Specific Inflammatory Biomarkers Research Articles

CARDIAC AND INFLAMMATORY BIOMARKERS IN PERINATALLY HIV-INFECTED AND HIV-EXPOSED UNINFECTED CHILDREN

OBJECTIVES To compare distributions of serum cardiac and inflammatory biomarkers between perinatally HIV-infected (PHIV) and perinatally HIV-exposed uninfected (PHEU) children, to evaluate their associations with echocardiographic measures, and among PHIV youth, with antiretroviral therapy (ART) and HIV disease severity measures. DESIGN Cross-sectional analysis of temporally paired serum samples for biomarkers and echocardiograms in a prospective multicenter cohort study of PHIV and PHEU youth. METHODS Serum samples were analyzed among 402 youth in the PHACS Adolescent Master Protocol (AMP) for high-sensitivity cardiac troponin-T (hs-cTnT, a cardiomyocyte injury marker), N-terminal-pro-brain natriuretic peptide (NT-proBNP, a myocardial stress marker), and inflammatory markers [high-sensitivity C-reactive protein, interleukin (IL)-1, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor-α (TNF-α), and soluble TNF receptor II (sTNF-RII)]. Echocardiograms were centrally measured and parameters converted to z cores to account for differences in age and body size. RESULTS Compared with PHEU (N = 156), PHIV youth (N = 246) more often had detectable hs-cTnT and higher levels of sTNF-RII and IL-18. Higher inflammatory biomarkers were generally associated with higher left ventricular (LV) wall stress and lower LV function and LV mass in the two groups. Among PHIV youth, the biomarkers were more strongly associated with current rather than historical immunologic and virologic status. CONCLUSION PHEU and PHIV have modest, significant differences in serum levels of specific inflammatory and active myocardial injury biomarkers. Higher biomarker levels were associated with lower LV mass and shifts in LV structure. Further study is warranted on the longitudinal role of cardiac and inflammatory biomarkers for targeting interventions among PHIV and PHEU youth.

Eucalyptus robusta leaves methanolic extract suppresses inflammatory mediators by specifically targeting TLR4/TLR9, MPO, COX2, iNOS and inflammatory cytokines in experimentally-induced endometritis in rats

Ethnopharmacological relevanceBacterial endometritis is one of the major causes of reproductive disorders including infertility in farm animals. Antibiotics are generally used for treatment of such disorders but now a days residues of antibiotics are of great public health concern, therefore, phytoremediation is being considered as an alternative to use of antibiotics. Aim of the studyPresent study was undertaken to investigate the efficacy of Eucalyptus robusta leaves methanolic extract against endometritis along with the possible mechanism of action especially targeting inflammatory biomarkers. Materials and methodsBacterial endometritis was produced using clinical isolates of E. coli and Staphyloccocus aureus from bovines (cows and buffaloes) endometritis cases. After seven days of inoculation of the mixed bacterial culture, endometritis was confirmed based on the presence of visible pus and edema, thinning of endometrial lining and presence of large number of polymorphonuclear cells and bacterial load in uterine flushing. Female Wistar rats were divided in to five groups namely control, sham-operated, endometritis, endometritis plus Eucalyptus leaves extract and endometritis plus cefixime. Serum specific inflammatory biomarkers (interleukin-1β, interleukin-10, tumor necrosis factor-α, intercellular adhesion molecule-1, serum amyloid A) and myleoperoxidase, toll like receptors-4 and -9, inducible nitric oxide synthase, nitric oxide, cyclooxygenase 1 and 2 were estimated in uterine tissues using ELISA kits. ResultsInterleukin-10, serum amyloid A, myleoperoxidase, toll like receptors-4 and-9, cyclooxygenase-2, inducible nitric oxide synthase and nitric oxide were significantly increased while non significant increase in interleukin-1β, cycloxygenase-1 and intercellular adhesion molecule-1 were observed but level of tumor necrosis factor-α was found decreased in rats of endometritis group. Histopathological lesions in uterus showed efficient induction of endometritis by presence of inflammatory cells which are lessened effectively after treatment with Eucalyptus leaves extract. Eucalyptus robusta leaves extract produced curative and protective effect against endometritis and results were comparable to or even better than cefixime. ConclusionsEucalyptus robusta leaves extract possess promising antibacterial activity and efficacy against experimental endometritis and, therefore, holds promising potential for development of effective formulation for treatment of endometritis in animals.

