Adiponectin,biomarkers of inflammation and changes in cardiac autonomic function: Whitehall II study

Background

Biomarkers of inflammation and adiponectin are associated with cardiovascular autonomic neuropathy (CAN) in cross-sectional studies, but prospective data are scarce. This study aimed to assess the associations of biomarkers of subclinical inflammation and adiponectin with subsequent changes in heart rate (HR) and heart rate variability (HRV) in non-diabetic and diabetic individuals.

Methods

Data are based on up to 25,050 person-examinations for 8469 study participants of the Whitehall II cohort study. Measures of CAN included HR and several HRV indices. Associations between baseline serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra) and adiponectin and 5-year changes in HR and six HRV indices were estimated using mixed-effects models adjusting for age, sex, ethnicity, body mass index (BMI), metabolic covariates and medication. A modifying effect of diabetes was tested.

Results

Higher levels of IL-1Ra were associated with higher increases in HR. Additional associations with measures of HRV were observed for hsCRP, IL-6 and IL-1Ra, but these associations were explained by BMI and other confounders. Associations between adiponectin, HR and HRV differed depending on diabetes status. Higher adiponectin levels were associated with more pronounced decreases in HR and increases in three measures of HRV reflecting both sympathetic and vagal activity, but these findings were limited to individuals with type 2 diabetes.

Conclusions

Higher IL-1Ra levels appeared as novel risk marker for increases in HR. Higher adiponectin levels were associated with a more favourable development of cardiovascular autonomic function in individuals with type 2 diabetes independently of multiple confounders.

     

Association of the FTO rs9939609 single nucleotide polymorphism with C-reactive protein levels

Adipose tissue is a key factor determining C-reactive protein (CRP) plasma levels. Variation at the fat-mass and obesity-associated (FTO) gene locus has been reported to be associated with increased body fat. We investigated whether the FTO rs9939609 T>A single nucleotide polymorphism might alter CRP levels in a population-based sample of 2,415 participants from a large prospective cohort study. Genotype/phenotype relationships were studied by linear trend analysis stratified by sex. The rs9939609 A-allele was significantly associated with CRP levels in both genders (men, +21%, P = 0.002; women, +14%, P = 0.01 per A-allele). The association was attenuated, but remained statistically significant after additional adjustment for BMI, waist-to-hip ratio, and other potential confounding factors (men, +14%, P = 0.03; women, +12%, P = 0.02; per A-allele). Similar results were obtained when subjects with CRP levels higher then 10 mg/l were excluded. Our data provide preliminary evidence that the FTO rs9939609 T>A polymorphism contributes to variation in plasma CRP levels independently of obesity indices.     

CRP is related to higher leptin levels in minority peripubertal females regardless of adiposity levels

Overweight is related to higher levels of C-reactive protein (CRP) and leptin, which have been independently associated with increased risk for diabetes, cardiovascular disease, and the metabolic syndrome. Elevated CRP may trigger leptin resistance by inhibiting the binding of leptin to its receptors. We cross-sectionally examined the relationship between CRP, leptin, BMI z-score, percent body fat (%BF) assessed by air plethysmography (BodPod), and insulin sensitivity (SI) and acute insulin response (AIRg) measured by intravenous glucose tolerance test in 51 Latina and African-American females (77% Latina), mean age 9.2 (±0.9) years, at either Tanner Pubertal Stage (TPS) 1 (n = 25) or TPS 2 (n = 26). Females at TPS 2 had higher BMI z-scores, %BF (23% ± 10.1 vs. 30% ± 10.0, P = 0.02), AIRg (976.7 ± 735.2 vs. 1555.3 ± 1,223 μIU/ml, P = 0.05), fasting insulin (11.0 ± 10.8 vs. 17.2 ± 13.6 μlU/ml, P = 0.00) and leptin levels (11.0 ± 7.1 vs. 19.6 ± 10.9 ng/ml, P < 0.001) than those at TPS 1. There were no ethnic differences in any of the measured variables. CRP was positively correlated with BMI z-score (P = 0.001), %BF (P = 0.006), fasting insulin and AIRg (P = 0.02), and fasting leptin (P = 0.00), and negatively correlated with SI (P = 0.05). A linear regression model showed that CRP independently explained 10% (P = 0.00) of the variance in leptin after adjusting %BF, TPS, ethnicity, habitual physical activity and SI. Hence, low-grade inflammation may contribute to prolonged leptin exposure and leptin resistance, even in healthy children.     

