Biomarkers Of Low-grade Inflammation Research Articles

Ambient PM2.5 and specific sources increase inflammatory cytokine responses to stimulators and reduce sensitivity to inhibitors

Ambient exposure to fine particulate matter (PM2.5) is associated with increased morbidity and mortality from multiple diseases. Recent observations suggest the hypothesis that trained immunity contributes to these risks, by demonstrating that ambient PM2.5 sensitizes innate immune cells to mount larger inflammatory response to subsequent bacterial stimuli. However, little is known about how general and durable this sensitization phenomenon is, and whether specific sources of PM2.5 are responsible. Here we consider these issues in a longitudinal study of children. The sample consisted of 277 children (mean age 13.92 years; 63.8% female; 38.4% Black; 32.2% Latinx) who completed baseline visits and were re-assessed two years later. Fasting whole blood was ex vivo incubated with 4 stimulating agents reflecting microbial and sterile triggers of inflammation, and with 2 inhibitory agents, followed by assays for IL-1β, IL-6, IL-8, and TNF-α. Blood also was assayed for 6 circulating biomarkers of low-grade inflammation: C-reactive protein, interleukin-6, -8, and -10, tumor necrosis factor-α, and soluble urokinase-type plasminogen activator receptor. Using machine learning, levels of 15 p.m.2.5 constituents were estimated for a 50 m grid around children's homes. Models were adjusted for age, sex, race, pubertal status, and household income. In cross-sectional analyses, higher neighborhood PM2.5 was associated with larger cytokine responses to the four stimulating agents. These associations were strongest for constituents released by motor vehicles and soil/crustal dust. In longitudinal analyses, residential PM2.5 was associated with declining sensitivity to inhibitory agents; this pattern was strongest for constituents from fuel/biomass combustion and motor vehicles. By contrast, PM2.5 constituents were not associated with the circulating biomarkers of low-grade inflammation. Overall, these findings suggest the possibility of a trained immunity scenario, where PM2.5 heightens inflammatory cytokine responses to multiple stimulators, and dampens sensitivity to inhibitors which counter-regulate these responses.

The association between dairy intake in adolescents on inflammation and risk markers of type 2 diabetes during young adulthood: results of the DONALD study.

The aim of this analysis was to investigate whether habitual intake of total dairy (TD) or different dairy types (liquid, solid, fermented, non-fermented, low-fat, high-fat, low-sugar and high-sugar dairy) during adolescence is associated with biomarkers of low-grade inflammation as well as risk factors of type 2 diabetes in young adulthood. Multivariable linear regression analyses were used to investigate prospective associations between estimated TD intake as well as intake of different types of dairy and a pro-inflammatory score, based on high-sensitivity C-reactive protein, IL-6, IL-18, leptin and adiponectin, and insulin resistance assessed as Homeostasis Model Assessment Insulin Resistance in an open-cohort study. Dortmund, Germany. Data from participants (n 375) of the DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study were included, for whom at least two 3-d weighed dietary records during adolescence (median age: 11 years) and one blood sample in young adulthood (>18 years) were available. There was no statistically significant association between TD intake or intake of any dairy type and the pro-inflammatory score (all P > 0·05). TD intake as well as each dairy type intake and insulin resistance also showed no association (all P > 0·05). The habitual intake of dairy or individual types of dairy during adolescence does not seem to have a major impact on low-grade systemic inflammation and insulin resistance in the long term. There was no indication regarding a restriction of dairy intake for healthy children and adolescents in terms of diabetes risk reduction.

Relationship between inflammatory biomarkers and insulin resistance in excess-weight Latin children.