Should We be Concerned About the Inflammatory Response to Endovascular Procedures?

Endovascular surgery represents a minimally invasive procedure for the treatment of occlusive and aneurysmal arterial disease. However, it is followed by inflammatory response, with a rise in specific inflammatory biomarkers, such as C-reactive protein, serum amyloid A and fibrinogen. Shear stress during balloon inflation and vascular injury represents triggering events for the inflammatory process, stimulating the production of proinflammatory molecules and activation of circulating monocytes. The current literature indicates that stent implantation induces more prominent inflammatory reaction. Additionally, it has been shown that muscular arteries of femoropopliteal segment react to a greater extent to stent implantation, compared with elastic carotid or iliac arteries. The endovascular treatment of thoracic and abdominal aortic aneurysm is frequently followed with post-implantation inflammatory syndrome. Most recent findings point out that stent graft material plays a significant role in the inflammatory response, representing a challenge for clinicians. Future studies should consider the pathophysiology of the inflammatory response associated with endovascular procedures as well as predictors and risk factors including preventive strategies and therapeutic algorithms. Although the potential role of anti-inflammatory drugs after endovascular procedures has been observed, it needs to be validated in upcoming trials. The Neutrophil Lymphocyte Ratio, platelet count, Platelet-to-Lymphocyte Ratio and other biomarkers should be considered in future trials to assess the inflammatory response after endovascular procedures. Inflammatory markers may also become therapeutic targets.

Inflammatory Biomarkers in Childhood Arterial Ischemic Stroke

Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS. In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-α. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS. Median age at index stroke was 8.2 years (interquartile range, 3.6-14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3-10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies. Among children with AIS, specific inflammatory biomarkers correlate with cause and-in the arteriopathy group-risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials.

Asthma control and exacerbations: two different sides of the same coin.

Optimal asthma management includes both the control of asthma symptoms and reducing the risk of future asthma exacerbations. Traditionally, treatment has been adjusted largely on the basis of symptoms and lung function and for many patients, this approach delivers both excellent symptom control and reduced risk. However, the relationship between these two key components of the disease may vary between different asthmatic phenotypes and disease severities and there is increasing recognition of the need for more individualized treatment approaches. A number of factors which predict exacerbation risk have been identified including demographic and behavioural features and specific inflammatory biomarkers. Type-2 cytokine-driven eosinophilic airways inflammation predisposes to frequent exacerbations and predicts response to corticosteroids, and the usefulness of sputum eosinophilia as both a marker of exacerbation risk and biomarker for adjustment of corticosteroid treatment has been established for some time. However, attempts to develop surrogate markers, which would be more straightforward to deliver in the clinic, have been challenging. Some patients with asthma have persistent symptoms in the absence of type-2 cytokine driven-eosinophilic airways inflammation due to noncorticosteroid responsive mechanisms (T2-low disease). Composite biomarker strategies using easily measured surrogate indicators of type-2 inflammation (such as fractional exhaled nitric oxide, blood eosinophil count and serum periostin levels) may predict exacerbation risk better but it is unclear if they can be used to adjust corticosteroid treatment. Biomarkers will be used to target novel biologic treatments but additionally may be used to optimize corticosteroid treatment dose and act as prognostics for exacerbation risk and potentially other important longer term asthma outcomes.

The role of inflammatory biomarkers in developing targeted cardiovascular therapies: lessons from the cardiovascular inflammation reduction trials.

