Soluble Tumor Necrosis Factor-α Research Articles

Clinical efficacy of aspirin combined with clopidogrel in treating cerebral infarction and its effect on serum hs-CRP, sICAM-1 and TNF-α.

Clinical efficacy of aspirin combined with clopidogrel in treating cerebral infarction and its influence on serum high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1) and tumor necrosis factor-α (TNF-α) were explored. Ninety patients with acute cerebral infarction treated in Yidu Central Hospital of Weifang were analyzed, and those treated with aspirin alone were group A (n=40) and those treated with aspirin and clopidogrel were group B (n=50) according to the different treatment plans. The NIHSS score, total effective rate and incidence rate of adverse reactions after treatment and admission were compared between the two groups. The expression level of hs-CRP was detected by enzyme-linked immunosorbent assay, and the expression levels of sICAM-1 and TNF-α were analyzed by radioimmunoassay before treatment and three weeks after surgery, respectively, and they were analyzed and compared. After treatment, the total effective rate of patients in group B was significantly higher than that of group A (P<0.05). The general clinical baseline information, NIHSS score, and the expression levels of hs-CRP, sICAM-1, and TNF-α of patients in group B were significantly improved after treatment compared with those before treatment (P<0.05), and the NIHSS score and the expression levels of serum hs-CRP, sICAM-1, and TNF-α of those in group B were significantly lower than those in group A (P<0.05). Combination therapy of aspirin and clopidogrel can improve cerebral infarction effectively, and inhibit the expression levels of hs-CRP, sICAM-1 and TNF-α more effectively than aspirin alone.

Interplay of TNF-α, soluble TNF receptors and oxidative stress in coronary chronic total occlusion of the oldest patients with coronary heart disease

BackgroundThe interplay of tumour necrosis factor-α (TNF-α) and oxidative stress was related to severities of coronary atherosclerosis and congestive heart failure. We tried to identify TNF-α, soluble tumour necrosis factor-α receptor-1 (sTNFR-1), soluble tumour necrosis factor-α receptor-2 (sTNFR-2) and oxidative stress as potential non-invasive diagnostic and therapeutic biomarkers for coronary chronic total occlusion (CCTO) in the oldest patients with coronary heart disease (CHD). MethodsWe determined the expression levels of TNF-α, sTNFR-1, sTNFR-2, oxidative stress biomarkers (malondialdehyde [MDA], aldosterone [ALD], angiotensin II [Ang II], and high sensitivity C-reactive protein [hs-CRP]) in oldest patients with CCTO. ResultsThe levels of TNF-α, sTNFR-1, sTNFR-2, MDA, ALD, Ang II and hs-CRP were increased in oldest patients with CCTO (P < 0.001). The CCTO of oldest patients with CHD may involve the interplay of TNF-α, sTNFR-1, sTNFR-2 and oxidative stress. ConclusionsThe TNF-α, sTNFR-1, sTNFR-2 and oxidative stress could be considered as potential non-invasive diagnostic and therapeutic biomarkers for CCTO in the oldest patients with CHD.

Organ dysfunction in cirrhosis: a mechanism involving the microcirculation.

Microcirculation is essential for adequate tissue perfusion and organ function. Microcirculatory changes may occur in cirrhosis, inducing loss of multiorgan function. The aim was to evaluate preliver transplantation and postliver transplantation aspects of multiorgan function, microcirculation, inflammatory, and endothelial biomarkers and survival in a controlled study including cirrhotic outpatients. We accessed functional capillary density (FCD) and red blood cell acceleration (RBCA) by nailfold videocapillaroscopy. Inflammatory and endothelial biomarkers [interleukin-6 (IL-6), soluble intercellular adhesion molecule-1, endothelin-1, and tumor necrosis factor-α] were analyzed. Cerebral and renal functions were assessed to represent organ dysfunction and regression analyses were carried out. Receiver operating characteristic curves were constructed and survival Kaplan-Meier analysis was carried out. Fifty-four patients and 18 controls were included. Inflammatory and endothelial markers increased in advanced disease. FCD was reduced and RBCA was progressively lower according to disease severity. RBCA correlated inversely with inflammatory and endothelial biomarkers, and directly with renal function. The presence of hepatic encephalopathy correlated inversely with RBCA and directly with IL-6 and endothelin-1. In multivariate analysis, RBCA was an independent factor for organ dysfunction. The area under the receiver operating chartacteristic curve for IL-6 for survival was 0.74 (0.59-0.89), P=0.05. Transplant-free survival was 97.5% for values under 5.78 ng/ml (IL-6 best cutoff) and 83.9% above 5.78 ng/ml, log-rank=0.018. Eleven patients underwent transplantation, with an overall improvement in microcirculatory function. Our results suggest a mechanism of organ damage in cirrhosis, where microcirculatory dysfunction could be correlated to inflammatory and endothelial biomarkers, and loss of multiorgan function. IL-6 seems to be an important survival marker of inflammation. Liver transplantation improved microcirculatory dysfunction, corroborating this hypothesis.