The association of leptin and C-reactive protein with the cardiovascular risk factors and metabolic syndrome score in Taiwanese adults

ABSTRACT: BACKGROUND: Serum C-reactive protein (CRP) and leptin levels have been independently associated with the cardiovascular risk factors. The aim of the present study was to determine if their serum levels were associated with cardiovascular risk factors or metabolic syndrome as well as their correlation in the Taiwanese population. METHODS: This retrospective study included 999 subjects (> 18 y), who underwent a physical examination in Chang-Gung Memorial Hospital-Linkou and Chiayi in Taiwan. The associations between CRP and/or leptin levels and cardiovascular risk factors and metabolic syndrome were determined using independent two sample t-tests to detect gender differences and chi-square tests to evaluate differences in frequencies. To compare the means of the variables measured among the four groups (high and low leptin and high and low CRP), analysis of variance (ANOVA) was used. RESULTS: Both CRP and leptin levels were independently associated with several cardiovascular risk factors, including diabetes, hypercholesterolemia and metabolic syndrome in both men and women (P < 0.05). In addition, a positive correlation between leptin and CRP levels was observed in both genders. Both high-CRP and high-leptin were associated with high blood glucose, waist circumference and serum triglyceride. Whereas increased metabolic syndrome incidence was observed in males with elevated leptin regardless of CRP levels, females with elevated CRP or leptin had increased incidence of metabolic syndrome. CONCLUSION: Both leptin and CRP levels were associated with cardiovascular risk factors as well as metabolic syndrome score in both men and women although gender-specific differences were observed. Thus, CRP and leptin may represent useful biomarkers for predicting the onset of cardiovascular disease or metabolic syndrome in Taiwanese adults. Trial registration IRB/CGMH 100-3514B.     

Social networks and inflammatory markers in the Framingham Heart Study

Lack of social integration predicts coronary heart disease mortality in prospective studies; however, the biological pathways that may be responsible are poorly understood. The specific aims of this study were to examine whether social networks are associated with serum concentrations of the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1). Participants in the Framingham Study attending examinations from 1998 to 2001 (n=3267) were eligible for inclusion in the study. Social networks were assessed using the Berkman-Syme Social Network Index (SNI). Concentrations of IL-6, CRP, sICAM-1 and MCP-1 were measured in fasting serum samples. Multivariable linear regression analyses were used to assess the association of social networks with inflammatory markers adjusting for potential confounders including age, smoking, blood pressure, total:HDL cholesterol ratio, body mass index, lipid-lowering and antihypertensive medication, diabetes, cardiovascular disease, depression and socioeconomic status. Results found that the SNI was significantly inversely associated with IL-6 in men (p=0.03) after adjusting for potential confounders. In age-adjusted analyses, social networks also were significantly inversely associated with IL-6 for women (p=0.03) and were marginally to modestly associated with CRP and sICAM-1 for men (p=0.08 and 0.02, respectively), but these associations were not significant in the multivariate analyses. In conclusion, social networks were found to be inversely associated with interleukin-6 levels in men. The possibility that inflammatory markers may be potential mediators between social integration and coronary heart disease merits further investigation.     

Obesity and C-reactive protein levels among white, black, and hispanic US adults

Objective: Studies suggest that obesity's adverse impact on cardiovascular mortality may be reduced in African Americans relative to white Americans. We examined whether obesity's association with novel cardiovascular risk factors such as C‐reactive protein (CRP) also varies by race and ethnicity. Methods and Procedures: We analyzed data from 10,492 white, African‐American, and Hispanic‐American participants of the 1999–2004 National Health and Nutrition Examination Survey, who were aged 20 years and older, with a BMI ≥18.5 kg/m² and CRP ≤10 mg/l. We fit sex‐specific multivariable models of the association of BMI or waist circumference with log CRP levels and tested for interactions of BMI or waist circumference with race/ethnicity. Results: Higher BMI was significantly associated with higher CRP in all racial/ethnic groups for both men and women (P > 0.05 for BMI–race/ethnicity interaction) before and after adjustment for age, education, and health behaviors. Larger waist circumference was also associated with higher CRP levels in all racial/ethnic groups before and after adjustment; among women, the relationship was strongest for Mexican Hispanics (P < 0.01 for waist circumference–race/ethnicity interaction). Results were similar after additional adjustment for medications that might affect CRP levels. Discussion: The association between obesity and CRP is at least as strong in African Americans and Hispanic Americans as in white Americans. Racial differences in the relationship between obesity and cardiovascular mortality are unlikely to be due to racial differences in obesity's impact on CRP.     