Anti-inflammatory add-on therapy to conventional cardiovascular prophylaxis has been proposed as a novel therapeutic approach to potentially reduce residual cardiovascular risk. This hypothesis has been challenged by a series of unsuccessful Phase III studies testing the impact on clinical outcomes of novel agents with immunomodulatory actions. Specifically, the apparent ability of phospholipase A2 (PLA2) inhibitors and of antioxidants to ameliorate inflammation and to reduce coronary disease in Phase II trials did not translate into improved secondary cardiovascular prevention in larger population-based studies. Other anti-inflammatory agents are still under scrutiny. However, studies to date have lacked information on the inflammatory profile of the participants, both at baseline and at follow-up, thereby limiting the possibility of identifying subgroups of patients in whom 'residual inflammation' can be detected despite optimal conventional therapy, and who could therefore benefit from a cardiovascular prevention strategy specifically targeting inflammation. This has also rendered it difficult to interpret the results as a conclusive demonstration of inefficacy of the tested anti-inflammatory strategies in the treatment of atherosclerosis. We here discuss the importance of better patient characterization to minimize heterogeneity of the study population, so that effectiveness of different anti-inflammatory strategies can be evaluated in targeted subgroups of patients. We also illustrate how specific inflammatory biomarkers could assist in this process, with particular emphasis on the roles of high-sensitivity C-reactive protein and circulating monocyte phenotype.

Effect of Vitamin D Supplementation on Glucose Control and Inflammatory Response in Type II Diabetes: A Double Blind, Randomized Clinical Trial.

Background:Diabetes mellitus (DM) and vitamin D deficiency are major health concerns around the world. Evidence suggests a possible role of vitamin D in improvement of insulin secretion and sensitivity.Objectives:We assessed whether vitamin D supplementation could be used in vitamin D deficient-type II diabetes to improve glucose metabolism, components of metabolic syndrome (MetS) and specific inflammatory biomarkers.Patients and Methods:A double blind, randomized clinical trial was conducted in King Khalid University Hospital, Saudi Arabia to evaluate the effect of cholecalciferol supplementation on glycemic control, MetS components and specific inflammatory biomarkers including tumor necrosis factor-alpha (TNF-α), Interleukin (IL-6), leptin, adiponectin and vascular cell adhesion molecule-1 (VCAM-1). Twenty-two patients with type II diabetes with insulin resistance, glycated hemoglobin (HbA1c) ≥ 6 (42 mmol/mol) and serum 25(OH)D < 50 nmol/L were randomized using a computer program to receive either supplementation with cholecalciferol (5000 IU/day) or placebo for 12 weeks. The primary outcome was change in HbA1c levels from baseline.Results:Median [IQR] 25(OH)D levels increased significantly in the vitamin D group as 58.1 [48, 67.3] nmol/L (P = 0.002). There was no significant difference in the change of HbA1c between the groups (P = 0.5) with a decrease of -0.1% [-1, 0.5] in the vitamin D group and an increase of 0.15% [0.1, 0.2] in the placebo group. A significant improvement was observed in the homeostasis model of assessment of β-cell activity (HOMA-%B) (P = 0.03) with vitamin D supplementation compared to baseline.Conclusions:Vitamin D repletion for 12 weeks increased serum vitamin D concentrations and improved β-cell activity in vitamin D-deficient type II diabetes with no significant changes in HbA1c or insulin sensitivity.

Associations between inflammation and cognitive function in African Americans and European Americans.

To examine associations between specific inflammatory biomarkers and cognitive function in African Americans (AAs) and European Americans (EAs) with prevalent vascular risk factors. Cross-sectional analysis using generalized estimating equations to account for familial clustering; standardized β-coefficients, adjusted for age, sex, and education are reported. Community cohort study in Jackson, Mississippi, and Rochester, Minnesota. Genetic Epidemiology Network of Arteriopathy (GENOA)-Genetics of Microangiopathic Brain Injury (GMBI) Study participants. Associations between inflammation (high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, soluble tumor necrosis factor (TNF) receptor 1 and 2 (sTNFR1, sTNFR2)) and cognitive function (global, processing speed, language, memory, and executive function) were examined in AAs and EAs (N = 1,965; aged 26-95, 64% women, 52% AA, 75% with hypertension). In AAs, higher sTNFR2 was associated with poorer cognition in all domains (global: -0.11, P = .009; processing speed: -0.11, P < .001; language: -0.08, P = .002; memory: -0.09, P = .008; executive function: -0.07, P = .03); sTNFR1 was associated with slower processing speed (-0.08, P < .001) and poorer executive function (-0.08, P = .008); higher CRP was associated with slower processing speed (-0.04, P = .024), and higher IL6 was associated with poorer executive function (-0.07, P = .02). In EA, only higher sTNFR1 was associated with slower processing speed (-0.05, P = .007). Associations were not found between cognition and sTNFR2, CRP, or IL6 in EA. In a population with high vascular risk, adverse associations between inflammation and cognitive function were especially apparent in AAs, primarily involving markers of TNFα activity.