Excess weight, inflammation, and insulin resistance (IR) are associated, but the prevalence of and biomarkers for IR in Latin children are unknown. This study aimed to determine the prevalence of IR in prepubertal and pubertal Latin children with excess weight and explore the usefulness of different biomarkers of low-grade inflammation for identifying IR status. Sixty-eight children (31 boys, 37 girls; approximately 11 years of age) with excess weight (overweight and obese) and 20 healthy normal-weight children (12 boys, 8 girls; approximately 12 years of age) were included. Anthropometric parameters, insulin, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, tumor necrosis factor- α (TNF-α), interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), soluble CD40 ligand (sCD40L), high-sensitivity C-reactive protein (hs-CRP), and myeloperoxidase were assessed and IR was determined by homeostasis model assessment index (cutoff points: 2.67 and 2.22 in prepubertal boys and girls and 5.55 and 3.82 in pubertal boys and girls, respectively). Intergroup differences were compared, correlations were investigated using Pearson correlation coefficient, and stepwise multiple linear regression analyses were performed to estimate the relationship between inflammatory biomarkers and IR. The prevalence of IR among overweight children was 62%. IL-6 levels differed between overweight and obese boys, while erythrocyte sedimentation rate, MCP-1, TNF-α, IL-6, hs-CRP, and sCD40L differed between obese and normal-weight boys. In contrast, sCD40L levels were increased in overweight versus normal-weight girls, while MCP-1, TNF-α, IL-6, and sCD40L differed between obese and normal-weight girls. Furthermore, MCP-1 and sCD40L levels and erythrocyte sedimentation rate were positively correlated with IR; however, a stepwise regression analysis that adjusted for the body mass index (BMI) z score, sex, and age showed that none were good predictors of IR status. The prevalence of IR is high among Latin children with excess weight. Although some inflammatory biomarkers differed among groups, none robustly predicted IR.

728-P: Biomarkers of Low-Grade Inflammation in Novel Subtypes of Patients at Risk for Diabetes

In the Tübingen Family Study recently 6 subtypes of prediabetic metabolism were identified. Cluster 3, 5 and 6 have a moderate to high risk for T2D or its associated complications. Cluster 3 is characterized by low insulin secretion, cluster 5 by insulin resistance and high liver fat content. Individuals in cluster 6 have an elevated risk of nephropathy despite a delayed diabetes development. Low-grade inflammation has been implicated in the development of T2D and cardiorenal complications. We hypothesized that the subtypes differ in levels of inflammatory biomarkers. Thus, we measured 31 inflammatory biomarkers associated with metabolic disease. We used Bio-Plex® multiplex immunoassays in 145 individuals who were recruited in Tübingen from the Prediabetes Lifestyle Intervention Study (PLIS) - a multicenter study conducted in individuals with ADA-defined prediabetes. Cluster comparison was done using ANOVA models, raw unadjusted values are reported. We identified eight biomarkers which differed among diabetes-risk subtypes, namely MIP1a, MIP1b, IL18, Osteopontin (OPN), IFNy, TNFb, and soluble TNFa-Receptor (sTNF-R)- 1 and -2. High risk cluster 3, 5 and 6 had significantly elevated levels of several inflammatory biomarkers compared to low risk cluster 2 with the lowest levels of these biomarkers. Within the high-risk groups, cluster 5 had increased biomarker levels compared to cluster 3 (e.g., IL-18: cluster 5: 86.2 pg/ml ± 3.9 vs cluster 3: 66.8 pg/ml ± 4.8, p=0.018; OPN: 16.8 ng/ml ± 1.0 vs. 12.8 ng/ml ± 0.8, p = 0.022; MIP1a 2.2 pg/ml ± 0.1 vs. 1.6 pg/ml ± 0.1, p < 0.001). Cluster 6 showed lower levels of IFNy than cluster 3 (2.2pg/ml ± 0.3 vs 3.5pg/ml ± 0.2, P=0.019). Our data show that the novel T2D risk subtypes differ in inflammatory biomarkers. This suggests that a low-grade inflammation may be involved in the progression from prediabetes to T2D and complications. A more precise mechanistic understanding is needed in order to establish precise preventive strategies for different risk phenotypes. Disclosure S.Katzenstein: None. J.Szendroedi: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. L.Fritsche: None. N.Stefan: Advisory Panel; Pfizer Inc., Research Support; Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. A.L.Birkenfeld: None. R.Jumpertz von schwartzenberg: Other Relationship; Sanofi, Amgen Inc., Lilly, Novo Nordisk. A.Sandforth: None. V.Minelli faiao: None. J.Seissler: None. S.R.Bornstein: None. N.Perakakis: Advisory Panel; Bayer Inc., Other Relationship; Novo Nordisk, Novo Nordisk. A.Schürmann: None. S.Kabisch: Other Relationship; Berlin-Chemie AG, Sanofi, Lilly, Boehringer Ingelheim Inc., JuZo Akademie, Research Support; J. Rettenmaier / Söhne, Wilhelm-Doerenkamp Foundation, German Center of Diabetes Research. M.Blüher: Advisory Panel; Boehringer Ingelheim Inc., Lilly, Novo Nordisk, Consultant; Novo Nordisk Foundation, Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo, Novartis, Sanofi-Aventis Deutschland GmbH.