The independent association between 25-hydroxyvitamin D and adiponectin and its relation with BMI in two large cohorts: the NHS and the HPFS

Low 25-hydroxyvitamin D (25(OH)D) and adiponectin levels are both associated with obesity and cardiovascular disease. Cross-sectional studies have suggested that 25(OH)D concentrations are positively associated with adiponectin, and that this relation may strengthen with increasing BMI. However, these studies had small samples sizes and did not account for many known confounders of adiponectin levels. We evaluated whether 25(OH)D was independently associated with circulating adiponectin in two large populations, and whether BMI modified this relationship. Cross-sectional analyses were performed on 1,206 women from the Nurses' Health Study I (NHS) and 439 men from the Health Professionals Follow-Up Study. Multivariable linear regression was used to analyze the independent association between 25(OH)D and adiponectin after controlling for potential confounders. Effect modification by BMI was examined by creating interaction terms between vitamin D and BMI. 25(OH)D concentrations were positively associated with circulating adiponectin in univariate analyses, and also independently associated with adiponectin after multivariable adjustments in both populations (women: β = 0.06, P < 0.001; men: β = 0.07, P < 0.05). BMI did not significantly modify the relation between 25(OH)D and adiponectin in either population. Higher 25(OH)D concentrations were independently associated with higher adiponectin concentrations in large populations of women and men. Since lower levels of 25(OH)D and adiponectin are associated with higher cardio-metabolic risk, assessing the effect of vitamin D supplementation on adiponectin levels is warranted.     

Interleukin-6, but not soluble adhesion molecules, predicts a subsequent mortality from cardiovascular disease in patients with acute ST-segment elevation myocardial infarction

Inflammatory responses are an important element in the atherosclerotic process. Therefore, inflammatory markers can potentially serve as predictors of cardiovascular risk. However, the existing data are limited and controversial. We conducted a prospective cohort study with 263 patients with first acute ST-segment elevation myocardial infarction (STEMI) who were admitted to our Hospital within 6 h after the symptoms onset. Clinical data were recorded and serum admission levels of interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble P-selectin (sP-selectin) were determined. The patients were then followed up for 3 years to document cardiovascular mortality. During the follow-up, 34 patients died from cardiovascular causes. The admission levels of IL-6 were significantly higher in these patients, whereas sICAM-1, sVCAM-1, and sP-selectin were comparable between these and the survived patients. The Kaplan–Meier plots revealed a significant increase in cardiovascular mortality with increasing levels of IL-6 (P = 0.0002, χ² test). The logistic regression analysis indicated that IL-6 was an independent predictor for cardiovascular mortality. To conclude, our findings indicate that elevated admission levels of IL-6, but not soluble adhesion molecules, provide valuable information for risk assessment of long-term cardiovascular mortality in patients with STEMI.     

Adiposity measures and oxidative stress among police officers

Our objective was to investigate associations between adiposity measures (BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio, and abdominal height) and biomarkers of oxidative stress (glutathione (GSH), GSH peroxidase (GSH-Px), vitamin C, thiobarbituric acid reactive substances (TBARS), and trolox equivalent antioxidant capacity (TEAC)) among police officers. This cross-sectional study included randomly selected police officers (43 policewomen; 67 policemen) from Buffalo, New York. Adiposity measures were performed using standardized methods. Biomarkers were measured on fasting blood specimens. An oxidative stress score (OSS) was created as a composite of the biomarkers. ANOVAs were used to compare mean levels of biomarkers across tertiles of the adiposity measures. Officers were 26- to 61-years old. GSH was inversely associated with waist circumference (trend P = 0.030) and waist-to-hip ratio (trend P = 0.026). GSH-Px was inversely associated with BMI (trend P = 0.004) and with waist-to-height ratio (trend P = 0.017). No associations were observed for TEAC, TBARS, or OSS with any adiposity measure. Significant interactions were observed by physical activity status for GSH with waist circumference and waist-to-hip ratio and for vitamin C with waist circumference, waist-to-hip and waist-to-height ratios. The above associations were inversely related only among officers who reported engaging in physical activity. Inverse associations were observed for BMI and waist circumference with GSH, but only among women; the interaction with gender was significant. Larger indices of adiposity were associated with increased levels of oxidative stress and decreased levels of antioxidant defense.     