Neurocognitive Impairment in Well-Controlled HIV-Infected Patients: A Cross-Sectional Study.

The reported prevalence of HIV-associated neurocognitive disorders in HIV people depends on the population studied and the methodology used. We analyze the prevalence of neurocognitive impairment (NCI) and associated factors in patients on successful antiretroviral therapy (ART), without comorbidities. Cross-sectional observational study in HIV subjects, ≥18 years old, on stable ART, and HIV viral load of <50 copies/mL. Patients with medical or psychiatric comorbidities and substance abuse were excluded. NCI was diagnosed using Frascati criteria, examining seven neurocognitive domains (NDs). We analyzed the association between NCI and HIV-related clinical variables, carotid intima-media thickness, bacterial translocation, and plasma inflammatory biomarkers [soluble CD14, interleukin-6 (IL-6), and tumor necrosis factor-α]. The prevalence of NCI was calculated with a 95% confidence interval (CI). We fitted a logistic regression model to assess the strength of the associations. Eighty-four patients were included with an observed NCI prevalence of 29.8% (95% CI: 21.0-40.2): 19% had asymptomatic NCI, 8.3% had mild neurocognitive disorder, and 2.4% had HIV-associated dementia. Delayed recall was the most commonly affected ND (27.4%). People diagnosed at least 10 years ago (odds ratio [OR]: 6.5, 95% CI: 1.6-21.7) and those with IL-6 levels above 1.8 pg/mL (OR: 6.0, 95% CI: 1.1-31.3) showed higher odds of NCI in adjusted analyses. Participants with carotid plaques had lower scores for delayed recall: -0.9 ± 1.1 versus -0.2 ± 1.1 (p = .04). Prevalence of NCI is high in otherwise healthy adults with HIV-infection. In this population, more than 10 years since HIV diagnosis and high IL-6 levels are associated with NCI. Delayed recall ND is worse in patients with subclinical atherosclerosis.

Pushing the limits of detection for proteins secreted from single cells using quantum dots.

Single cell analysis methods are increasingly being utilized to investigate how individual cells process information and respond to diverse stimuli. Soluble proteins play a critical role in controlling cell populations and tissues, but directly monitoring secretion is technically challenging. Microfabricated well arrays have been developed to assess secretion at the single cell level, but these systems are limited by low detection sensitivity. Semiconductor quantum dots (QD) exhibit remarkably bright and photostable luminescence signal, but to date they have not been evaluated in single cell secretion studies using microfabricated well arrays. Here, we used QDs in a sandwich immunoassay to detect secretion of the soluble cytokine tumor necrosis factor-α (TNF-α) from single cells. To enhance detection sensitivity, we employed two different strategies. First, we used a unique single QD imaging approach, which provided a detection threshold (180 attomolar) that was >100-fold lower than previously reported results using QDs. We also amplified QD binding to each captured TNF-α molecule using the bioorthogonal cycloaddition reaction between trans-cyclooctene and tetrazine, which further lowered detection threshold to 60 attomolar. This is 6 orders of magnitude more sensitive than organic fluorophores that have been used for single cell secretion studies, and far surpasses single molecule resolution within sub-picoliter microwells that are used to assess single cell secretion. Finally, single cell secretion studies were performed using phorbol 12-myristate 13-acetate (PMA) differentiated and lipopolysaccharide (LPS) activated U-937 cells. TNF-α secretion was detected from 3-fold more single cells using the QD-based method in comparison to rhodamine, which was accomplished by extending sensitivity into the range of ∼2 to 10 000 molecules captured per microwell. In future work, we will apply this technique to assess immune cell secretion dynamics under diverse stimuli and disease settings. We will also incorporate multiplexing capabilities to evaluate the secretome at the resolution of single molecules.