273-LB: The Effect of Bispecific GLP-1R/GLP-2R Agonist Compared with Dual GLP-1R/GLP-2R Agonist and Dual GLP-1R/GIPR Agonist in Diet-Induced Obesity Mouse Model

Obesity is a global health challenge with few pharmacological options associated with type 2 diabetes and cardiovascular (CV) complications. MG12, a bispecific GLP-1R/GLP-2R Fc-fused agonist, was manufactured to show its potential advantage over current comparable dual incretin agonists. In this study, we observed that MG12 was superior in body weight (BW) reduction when compared to dual GLP-1R/GLP-2R agonist as well as combination therapy of GLP-1R and GLP-2R Fc-fused agonist. We predicted this as the result of the optimized state of increasing GLP-1 activity and the bispecific structural nature. Also, MG12 showed BW reduction in a dose-dependent manner. Interestingly, MG12 at a high dose showed similar BW reduction to dual GLP-1R/GIPR agonist despite a lesser decrease in food intake after the first injection. Additionally, we noted a higher reduction in fat/muscle mass ratio after the last injection in the comparable BW reduced group. Furthermore, MG12 showed a decrease in low grade inflammation biomarkers, which may indicate a potential CV outcome benefit. Therefore, MG12 may be a promising new therapeutic approach for obesity-related metabolic disorders. Disclosure T. Oh: Employee; Progen. Co., Ltd, SL Metagen. Co., Ltd. S. Yang: None. J. Roh: None. J. Sung: None.

Association of Epicardial Adipose Tissue Adipocytes Hypertrophy with Biomarkers of Low-Grade Inflammation and Extracellular Matrix Remodeling in Patients with Coronary Artery Disease

The aim of the study was to compare the morphological features of epicardial adipose tissue (EAT) adipocyte with the circulating inflammatory biomarkers and parameters of extracellular matrix remodeling in patients with coronary artery disease (CAD). We recruited 42 patients with CAD (m/f 28/14) who were scheduled for coronary artery bypass graft surgery (CABG). EAT adipocytes were obtained by the enzymatic method from intraoperative adipose tissue samples. Concentrations of secreted and lipoprotein-associated phospholipase A2 (sPLA2 and LpPLA2), TNF-α, IL-1β, IL-6, IL-10, high-sensitive C-reactive protein (hsCRP), metalloproteinase-9 (MMP-9), MMP-2, C-terminal cross-linking telopeptide of type I collagen (CTX-I), and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in blood serum. Patients were divided into two groups: group 1-with mean EAT adipocytes' size ≤ 87.32 μm; group 2-with mean EAT adipocytes' size > 87.32 μm. Patients of group 2 had higher concentrations of triglycerides, hsCRP, TNF-α, and sPLA2 and a lower concentration of CTX-I. A multiple logistic regression model was created (RN2 = 0.43, p = 0.0013). Concentrations of TNF-α, sPLA2 and CTX-I appeared to be independent determinants of the EAT adipocyte hypertrophy. ROC analysis revealed the 78% accuracy, 71% sensitivity, and 85% specificity of the model, AUC = 0.82. According to our results, chronic low-grade inflammation and extracellular matrix remodeling are closely associated with the development of hypertrophy of EAT adipocytes, with serum concentrations of TNF-α, sPLA2 and CTX-I being the key predictors, describing the variability of epicardial adipocytes' size.

The Relationship between Serum Ferritin Level and Insulin Resistance in Metabolic Syndrome