Raised CRP levels in obese patients: symptoms of depression have an independent positive association

Background: Depression and obesity, the two common ailments of modern society, are associated with increased risk of coronary artery disease and raised C‐reactive protein (CRP) levels. Are the effects of depression and obesity related or do they influence CRP levels independently? Objective: In 493 consecutive patients presenting for obesity surgery, we explored the relationship between symptoms of depression and raised CRP levels after controlling for confounding factors. Methods and Procedures: Depression was measured using the Beck Depression Inventory (BDI). Confounding variables were age, gender, BMI, waist and hip measures, smoking and alcohol habits, medications, biochemical measures of the metabolic syndrome, and indirect measures of insulin resistance. General linear regression sought variables independently associated with CRP levels. Results: These patients had a BMI range from 31 to 91 kg/m², participants age ranged from 14 to 71 years, and 76% were women. The median CRP concentration was 7.7 mg/l (interquartile range: 3.9–14), 40% had an abnormally raised concentration (>10 mg/l). The mean BDI score was 17.0 ± 9.0, indicating symptoms of moderate depression. We found five independent factors associated with raised CRP levels. In order of strength of association, these were: higher BMI (β = 0.36, P < 0.001), female gender (β = ?0.19, P < 0.001), estrogen therapy (β = 0.18, P < 0.001), higher BDI score (β = 0.11, P = 0.01), and insulin resistance index (β = 0.11, P = 0.01), and with a combined R ² = 0.24, (P < 0.001). Discussion: In obese patients, symptoms of depression were associated with raised CRP levels after controlling for confounding variables. Obese women on estrogen therapy are at risk of high CRP levels.     

The effects of peritoneal dialysis and hemodialysis on serum tumor necrosis factor-alpha, interleukin-6, interleukin-10 and C-reactive-protein levels

BACKGROUND: Markers of an acute phase reaction, such as C-reactive protein (CRP) or tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, are predictive for cardiovascular morbidity and mortality in normal subjects and in chronic renal failure patients. In this study, we aimed to investigate serum TNF-alpha, IL-6, IL-10 and CRP levels in continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) patients. MATERIALS AND METHODS: Serum levels of TNF-alpha, IL-6, IL-10 and CRP levels were measured in 30 patients who were just diagnosed with end-stage renal failure and treated, with 16 CAPD (nine female, seven male) and 14 HD (eight female, six male) patients, before CAPD or HD treatment and after 3 months from the beginning of CAPD or HD in patients with no clinical signs of infection. The control groups were 20 healthy persons of similar age and sex. Serum levels of TNF-alpha, IL-6, IL-10 and CRP were measured by enzyme-linked immunosorbent assay in stable CAPD and HD patients and in healthy persons. RESULTS: The mean serum levels of TNF-alpha, IL-6, IL-10 and CRP showed no significant differences between the CAPD and HD patients for the beginning values and the third month of treatment. However, serum TNF-alpha, IL-6, IL-10 and CRP levels were higher than the control group in the CAPD and HD patients regarding the beginning values and the third month of treatment (p < 0.001). CONCLUSIONS: CAPD and HD of the renal replacement therapy have no effects on serum CRP and cytokines.     

Total tooth loss and systemic correlates of inflammation: role of obesity

Obesity and edentulism are both associated with multiple systemic disorders with an inflammatory background including periodontal diseases. This study aimed to evaluate the different impact of obesity on inflammation in dentate and toothless subjects. The data came from the population-based, cross-sectional study SHIP (Study of Health in Pomerania). We determined anthropometric measures including BMI, waist-to-hip ratio (WHR), diagnostic periodontal parameters, and systemic metabolites. It was shown that measures of systemic markers of inflammation and lipid or glucose metabolism (P < 0.001) were increased with higher WHR. When adjusted for age, sex, smoking, diabetes, education, physical activity, and last dentist's appointment, C-reactive protein (CRP), fibrinogen, and leukocyte count were significantly related to WHR increasing from the first to the fourth WHR quartile (P < 0.001) as well as to the BMI. In both dentate and edentulous subjects higher WHR contributes significantly to increasing systemic CRP and fibrinogen with sex differences. In toothless subjects, while still dependent on increasing WHR, the inflammatory markers CRP and fibrinogen were higher than in dentate subjects, thereby revealing effect modification between sex and edentulism (P < 0.010). In conclusion, subjects with total tooth loss, although devoid of periodontal inflammation, may exhibit increased levels of systemic inflammatory mediators. Possible implications are discussed with respect to obesity and its relationship to inflammation.     

