile. The unadjusted prevalence of VAD was 24.7%. Children with elevated CRP and/or AGP had significantly lower RBP concentrations than their apparently healthy peers (geometric mean RBP 0.79μmol/L (95% CI: 0.76, 0.82) vs. 0.95μmol/L (95% CI: 0.92, 0.97), P<0.001). Using approaches 2-5 resulted in a prevalence of VAD of 11.6%, 14.3%, 13.5% and 7.3%, respectively. Depending on the approach, the VAD prevalence is reduced 10-17 percentage points when inflammation is taken into account. Further quantification of the influence of inflammation on biomarkers of vitamin A status from other national surveys is needed to compare and recommend the preferred adjustment approach across populations.
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Rebecca D. Merrill;
Rachel M. Burke;
Christine A. Northrop-Clewes;
Pura Rayco-Solon;
Rafael Flores-Ayala;
Sorrel M.L. Namaste;
Mary K. Serdula;
Parminder S Suchdev
Background: In many settings, populations experience recurrent exposure to inflammatory agents that catalyze fluctuations in the concentrations of acute-phase proteins and certain micronutrient biomarkers such as C-reactive protein (CRP), α-1-acid glycoprotein (AGP), ferritin, and retinol. Few data are available on the prevalence and predictors of inflammation in diverse settings.Objective: We aimed to assess the relation between inflammation (CRP concentration > 5 mg/L or AGP concentration > 1 g/L) and covariates, such as demographics, reported illness, and anthropometric status, in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y).Design: Cross-sectional data from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project from 29,765 PSC in 16 surveys and 25,731 WRA in 10 surveys were used to model bivariable and multivariable relations.Results: The inflammation prevalence was 6.0-40.2% in PSC and 7.9-29.5% in WRA (elevated CRP) and 21.2-64.3% in PSC and 7.1-26.7% in WRA (elevated AGP). In PSC, inflammation was consistently positively associated with recent fever and malaria but not with other recent illnesses. In multivariable models that were adjusted for age, sex, urban or rural residence, and socioeconomic status, elevated AGP was positively associated with stunting (height-for-age z score < -2) in 7 of 10 surveys. In WRA, elevated CRP was positively associated with obesity [body mass index (in kg/m2) ≥30] in 7 of 9 surveys. Other covariates showed inconsistent patterns of association with inflammation. In a pooled analysis of surveys that measured malaria, stunting was associated with elevated AGP but not CRP in PSC, and obesity was associated with both elevated CRP and AGP in WRA.Conclusions: Recent morbidity and abnormal anthropometric status are consistently associated with inflammation across a range of environments, whereas more commonly collected demographic covariates were not. Because of the challenge of defining a general demographic population or environmental profile that is more likely to experience inflammation, inflammatory markers should be measured in surveys to account for their effects.
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Baback Roshanravan;
Leila R. Zelnick;
Daniel Djucovic;
Haiwei Gu;
Jessica A. Alvarez;
Thomas R Ziegler;
Jorge L. Gamboa;
Kristina Utzschneider;
Bryan Kestenbaum;
Jonathan Himmelfarb;
Steven E. Kahn;
Daniel Raftery;
Ian H. de Boer
Chronic kidney disease (CKD) leads to decreased sensitivity to the metabolic effects of insulin, contributing to protein energy wasting and muscle atrophy. Targeted metabolomics profiling during hyperinsulinemic-euglycemic insulin clamp testing may help identify aberrant metabolic pathways contributing to insulin resistance in CKD. Using targeted metabolomics profiling, we examined the plasma metabolome in 95 adults without diabetes in the fasted state (58 with CKD, 37 with normal glomerular filtration rate [GFR]) who underwent hyperinsulinemic-euglycemic clamp. We assessed heterogeneity in fasting metabolites and the response to insulin to identify potential metabolic pathways linking CKD with insulin resistance. Baseline differences and effect modification by CKD status on changes with insulin clamp testing were adjusted for confounders. Mean GFR among participants with CKD was 37.3 compared with 89.3 ml/min per 1.73 m2 among controls. Fasted-state differences between CKD and controls included abnormalities in tryptophan metabolism, ubiquinone biosynthesis, and the TCA cycle. Insulin infusion markedly decreased metabolite levels, predominantly amino acids and their metabolites. CKD was associated with attenuated insulin-induced changes in nicotinamide, arachidonic acid, and glutamine/glutamate metabolic pathways. Metabolomics profiling suggests disruption in amino acid metabolism and mitochondrial function as putative manifestations or mechanisms of the impaired anabolic effects of insulin in CKD.