Introduction: Insulin resistance and metabolic syndrome (MetS) are risk factors for diabetes mellitus, and their prevalence is increasing. Ferritin has emerged as a biomarker of low-grade inflammation in addition to its role in iron metabolism. The study aims to determine the correlation between ferritin and insulin resistance (IR) in MetS. Materials and Methods: In this study, ferritin, glucose (fasting), and HOMA-IR were measured from serum samples obtained from 98 MetS patients and 100 healthy volunteers. Serum ferritin, glucose, insulin, and HOMA-IR results were compared between the MetS and the control group. Correlation analysis was performed between ferritin and HOMA-IR in control and MetS patients. Results: Serum ferritin (Control: 93,9±30,13; MetS:200±57,31 ng/ml), glucose (Control: 100,9±11,86, 123,9±21,52 ng/dl), insulin (Control: 4,11±2,57; MetS:15,99±5,71 µU/ml) and HOMA-IR (Control: 1,04±0,74; MetS:5,07±2,33) revealed to be higher in MetS compared to control. The correlation between serum ferritin level and HOMA-IR in MetS patients was revealed. This correlation was not found in the control group. Conclusion: In MetS, high serum ferritin level increases insulin resistance. While the positive correlation of ferritin with insulin resistance occurs at high ferritin levels, this is not observed at low ferritin levels.

Chronic Home Radon Exposure Is Associated with Higher Inflammatory Biomarker Concentrations in Children and Adolescents.

Children are particularly vulnerable to the deleterious impacts of toxic environmental exposures, though the effects of some rather ubiquitous toxins have yet to be characterized in youths. One such toxin, radon gas, is known to accumulate to hazardous levels in homes, and has been linked with the incidence of lung cancer in aging adults. However, the degree to which chronic home radon exposure may impact risk for health problems earlier in life is unknown. Herein, we explored the degree to which chronic home radon exposure relates to biomarkers of low-grade inflammation in 68 youths ages 6- to 14 years old residing in an area of the United States prone to high home radon concentrations. Parents completed a home radon test kit, and youths provided a saliva sample to assess concentrations of five biomarkers. Using a multiple regression approach, we found that greater radon exposure was specifically associated with higher levels of C-reactive protein (β = 0.31, p = 0.007) and interleukin-1β (β = 0.33, p = 0.016). The data suggested specificity in associations between chronic home radon exposure and different biomarkers of inflammatory activity and highlight a pathway which may confer risk for future mental and physical health maladies.

GlycA, a Biomarker of Low-Grade Inflammation, Is Increased in Male Night Shift Workers.

Sustained night shift work is associated with various adverse health risks, including an increased risk of cardiovascular disease, type II diabetes, and susceptibility to infectious respiratory diseases. The extent of these adverse health effects, however, seems to greatly vary between night shift workers, yet the underlying reasons and the mechanisms underlying these interindividual differences remain poorly understood. Metabolomics assays in the blood have recently gained much attention as a minimally invasive biomarker platform capturing information predictive of metabolic and cardiovascular diseases. In this cross-sectional study, we explored and compared the metabolic profiles of 1010 night shift workers and 1010 age- and sex-matched day workers (non-shift workers) from the Lifelines Cohort Study. The metabolic profiles were determined using the 1H-NMR Nightingale platform for the quantification of 250 parameters of metabolism, including routine lipids, extensive lipoprotein subclasses, fatty acid composition, and various low-molecular metabolites, including amino acids, ketone bodies, and gluconeogenesis-related metabolites. Night shift workers had an increased BMI (26.6 vs. 25.9 kg/m2) compared with day workers (non-shift workers) in both sexes, were slightly more likely to be ever smokers (only in males) (54% vs. 46%), worked on average 5.9 ± 3.7 night shifts per month, and had been working in night shifts for 18.3 ± 10.5 years on average. We observed changes in several metabolic markers in male night shift workers compared with non-shift workers, but no changes were observed in women. In men, we observed higher levels of glycoprotein acetyls (GlycA), triglycerides, and fatty acids compared with non-shift workers. The changes were seen in the ratio of triglycerides and cholesterol(esters) to total lipids in different sizes of VLDL particles. Glycoprotein acetyls (GlycAs) are of particular interest as markers since they are known as biomarkers for low-grade chronic inflammation. When the analyses were adjusted for BMI, no significant associations were observed. Further studies are needed to better understand the relationship between night shift work and metabolic profiles, particularly with respect to the role of sex and BMI in this relationship.