Effects of exercise and diet interventions on obesity-related sleep disorders in men: study protocol for a randomized controlled trial.

BackgroundSleep is essential for normal and healthy living. Lack of good quality sleep affects physical, mental and emotional functions. Currently, the treatments of obesity-related sleep disorders focus more on suppressing sleep-related symptoms pharmaceutically and are often accompanied by side effects. Thus, there is urgent need for alternative ways to combat chronic sleep disorders. This study will investigate underlying mechanisms of the effects of exercise and diet intervention on obesity-related sleep disorders, the role of gut microbiota in relation to poor quality of sleep and day-time sleepiness, as well as the levels of hormones responsible for sleep-wake cycle regulation.Methods/designParticipants consist of 330 (target sample) Finnish men aged 30 to 65 years. Among them, we attempt to randomize 180 (target sample) with sleep disorders into exercise and diet intervention. After screening and physician examination, 101 men with sleep disorders are included and are randomly assigned into three groups: exercise (n = 33), diet (n = 35), and control (n = 33). In addition, we attempt to recruit a target number of 150 healthy men without sleep disorders as the reference group. The exercise group undergoes a six-month individualized progressive aerobic exercise program based on initial fitness level. The diet group follows a six month specific individualized diet program. The control group and reference group are asked to maintain their normal activity and diet during intervention. Measurements are taken before and after the intervention. Primary outcomes include objective sleep measurements by polysomnography and a home-based non-contact sleep monitoring system, and subjective sleep evaluation by questionnaires. Secondary outcome measures include anthropometry, body composition, fitness, sleep disorder-related lifestyle risk factors, composition of gut microbiota and adipose tissue metabolism, as well as specific hormone and neurotranmitter levels and inflammatory biomarkers from venous blood samples.DiscussionIt is expected that the improvement of sleep quality after exercise and diet intervention will be evident both in subjective and objective measures of quality of sleep. Additionally, the change of sleep quality induced by exercise and diet intervention is expected to be related to the changes in specific hormones and inflammatory biomarkers, and in the composition of gut microbiota.Trial registrationCurrent Controlled Trials ISRCTN77172005

Biomarkers of therapy responsiveness in asthma: pitfalls and promises

Asthma is one of the most common chronic diseases worldwide. There is a large inter-individual variability in response to asthma treatment. Most patients respond well to standard therapy; however, a small proportion of the patients remain symptomatic despite treatment with high dosages of corticosteroids. Uncontrolled asthma leads to a decreased quality of life. Therefore, it is important to identify individuals who will respond poorly to standard asthma medication, especially to standard maintenance therapy with inhaled corticosteroids, at an early stage. Response to anti-inflammatory therapy is generally monitored by the assessment of clinical symptoms, which only partially correlates with underlying airway inflammation. The identification of specific inflammatory biomarkers might help to guide treatment or predict a corticosteroid response more accurately. Some inflammatory biomarkers are already finding their way into clinical practice (e.g. fraction of nitric oxide in exhaled breath), whereas others are predominantly used as a research tool (e.g. profiles of volatile organic compounds). Currently, there is no inflammatory biomarker used in routine clinical practice to predict a corticosteroid response. More knowledge on the underlying biological mechanism(s) of heterogeneous therapeutic responses could help to identify novel biomarkers. This review will focus on inflammatory patterns and genetic variations that may underlie differences in treatment response in patients with asthma, and will provide an overview of inflammatory biomarkers that could potentially serve as response predictors.