Stress-induced eating disorders cause significant health problems and are often comorbid with mood disorders. Emotional feeding, particularly in women, may be important for the development of obesity and failed attempts to lose weight. However, prospective studies assessing the effect of chronic psychosocial stress on appetite in different dietary environments in females are lacking. The present study tested the hypothesis that chronic psychosocial stress would increase consumption of high caloric diet and this emotional feeding would persist even when a healthier diet was available. Socially housed female rhesus monkeys were studied to address whether subordination increases caloric intake when a high fat and sugar diet (HFSD) was available concurrently with a low fat, high fiber diet (LCD). Cortisol responsivity and food intake were quantified during this choice phase and when only the LCD was available. The order of diet condition was counterbalanced to assess whether a history of HFSD would affect appetite. All females preferred the HFSD but subordinates consumed significantly more calories during the choice phase. The increased calorie intake was maintained in subordinate monkeys even after withdrawal of the HFSD. Subordinate females demonstrated reduced glucocorticoid negative feedback, with post dexamethasone serum cortisol levels significantly predicting intake of the HFSD but not the LCD during the choice condition. The cortisol response to an acute stressor significantly predicted subsequent intake of a HFSD in all females. Continual exposure to the psychosocial stress of subordination in female monkeys results in excess caloric intake of foods that mimic a western dietary environment. In addition, this social stressor interacts with a history of HFSD intake to promote increased feeding even in a healthy dietary environment.
Objectives: We aimed to describe and compare the prevalence of vitamin D deficiency between HIV-negative and HIV-infected veterans in the southern United States, and to determine risk factors for vitamin D deficiency for HIV infected patients. Methods: Cross-sectional, retrospective study including all patients followed at the Atlanta VA Medical Center with the first 25-hydroxyvitamin D [25(OH)D] level determined between January 2007 and August 2010. Multivariate logistic regression analysis was used to determine risk factors associated with vitamin D deficiency (< 20 ng/ml). Results: There was higher prevalence of 25(OH)D deficiency among HIV-positive compared to HIV-negative patients (53.2 vs. 38.5%, p <0.001). Independent risk factors for vitamin D deficiency in HIV + patients included black race (OR 3.24, 95% CI 2.28-4.60), winter season (OR 1.39, 95% CI 1.05-1.84) and higher GFR (OR 1.01, CI 1.00-1.01); increasing age (OR 0.98, 95% CI 0.95-0.98), and tenofovir use (OR 0.72, 95% CI 0.54-0.96) were associated with less vitamin D deficiency. Conclusions: Vitamin D deficiency is a prevalent problem that varies inversely with age and affects HIV-infected patients more than other veterans in care. In addition to age, tenofovir and kidney disease seem to confer a protective effect from vitamin D deficiency in HIV-positive patients.
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Cara L Green;
Quinlyn Soltow;
Sharon E Mitchell;
Davina Derous;
Yingchun Wang;
Luonan Chen;
Jing-Dong J Han;
Daniel E L Promislow;
David Lusseau;
Alex Douglas;
Dean Jones;
John R Speakman
Calorie restriction (CR) remains the most robust intervention to extend life span and improve health span. Using a global mass spectrometry-based metabolomics approach, we identified metabolites that were significantly differentially expressed in the plasma of C57BL/6 mice, fed graded levels of calorie restriction (10% CR, 20% CR, 30% CR, and 40% CR) compared with mice fed ad libitum for 12 hours a day. The differential expression of metabolites increased with the severity of CR. Pathway analysis revealed that graded CR had an impact on vitamin E and vitamin B levels, branched chain amino acids, aromatic amino acids, and fatty acid pathways. The majority of amino acids correlated positively with fat-free mass and visceral fat mass, indicating a strong relationship with body composition and vitamin E metabolites correlated with stomach and colon size, which may allude to the beneficial effects of investing in gastrointestinal organs with CR. In addition, metabolites that showed a graded effect, such as the sphinganines, carnitines, and bile acids, match our previous study on liver, which suggests not only that CR remodels the metabolome in a way that promotes energy efficiency, but also that some changes are conserved across tissues.