Biomarkers of endothelial dysfunction,cardiovascular risk factors and atherosclerosis in rheumatoid arthritis

Cardiovascular event rates are markedly increased in rheumatoid arthritis (RA), and RA atherogenesis remains poorly understood. The relative contributions of traditional and nontraditional risk factors to cardiovascular disease in RA await elucidation. The present study comprises three components. First, we compared biomarkers of endothelial dysfunction (vascular cell adhesion molecule [VCAM]-1, intercellular adhesion molecule [ICAM]-1 and endothelial leucocyte adhesion molecule [ELAM]-1) in 74 RA patients and 80 healthy control individuals before and after controlling for traditional and nontraditional cardiovascular risk factors, including high-sensitivity C-reactive protein (hs-CRP), IL-1, IL-6 and tumor necrosis factor-α. Second, we investigated the potential role of an extensive range of patient characteristics in endothelial dysfunction in the 74 RA patients. Finally, we assessed associations between biomarkers of endothelial dysfunction and ultrasonographically determined common carotid artery intima–media thickness and plaque in RA. The three biomarkers of endothelial dysfunction, as well as hs-CRP, IL-1, IL-6 and tumor necrosis factor-α, were higher in patients than in control individuals (P < 0.0001). Patients were also older, exercised less and had a greater waist circumference, blood pressure and triglyceride levels (P ≤ 0.04). Five patients had diabetes. Differences in endothelial function were no longer significant between patients and controls (P = 0.08) only after both traditional and nontraditional cardiovascular risk factors were controlled for. In the 74 RA patients, IL-6 predicted levels of all three biomarkers (P ≤ 0.03), and rheumatoid factor titres and low glomerular filtration rate (GFR) both predicted levels of VCAM-1 and ICAM-1, independent of traditional cardiovascular risk factors (P ≤ 0.02). VCAM-1 was associated with common carotid artery intima–media thickness (P = 0.02) and plaque (P = 0.04) in RA. Patients had impaired endothelial function, less favourable traditional cardiovascular risk factor profiles, and higher circulating concentrations of hs-CRP and cytokines compared with healthy control individuals. Both traditional and nontraditional cardiovascular risk factors contributed to the differences in endothelial function between RA patients and healthy control individuals. IL-6, rheumatoid factor titres and low GFR were independently predictive of endothelial dysfunction in RA. Disease-modifying agents that effectively suppress both cytokine and rheumatoid factor production, and interventions aimed at preserving renal function may attenuate cardiovascular risk in RA.     

Moléculas solubles de adhesión intercelular tipo 1 y proteína C reactiva tras cirugía bariátrica

Background and objectivesObesity is associated with a state of chronic low-grade inflammation. A causal association between inflammatory processes and atherogenesis has been proposed. The aim of this study was to evaluate changes in the proinflammatory profile of morbidly obese patients who underwent bariatric surgery. Serum C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) concentrations were measured before and after massive weight loss due to gastric bypass.MethodsIn this prospective study we measured CRP and sICAM-1 concentrations in 50 morbidly obese patients (19 men and 31women) at baseline and 3, 6 and 12 months after gastric bypass.ResultsBody mass index (BMI), CRP, and sICAM-1 decreased significantly. BMI correlated with CRP but not with sICAM-1.ConclusionsThe improvement in vascular risk profile after weight loss in morbidly obese patients could be partially explained by changes in inflammatory status.     

Selected immunological changes in patients with Goeckerman's therapy TNF-alpha, sE-selectin, sP-selectin, sICAM-1 and IL-8