PS3-58 Comprehensive Borrelia burgdorferi specific inflammatory immune response analysis in patients with Lyme disease

Background: Lyme disease is the most prevalent vector-borne infectious disorder in humans in the United States, caused by the spirochete Borrelia burgdorferi. The inflammatory processes induced by B. burgdorferi remains largely unknown. Objective: The purpose of this study was to examine the inflammatory immune response to B. burgdorferi specific antigens in patients diagnosed with Lyme disease compared with asymptomatic healthy subjects. Methods: Recombinant B. burgdorferi antigens (OspC, VlsE-1, p41, p100) were prepared and used in the study. Peripheral blood mononuclear cells (PBMCs) were purified from whole blood obtained from patients with Lyme disease (n = 40) and asymptomatic healthy subjects (n =10). Purified PBMCs were exposed to each of the specific B. burgdorferi antigens. A comprehensive multiplex cytokine analysis was performed on the supernatant of the PBMCs after the exposure of the B. burgdorferi specific antigens and compared to un-stimulated controls. Results: A trend for elevated levels of IL-1 , IL-6, TNF- , IFN- , IL-8, IL-10, G-CSF and GM-CSF was observed in patients with Lyme disease compared to healthy subjects upon spontaneous release as well as following stimulation with B. burgdorferi antigens. Compared to healthy subjects, significant elevated levels (p<0.05) of IL-6 and TNF- were observed upon p41 stimulation, and of IL-8 upon p100 stimulation in patients with Lyme disease. Conclusion: These findings indicate that the patients with Lyme disease had an active immune response with pronounced inflammation. The etiology of an active immune response in Lyme patients needs to be explored further to identify treatment regimens that go beyond antibacterial drugs. This study emphasizes the assessment of B. burgdorferi specific inflammatory biomarkers for Lyme disease in clinical practice.

Novel nasal secretion collection method for the analysis of allergen specific antibodies and inflammatory biomarkers

The analysis of immunological markers in nasal secretions provides valuable information for studying nasal mucosa diseases and monitoring immunotherapy and immunity to vaccines administered locally. However, the concentration of biomarkers is highly variable in nasal secretions because of the diversity of collection methods. A nasal secretion collection device was developed to increase detectability of the assay, standardize the sampling technique, eliminate unknown dilution factor, and minimize analyte loss during the sample processing. To develop and demonstrate the performance characteristics of a novel nasal secretion collector and its advantages over nasal lavage techniques. Characteristics of absorption and recovery of the liquid or proteins by different types of polyurethane foam were evaluated. The concentration of immunoglobulins, inflammatory mediators and allergen specific antibodies was comparatively measured in nasal secretions collected by the novel nasal secretion collector and nasal lavages. The concentrations of cytokines, eosinophil cationic protein, and tryptase in nasal secretions obtained by the nasal secretion collector were at least 8-fold higher than those tested in nasal lavages. Furthermore, the levels of immunoglobulins and the grass/weed pollen allergen specific antibodies were 6- to 290-fold increased when the nasal secretion collector was used. The nasal secretion collector was easy to use, non-invasive, and caused minimal discomfort to subjects during sampling. A novel nasal secretion collector shows a significantly higher detectability and reproducibility than nasal lavages for analyzing immunological markers in nasal secretions. The nasal secretion collector represented an approach for collecting nasal secretions and can be applied for routine evaluations of nasal immune responses induced by mucosal vaccinations or infections, inflammations and therapeutic interventions.

5-15-DiHETE and Lipoxins Generated by Neutrophils from Endogenous Arachidonic Acid as Asthma Biomarkers

5-Lipoxygenase (5-LO) activation of human blood polymorphonuclear cells (PMN) from healthy subjects (HS) and from asthmatic patients (AP) was investigated comparing their respective capacities to produce lipoxins, 5,15-dihydroxyeicosatetraenoic acid (5,15-diHETE) and leukotrienes, under in vitro stimulation by ionophore A23187. PMN from AP were able to generate higher leukotriene levels from endogenous sources than PMN from HS. Moreover they produced 5,15-diHETE (from 50 to 280ng / 10 7 cells) and lipoxins (from 1 to 30ng / 10 7 cells), in a linear manner, whereas in the same experimental conditions no detectable amounts of these compounds appeared in PMN from HS. The enhanced 5-LO activation of blood PMN may reflect transcellular signalisation priming indicating that lipoxins and 5,15-diHETE could be much more specific inflammatory state biomarkers than leukotriene B 4.