BACKGROUND: Anemia and vitamin D deficiency are highly prevalent in critical illness, and vitamin D status has been associated with hemoglobin concentrations in epidemiologic studies. We examined the effect of high-dose vitamin D therapy on hemoglobin and hepcidin concentrations in critically ill adults. MATERIALS AND METHODS: Mechanically ventilated critically ill adults (N = 30) enrolled in a pilot double-blind, randomized, placebo-controlled trial of high-dose vitamin D3 (D3 ) were included in this analysis. Participants were randomized to receive placebo, 50,000 IU D3 , or 100,000 IU D3 daily for 5 days (totaling 250,000 IU D3 and 500,000 IU D3 , respectively). Blood was drawn weekly throughout hospitalization for up to 4 weeks. Linear mixed-effects models were used to assess change in hemoglobin and hepcidin concentrations by treatment group over time. RESULTS: At enrollment, >75% of participants in all groups had plasma 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL, and >85% of participants across groups were anemic. In the 500,000-IU D3 group, hemoglobin concentrations increased significantly over time (Pgroup × time = .01) compared with placebo but did not change in the 250,000-IU D3 group (Pgroup × time = 0.59). Hepcidin concentrations decreased acutely in the 500,000-IU D3 group relative to placebo after 1 week (P = .007). Hepcidin did not change significantly in the 250,000-IU D3 group. CONCLUSION: In these critically ill adults, treatment with 500,000 IU D3 was associated with increased hemoglobin concentrations over time and acutely reduced serum hepcidin concentrations. These findings suggest that high-dose vitamin D may improve iron metabolism in critical illness and should be confirmed in larger studies.
Mortality risk across metabolic health-by-BMI categories in NHANES-III was examined. Metabolic health was defined as: (1) homeostasis model assessment-insulin resistance (HOMA-IR) <2.5; (2) ≤2 Adult Treatment Panel (ATP) III metabolic syndrome criteria; (3) combined definition using ≤1 of the following: HOMA-IR ≥1.95 (or diabetes medications), triglycerides ≥1.7 mmol/L, HDL-C <1.04 mmol/L (males) or <1.30 mmol/L (females), LDL-C ≥2.6 mmol/L, and total cholesterol ≥5.2 mmol/L (or cholesterol-lowering medications). Hazard ratios (HR) for all-cause mortality were estimated with Cox regression models. Nonpregnant women and men were included (n = 4373, mean ± SD, age 37.1 ± 10.9 years, BMI 27.3 ± 5.8 kg/m 2, 49.4% female). Only 40 of 1160 obese individuals were identified as MHO by all definitions. MHO groups had superior levels of clinical risk factors compared to unhealthy individuals but inferior levels compared to healthy lean groups. There was increased risk of all-cause mortality in metabolically unhealthy obese participants regardless of definition (HOMA-IR HR 2.07 (CI 1.3-3.4), P < 0.01; ATP-III HR 1.98 (CI 1.4-2.9), P < 0.001; combined definition HR 2.19 (CI 1.3-3.8), P < 0.01). MHO participants were not significantly different from healthy lean individuals by any definition. While MHO individuals are not at significantly increased risk of all-cause mortality, their clinical risk profile is worse than that of metabolically healthy lean individuals.
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Somdat Mahabir;
David J. Baer;
Laura L. Johnson;
Joanne F. Dorgan;
William Campbell;
Ellen Brown;
Terryl Hartman;
Beverly Clevidence;
Demetrius Albanes;
Joseph T. Judd;
Philip R. Taylor
Background: We have demonstrated that moderate alcohol consumption (15 g/d, 30 g/d) for 8 weeks resulted in significantly increased levels of serum estrone sulfate and DHEAS in 51 postmenopausal women in a randomized, placebo-controlled trial. We now report on the relationships between serum estrone sulfate and dehydroepiandrosterone sulfate (DHEAS) levels after 4 weeks of moderate alcohol supplementation, and compare the results to the 8 weeks data to elucidate time-to-effect differences. Methods: Postmenopausal women (n = 51) consumed 0 (placebo), 15 (1 drink), and 30 (2 drinks) g alcohol (ethanol)/ day for 8 weeks as part of a controlled diet in a randomized crossover design. Blood samples were drawn at baseline, at 4 weeks and at 8 weeks. Changes in estrone sulfate and DHEAS levels from placebo to 15 g and 30 g alcohol per day were estimated using linear mixed models. Results and Discussion: At week 4, compared to the placebo, estrone sulfate increased an average 6.9% (P = 0.24) when the women consumed 15 g of alcohol per day, and 22.2% (P = 0.0006) when they consumed 30 g alcohol per day. DHEAS concentrations also increased significantly by an average of 8.0% (P < 0.0001) on 15 g of alcohol per day and 9.2% (P < 0.0001) when 30 g alcohol was consumed per day. Trend tests across doses for both estrone sulfate (P = 0.0006) and DHEAS (P < 0.0001) were significant. We found no significant differences between the absolute levels of serum estrone sulfate at week 4 versus week 8 (P = 0.32) across all doses. However, absolute DHEAS levels increased from week 4 to week 8 (P < 0.0001) at all three dose levels. Conclusions: These data indicate that the hormonal effects due to moderate alcohol consumption are seen early, within 4 weeks of initiation of ingestion.