Ethnic disparities in the association between low-grade inflammation biomarkers and chronic kidney disease: The HELIUS Cohort Study

AimsEthnic differences exist in the prevalence and progression of chronic kidney disease (CKD). However, underlying mechanisms remain unclear. It has been proposed that chronic low-grade inflammation plays an important role in CKD pathogenesis. In the current analysis, we study the association between systemic inflammatory biomarkers and CKD prevalence in different ethnic groups. MethodsWe examined cross-sectional associations between biomarkers of low-grade inflammation, including serum high-sensitive (hs)-CRP, fibrinogen, and D-dimer, and CKD prevalence in different ethnic groups residing in Amsterdam, the Netherlands. We included 5740 participants (similar-sized Dutch, African Surinamese, South-Asian Surinamese, Ghanaian, Turkish and Moroccan populations) aged 18 to 70 years of the Healthy Life in an Urban Setting study (HELIUS) cohort. ResultsIn the fully adjusted models, adjusted for ethnicity-specific cut-off values, elevated fibrinogen [odds ratio 2.50 (95 % confidence interval 1.10–5.78)] and D-dimer [2.99 (1.28–7.00)] were significantly associated with CKD in Dutch. In South-Asian Surinamese, a significant association with elevated D-dimer [2.66 (1.32–5.37)] was found. ConclusionsOur study shows that there are both differences in biomarker levels and the association with CKD across ethnic groups. Future research to identify potential drivers of the differential associations and susceptibility of CKD among ethnic groups to reduce the CKD burden is necessary.

Discrimination and Inflammation in Adolescents of Color

BackgroundThis study examined how experiences with discrimination relate to inflammation, a key biological pathway in mental and physical illnesses, and whether associations are moderated by gender across two samples of adolescents of color. MethodsStudy 1 was a longitudinal study of 419 African American adolescents assessed on discrimination (ages 19–20), with trajectories of biomarkers of low-grade inflammation (C-reactive protein and soluble urokinase plasminogen activator receptor) measured from ages 25 to 29. Study 2 was a cross-sectional study of 201 eighth graders of color assessed on discrimination and mechanistic indicators of a proinflammatory phenotype: 1) in vitro studies of immune cells’ inflammatory cytokine responses to stimuli; 2) in vitro studies of cells’ sensitivity to anti-inflammatory agents; 3) circulating numbers of classical monocytes, key cellular drivers of low-grade inflammation; and 4) a composite of six biomarkers of low-grade inflammation. ResultsInteractions of discrimination by gender were found across both studies. In study 1, African American males experiencing high discrimination showed increasing trajectories of soluble urokinase plasminogen activator receptor over time (p < .001). In study 2, adolescent boys of color experiencing greater discrimination evinced a more proinflammatory phenotype: larger cytokine responses to stimuli (p = .003), lower sensitivity to anti-inflammatory agents (p = .003), higher numbers of classical monocytes (p = .008), and more low-grade inflammation (p = .003). No such associations were found in females. ConclusionsDiscrimination is a pressing societal issue that will need to be addressed in efforts to promote health equity. This study suggests that adolescent males of color may be particularly vulnerable to its effects on mental health–relevant inflammatory processes.

Serum Levels of PCSK9 Are Increased in Patients With Active Ulcerative Colitis Representing a Potential Biomarker of Disease Activity: A Cross-sectional Study.

Ulcerative colitis (UC) is characterized by chronic inflammation and progressive course, with potential extraintestinal complications including cardiovascular mortality. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels have been recently recognized as biomarkers of low-grade inflammation and cardiovascular disease. The aim of our study was to evaluate PCSK9 levels in patients with UC and different degrees of disease activity. We prospectively recruited consecutive patients with UC attending our center at the University Hospital of Padua. Demographics, clinical characteristics, and biochemical data, including PCSK9, high sensitivity C-reactive protein, and fecal calprotectin, were recorded. Moreover, endoscopic procedures were performed in all subjects. We included 112 patients with UC (mean age=52.62±12.84 y; 52.62% males). Patients with UC and abnormal fecal calprotectin (≥250 µg/g) and/or C-reactive protein (≥3 mg/L) had greater levels of PCSK9 compared with UC patients with normal fecal calprotectin and high sensitivity C-reactive protein ( P =0.03 and 0.005, respectively). Higher endoscopic scores in UC were characterized by greater levels of PCSK9 ( P =0.03). Furthermore, we found a positive correlation between PCSK9 levels and fecal calprotectin ( r =0.18, P =0.04), endoscopic Mayo Score ( r =0.25, P =0.007), and UC-Riley Index ( r =0.22, P =0.01). We also found a positive correlation between PCSK9 levels and both total and low-density lipoprotein cholesterol values ( P <0.05). Serum PCSK9 levels are increased in patients with biochemical and endoscopic evidence of active disease in UC. Further longitudinal studies are necessary to evaluate the role of PCSK9 as a potential biomarker of disease activity and cardiovascular risk in UC.