Psoriasis is one of the most frequent inflammatory skin diseases in which abnormal individual immune reactivity plays an important role. The aim of the present study was to describe selected immunological changes, concerning pro-inflammatory cytokines (TNF-alpha, IL-8) and adhesion molecules (sE-selectin, sP-selectin, sICAM-1), in 56 patients cured by Goeckerman's therapy (GT). GT includes dermal application of crude coal tar (containing polycyclic aromatic hydrocarbons) and exposure to UV radiation. When compared with the control group (healthy blood donors), the patients before GT had significantly increased serum levels of sE-selectin (p<0.001), sP-selectin (p<0.001), sICAM-1 (p<0.001) and IL-8 (p<0.001). Significantly decreased serum levels of sE-selectin (p<0.05) and significantly increased serum levels of IL-8 (p<0.05) were found after GT therapy. Serum levels of sICAM significantly correlated with the disease activity and with serum levels of sE-selectin. The level of PASI score (Psoriasis Area and Severity Index) significantly decreased after GT (p<0.001) and confirms the high efficiency GT. These findings confirmed that pro-inflammatory chemokine (IL-8) and adhesion molecules (sE-selectin, sP-selectin, sICAM-1) play an important role in the development and regulation of inflammation in psoriasis. Determination of sE-selectin and sICAM seems to be a promising marker of psoriasis's activity. Chemokine pathway (IL-8) and TNF-alpha activity seem to be modulated by Goeckerman's therapy (polycyclic aromatic hydrocarbons).     

Levels of soluble ICAM-1 in premature and full-term neonates with infection

BACKGROUND: Infection in the neonatal period is an extremely serious condition and diagnosis is difficult. C-reactive protein (CRP) is widely used as a marker of infection; however, its usefulness is limited in the early phase. The role of soluble intracellular adhesion molecule-1 (sICAM-1), an adhesion molecule, has been examined in recent studies as an early marker of neonatal infection with controversial results. AIM: Assessment of sICAM-1 concentrations and correlation with CRP, which is the currently used marker of infection, in order to use sICAM as an early diagnostic tool in neonates suspected for infection METHODS: Blood samples and blood cultures were obtained from two groups of pre-term and full-term neonates with clinical suspicion of infection prior to the initiation of antibiotics. The sICAM-1 and CRP values were compared with the corresponding noninfected ones (n = 10 each). RESULTS: The sICAM-1 levels were found increased in the group of both premature and term neonates with infection compared with the corresponding healthy ones (P < 0.0001). Prematurity combined with infection resulted in excessive increase of the levels of sICAM-1 in comparison with full-term infected newborns (p < 0.001). CRP values were normal in all samples except one in both full-term and premature infected neonates on day 1 of clinically suspected infection. Serial detection of CRP values on days 2 and 4 of infection revealed a pattern according to which CRP values in premature neonates continued rising, while in the group of full terms these values, after rising on the second day, lowered on day 4. CONCLUSIONS: Increased sICAM-1 levels can be detected early in both full-term and premature neonates with sepsis while CRP levels are within normal range at the same time. Assessment of sICAM-1 concentrations may be used as a diagnostic tool in neonates suspected for infection, resulting in earlier initiation of antibiotic therapy and therefore improving their outcome.     

Interleukin-6 and C-reactive protein,successful aging,and mortality: the PolSenior study

Background

In the elderly, chronic low-grade inflammation (inflammaging) is a risk factor for the development of aging-related diseases and frailty. Using data from several thousand Eastern Europeans aged 65 years and older, we investigated whether the serum levels of two proinflammatory factors, interleukin-6 (IL-6) and C-reactive protein (CRP), were associated with physical and cognitive performance, and could predict mortality in successfully aging elderly.

Results

IL-6 and CRP levels systematically increased in an age-dependent manner in the entire study group (IL-6: n?=?3496 individuals, p?<?0.001 and CRP: n?=?3632, p?=?0.003), and in the subgroup of successfully aging individuals who had never been diagnosed with cardiovascular disease, myocardial infarction, stroke, type 2 diabetes, or cancer, and had a Mini Mental State Examination (MMSE) score ≥24 and a Katz Activities of Daily Living (ADL) score ≥5 (IL-6: n?=?1258, p?<?0.001 and CRP: n?=?1312, p?<?0.001). In the subgroup of individuals suffering from aging-related diseases/disability, only IL-6 increased with age (IL-6: n?=?2238, p?<?0.001 and CRP: n?=?2320, p?=?0.249). IL-6 and CRP levels were lower in successfully aging individuals than in the remaining study participants (both p?<?0.001). Higher IL-6 and CRP levels were associated with poorer physical performance (lower ADL score) and poorer cognitive performance (lower MMSE score) (both p?<?0.001). This association remained significant after adjusting for age, gender, BMI, lipids, estimated glomerular filtration rate, and smoking status. Longer survival was associated with lower concentrations of IL-6 and CRP not only in individuals with aging-related diseases/disability (HR?=?1.063 per each pg/mL, 95 % CI: 1.052-1.074, p?<?0.001 and HR?=?1.020 per each mg/L, 95 % CI: 1.015-1.025, p?<?0.001, respectively) but also in the successfully aging subgroup (HR?=?1.163 per each pg/mL, 95 % CI: 1.128-1.199, p?<?0.001 and HR?=?1.074 per each mg/L, 95 % CI: 1.047-1.100, p?<?0.001, respectively). These associations remained significant after adjusting for age, gender, BMI, lipids and smoking status. The Kaplan-Meier survival curves showed similar results (all p?<?0.001).