Effect of Advanced Glycation End-Products and Excessive Calorie Intake on Diet-Induced Chronic Low-Grade Inflammation Biomarkers in Murine Models.

Chronic Low-Grade Inflammation (CLGI) is a non-overt inflammatory state characterized by a continuous activation of inflammation mediators associated with metabolic diseases. It has been linked to the overconsumption of Advanced Glycation End-Products (AGEs), and/or macronutrients which lead to an increase in local and systemic pro-inflammatory biomarkers in humans and animal models. This review provides a summary of research into biomarkers of diet-induced CLGI in murine models, with a focus on AGEs and obesogenic diets, and presents the physiological effects described in the literature. Diet-induced CLGI is associated with metabolic endotoxemia, and/or gut microbiota remodeling in rodents. The mechanisms identified so far are centered on pro-inflammatory axes such as the interaction between AGEs and their main receptor AGEs (RAGE) or increased levels of lipopolysaccharide. The use of murine models has helped to elucidate the local and systemic expression of CLGI mediators. These models have enabled significant advances in identification of diet-induced CLGI biomarkers and resultant physiological effects. Some limitations on the translational (murine → humans) use of biomarkers may arise, but murine models have greatly facilitated the testing of specific dietary components. However, there remains a lack of information at the whole-organism level of organization, as well as a lack of consensus on the best biomarker for use in CLGI studies and recommendations as to future research conclude this review.

A Score of Low-Grade Inflammation for Predicting Stroke Recurrence in Patients with Ischemic Stroke.

Background and PurposeThe impact of low-grade inflammation (LGI) on stroke recurrence has not been well studied yet. We aimed to evaluate the association between LGI and stroke recurrence in patients with ischemic stroke.MethodsPatients with first-ever ischemic stroke diagnosed within 72 hours of symptoms onset were consecutively recruited from the Nanjing Stroke Registry Program. C-reactive protein (CRP) level, white blood cell (WBC) count, platelet (PLT) count, and neutrophil-to-lymphocyte ratio (NLR) were conceived as low-grade inflammation biomarkers and combined into a standardized LGI score. The association of LGI score with the risk of stroke recurrence was analyzed with multivariate Cox regression models. Analyses accounting for the competing risk of stroke recurrence and death were also performed.ResultsOf the 1214 patients studied (median age, 61 years; male, 71.6%), 177 (14.6%) patients experienced a recurrent stroke with a median follow-up of 23.0 (interquartile ranges, 14.5–34.0) months. Patients with stroke recurrence had a higher LGI score (median, 3 versus −2; P < 0.001) than those without recurrence. The univariate analysis indicated that patients with LGI scores in the fourth quartile were more likely to have a stroke recurrence (hazard ratios [HR], 4.312; 95% confidence interval [CI], 2.675–6.952; P < 0.001). After adjusting for potential confounders, the association remained significant in the multivariate Cox regression model (HR, 4.080; 95% CI, 2.420–6.879; P < 0.001). Competing risks model and sensitivity analysis further confirmed this conclusion.ConclusionThis study showed that an elevated LGI score was associated with a higher risk of stroke recurrence, independent of other vascular risk factors.

Higher rates of allergies, autoimmune diseases and low-grade inflammation markers in treatment-resistant major depression

Only 30% of patients with major depressive disorder (MDD) reach full recovery or remission. Treatment-resistant depression (TRD) is MDD that does not respond to adequate treatment attempts with at least two antidepressants. TRD is associated more with immune activation than with treatment responsive depression. The current retrospective population-based cross-sectional study, utilizing data from a large nation-wide health maintenance organization in Israel which provides services to estimated 725,000 members, aimed to assess the clinical signs and laboratory markers of autoimmune comorbidity and low-grade inflammation, in patients with TRD. Included were participants aged 18–70 years, diagnosed twice within one year with ICD-9-CM MDD and two control groups, MDD responders (MDD-r) consisting of people with MDD and no TRD and a non-MDD group that included people with no MDD or TRD. The case (570 subjects in TRD group) to control ratio in both control groups (2850 subjects in MDD-r and 2850 subjects in non-MDD control group) was 1:5. Compared to MDD-r, the overall proportion of allergic diseases was higher among the TRD than among the MDD-r [OR 1.52 (1.19–1.94); p ​< ​0.001]. Any systemic autoimmune disease was associated with increased likelihood of MDD-r [OR 1.52 (1.04–2.24); p ​= ​0.03] or TRD [OR 2.22 (1.30–3.78); p ​= ​0.003]. Higher rates of positive (>1:80) antinuclear antibodies [33 (5.79%)] were found among the TRD than among the MDD-r [98 (3.44%); p ​= ​0.011). More allergy and autoimmune comorbidities and presence of low-grade inflammation biomarkers, were found mainly in TRD.