Conclusions

Both IL-6 and CRP levels were good predictors of physical and cognitive performance and the risk of mortality in both the entire elderly population and in successfully aging individuals.

     

BMI, waist circumference, and selected cardiovascular disease risk factors among preschool-age children

In adults, overweight is often associated with other cardiovascular disease (CVD) risk factors. We determined whether these associations were also present in young children. This study examined the relationships between elevated BMI (≥85th and ≥95th percentiles for age and sex) and the highest quintile of waist circumference (WC) with CVD risk factors, including fasting triglyceride (TGL), high- and low-density lipoprotein (HDL and LDL), total cholesterol (TC), non-HDL cholesterol, and C-reactive protein (CRP) in 3,644 3- to 6-year-old children included in the 1999-2008 National Health and Nutrition Examination Surveys (NHANES). Results showed that 20% (highest quintile) of the sample had a TC >170 mg/dl, LDL >109 mg/dl, TGL >103 mg/dl, non-HDL >128 mg/dl, CRP >0.13 mg/dl, WC >57.2 cm, and HDL <42 mg/dl. Increased BMI and WC were associated with increased CRP levels in non-Hispanic black boys and girls, Hispanic boys, and non-Hispanic white girls, whereas elevated TGL and non-HDL cholesterol and low HDL cholesterol were generally associated with elevated BMI and WC in Hispanic children. TC and LDL cholesterol were not significantly associated with elevated weight in 3- to 6-year-olds. BMI and WC were similar in predicting the same risk factors. In summary, this analysis shows that in preschool-age children, greater BMI and WC are associated with biomarkers that are related to CVD risk, but these associations vary by ethnicity. Child health providers should consider using both BMI and WC to identify young children who may be at risk for elevated CVD biomarkers.     

Circulating oxidized LDL and inflammation in extreme pediatric obesity

Oxidative stress and inflammation have not been well-characterized in extreme pediatric obesity. We compared levels of circulating oxidized low-density lipoprotein (oxLDL), C-reactive protein (CRP), and interleukin-6 (IL-6) in extremely obese (EO) children to normal weight (NW) and overweight/obese (OW/OB) children. OxLDL, CRP, IL-6, BMI, blood pressure, and fasting glucose, insulin, and lipids were obtained in 225 children and adolescents (age 13.5 ± 2.5 years; boys 55%). Participants were classified into three groups based on gender- and age-specific BMI percentile: NW (<85th, n = 127), OW/OB (85th- <1.2 times the 95th percentile, n = 64) and EO (≥1.2 times the 95th percentile or BMI ≥35 kg/m(2), n = 34). Measures were compared across groups using analysis of covariance, adjusted for gender, age, and race. Blood pressure, insulin, and lipids worsened across BMI groups (all P < 0.0001). OxLDL (NW: 40.8 ± 9.0 U/l, OW/OB: 45.7 ± 12.1 U/l, EO: 63.5 ± 13.8 U/l) and CRP (NW: 0.5 ± 1.0 mg/l, OW/OB: 1.4 ± 2.9 mg/l, EO: 5.6 ± 4.9 mg/l) increased significantly across BMI groups (all groups differed with P < 0.01). IL-6 was significantly higher in EO (2.0 ± 0.9 pg/ml) compared to OW/OB (1.3 ± 1.2 pg/ml, P < 0.001) and NW (1.1 ± 1.0 pg/ml, P < 0.0001) but was not different between NW and OW/OB. Extreme pediatric obesity, compared to milder forms of adiposity and NW, is associated with higher levels of oxidative stress and inflammation, suggesting that markers of early cardiovascular disease and type 2 diabetes mellitus are already present in this young population.     

Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study

Background

Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible.

Methods and Findings

We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1–5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p≤0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7–25.6, p<0.001).

Conclusions

Pre-ART increases in Th₁₇ and Th₂ responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-α, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions. Please see later in the article for the Editors'' Summary