Metabolic biomarker profiling for identification of susceptibility to severe pneumonia and COVID-19 in the general population.

Biomarkers of low-grade inflammation have been associated with susceptibility to a severe infectious disease course, even when measured prior to disease onset. We investigated whether metabolic biomarkers measured by nuclear magnetic resonance (NMR) spectroscopy could be associated with susceptibility to severe pneumonia (2507 hospitalised or fatal cases) and severe COVID-19 (652 hospitalised cases) in 105,146 generally healthy individuals from UK Biobank, with blood samples collected 2007-2010. The overall signature of metabolic biomarker associations was similar for the risk of severe pneumonia and severe COVID-19. A multi-biomarker score, comprised of 25 proteins, fatty acids, amino acids, and lipids, was associated equally strongly with enhanced susceptibility to severe COVID-19 (odds ratio 2.9 [95%CI 2.1-3.8] for highest vs lowest quintile) and severe pneumonia events occurring 7-11 years after blood sampling (2.6 [1.7-3.9]). However, the risk for severe pneumonia occurring during the first 2 years after blood sampling for people with elevated levels of the multi-biomarker score was over four times higher than for long-term risk (8.0 [4.1-15.6]). If these hypothesis generating findings on increased susceptibility to severe pneumonia during the first few years after blood sampling extend to severe COVID-19, metabolic biomarker profiling could potentially complement existing tools for identifying individuals at high risk. These results provide novel molecular understanding on how metabolic biomarkers reflect the susceptibility to severe COVID-19 and other infections in the general population.

Osteopontin's relationship with malnutrition and oxidative stress in adolescents. A pilot study.

Osteopontin (OPN) is a protein involved in inflammatory illnesses such as fibrosis and cancer; its overexpression in cardiovascular diseases promotes the biomineralization of blood vessels and other soft tissues. Moreover, there is an active component of oxidative stress related with those diseases. The present study relates serum OPN levels with nutritional condition and oxidative stress in a group of adolescents. Anthropometric measurements were performed, and fasting blood samples were analyzed to determine OPN concentrations, blood chemistry parameters (glucose, triglycerides, total cholesterol, urea, uric acid, and creatinine) and oxidative stress biomarkers (Paraoxonase-1, Glutathione S-Transferase, Catalase, NAD(P)H Quinone Oxidoreductase, free carbonyl groups and malondialdehyde). Adolescents were categorized according to body mass index (BMI) and metabolic syndrome (MetS) criteria. We found increased OPN serum concentrations in overweight and obese adolescents, as well as in adolescents with MetS. Rises in OPN correlated with arm circumference and biomarkers of lipid peroxidation; with regard to serum glucose there was a trend to positive correlation. Our results suggest that serum OPN is associated to nutritional status and could be considered as an early biomarker of low-grade inflammation and probably the early biomineralization of soft tissues in adolescence.

Metabolic Groups Related to Blood Vitamin Levels and Inflammatory Biomarkers in Brazilian Children and Adolescents.

Certain B-vitamins and vitamin A may be involved in inflammatory pathways associated with homocysteine and omega-3 fatty acids. The aims of this study were (i) to determine whether different metabolic profiles of B-vitamins and vitamin A in Brazilian children and adolescents were positively or negatively related to homocysteine and omega-3 fatty acids using k-means clustering analysis, (ii) compare nutrient intakes and metabolites between the different metabolic profiles, (iii) evaluate if the statistically significant metabolites found between the metabolic groups, can predict the variation of leukotriene A4 hydrolase (LTA4H) levels, a biomarker of low-grade inflammation, in the total studied population. This cross-sectional study included 124 children and adolescents, aged 9-13 y old. Dietary intake was assessed by the food frequency questionnaire and 24-hour recall. Biomarkers for vitamins B2, B6, B12, folate and vitamin A were measured in plasma. Omega-3 fatty acids and homocysteine were measured in red blood cells (RBC). Two different metabolic profiles were found. Thirty of these individuals had overall average higher riboflavin, pyridoxal, and vitamin B12 plasma levels (metabolic group 1) compared to 94 individuals (group 2). Group 2 had lower dietary intake of vitamin B2, vitamin A, and vitamin B12 and higher RBC levels of homocysteine. EPA and DHA erythrocyte levels were not different between metabolic groups. Multiple linear regression analyses showed that blood cobalamin, riboflavin, pyridoxal and homocysteine combined, explained 9.0% of LTA4H levels variation in the total studied population. The metabolic group that had low plasma levels of riboflavin, pyridoxal, and cobalamin also had a lower dietary intake of B-vitamin and higher RBC homocysteine. The combined levels of the riboflavin, pyridoxal, cobalamin and homocysteine biomarkers can predict the variation of LTA4H in the total population studied, but it is not clear how this regulation occurs.

Effects of Mindfulness-Based Interventions on Biomarkers and Low-Grade Inflammation in Patients with Psychiatric Disorders: A Meta-Analytic Review.

Mindfulness-Based Interventions (MBIs) present positive effects on mental health in diverse populations. However, the detailed associations between MBIs and biomarkers in patients with psychiatric disorders remain poorly understood. The aim of this study was to examine the effects of MBIs on biomarkers in psychiatric illness used to summarise the effects of low-grade inflammation. A systematic review of PubMed, EMBASE, PsycINFO, and the Cochrane Library was conducted. Effect sizes (ESs) were determined by Hedges’ g and the number needed to treat (NNT). Heterogeneity was evaluated. A total of 10 trials with 998 participants were included. MBIs showed significant improvements in the event-related potential amplitudes in attention-deficit hyperactivity disorder, the methylation of serotonin transporter genes in post-traumatic stress disorder, the salivary levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) in depression, and the blood levels of adrenocorticotropic hormone (ACTH), IL-6, and TNF-α in generalised anxiety disorder. MBIs showed low but significant effects on health status related to biomarkers of low-grade inflammation (g = −0.21; 95% confidence interval (CI) –0.41 to −0.01; NNT = 8.47), with no heterogeneity (I2 = 0; 95% CI 0 to 79). More trials are needed to establish the impact of MBIs on biomarkers in psychiatric illness.

Microvascular Dysfunction Is Associated With Worse Cognitive Performance: The Maastricht Study.

Microvascular dysfunction may be associated with worse cognitive performance. Most previous studies did not adjust for important confounders, evaluated only individual measures of microvascular dysfunction, and showed inconsistent results. We evaluated the association between a comprehensive set of measures of microvascular dysfunction and cognitive performance in the population-based Maastricht Study. We used cross-sectional data including 3011 participants (age 59.5±8.2; 48.9% women; 26.5% type 2 diabetes mellitus [oversampled by design]). Measures of microvascular dysfunction included magnetic resonance imaging features of cerebral small vessel disease, plasma biomarkers of microvascular dysfunction, albuminuria, flicker light-induced retinal arteriolar and venular dilation response and heat-induced skin hyperemia. These measures were summarized into a microvascular dysfunction composite score. Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the sum of the scores on these 3 cognitive domains. The microvascular dysfunction score was associated with a worse cognitive function score (standardized β, -0.087 [95% CI, -0.127 to -0.047]), independent of age, education level, sex, type 2 diabetes mellitus, smoking, alcohol use, hypertension, total/HDL (high-density lipoprotein) cholesterol ratio, triglycerides, lipid-modifying medication, prior cardiovascular disease, depression and plasma biomarkers of low-grade inflammation. The fully adjusted β-coefficient of the association between the microvascular dysfunction score and the cognitive function score was equivalent to 2 (range, 1-3) years of aging for each SD higher microvascular dysfunction score. The microvascular dysfunction score was associated with worse memory and processing speed but not with worse executive function. The present study shows that microvascular dysfunction is associated with worse cognitive performance.