Levels of IL-17F and IL-33 correlate with HLA-DR activation in clinical-grade human bone marrow–derived multipotent mesenchymal stromal cell expansion cultures

Background aimsMultipotent mesenchymal stromal cell (MSC)-based medicines are extensively investigated for use in regenerative medicine and immunotherapy applications. The International Society for Cell and Gene Therapy (ISCT) proposed a panel of cell surface molecules for MSC identification that includes human leukocyte antigen (HLA)-DR as a negative marker. However, its expression is largely unpredictable despite production under tightly controlled conditions and compliance with current Good Manufacturing Practices. Herein, we report the frequency of HLA-DR expression in 81 batches of clinical grade bone marrow (BM)-derived MSCs and investigated its impact on cell attributes and culture environment. MethodsThe levels of 15 cytokines (interleukin [IL]-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, interferon-γ, soluble CD40 ligand and tumor necrosis factor-α) were determined in sera supplements and supernatants of BM-MSC cultures. Identity, multipotentiality and immunopotency assays were performed on high (>20% of cells) and low (≤20% of cells) HLA-DR+ cultures. ResultsA correlation was found between HLA-DR expression and levels of IL-17F and IL-33. Expression of HLA-DR did neither affect MSC identity, in vitro tri-lineage differentiation potential (into osteogenic, chondrogenic and adipogenic lineages), nor their ability to inhibit the proliferation of stimulated lymphocytes. DiscussionOut of 81 batches of BM-MSCs for autologous use analyzed, only three batches would have passed the ISCT criteria (<2%), whereas 60.5% of batches were compliant with low HLA-DR values (≤20%). Although a cause–effect relationship cannot be drawn, we have provided a better understanding of signaling events and cellular responses in expansion culture conditions relating with HLA-DR expression.

Exclusive expression of transmembrane TNF aggravates acute glomerulonephritis despite reduced leukocyte infiltration and inflammation

Tumor necrosis factor-α (TNF) is a cytokine mediating inflammatory kidney diseases such as immune complex glomerulonephritis. Its two receptors, TNFR1 and TNFR2, play distinct roles in this process, with TNFR2 strongly required for induction of disease. In contrast to soluble TNF (sTNF), transmembrane TNF robustly activates TNFR2. Thus, we examined the functional role of transmembrane TNF by inducing heterologous nephrotoxic serum nephritis in wild-type and transgenic TNFΔ1-9,K11E knock-in mice expressing transmembrane TNF but no sTNF (memTNF mice). Compared to wild-type, nephritis was exacerbated in memTNF mice on day 5, indicated by increased albuminuria, higher serum urea levels, and more pronounced glomerular deposits, together with higher numbers of dying and proliferating glomerular cells. This was associated with greater loss of glomerular endothelial cells, increased podocyte stress, and signs of augmented necroptosis in memTNF kidneys. Aggravation of nephritis was dependent on transmembrane TNF expression in parenchymal cells, but not leukocytes. Surprisingly, increased kidney injury was associated with reduced renal leukocyte infiltration in memTNF mice, which correlated with decreased renal mRNA expression of pro-inflammatory mediators. This effect was also present in isolated memTNF glomeruli stimulated with interleukin-1β invitro. Thus, uncleaved transmembrane TNF is an important mediator of renal tissue damage characterized by increased renal cell death and loss of glomerular endothelial cells in murine glomerulonephritis. In contrast, sTNF predominantly mediates renal leukocyte recruitment and inflammation. These findings highlight the importance of transmembrane TNF in inflammatory kidney disease as a possible therapeutic target.

Frailty, Inflammatory Markers, and Waitlist Mortality Among Patients With End-stage Renal Disease in a Prospective Cohort Study.

Among community-dwelling older adults, frailty is associated with heightened markers of inflammation and subsequent mortality. Although frailty is common among end-stage renal disease (ESRD) patients, the role of frailty and markers of inflammation in this population remains unclear. We quantified these associations in patients on the kidney transplant waitlist and tested whether frailty and/or markers of inflammation improve waitlist mortality risk prediction. We studied 1975 ESRD patients on the kidney transplant waitlist (November 1, 2009, to February 28, 2017) in a multi-center cohort study of frailty. Serum inflammatory markers (interleukin-6 [IL-6], soluble tumor necrosis factor-α receptor-1 [sTNFR1], and C-reactive protein [CRP]) were analyzed in 605 of these participants; we calculated the inflammatory index score using IL-6 and sTNFR1. We compared the C-statistic of an established registry-based prediction model for waitlist mortality adding frailty and/or inflammatory markers (1 SD change in log IL-6, sTNFR1, CRP, or inflammatory index). The registry-based model had moderate predictive ability (c-statistic = 0.655). Frailty was associated with increased mortality (2.19; 95% confidence interval [CI], 1.26-3.79) but did not improve risk prediction (c-statistic = 0.646; P = 0.65). Like frailty, IL-6 (2.13; 95% CI, 1.41-3.22), sTNFR1 (1.70; 95% CI, 1.12-2.59), CRP (1.68; 95% CI, 1.06-2.67), and the inflammatory index (2.09; 95% CI, 1.38-3.16) were associated with increased mortality risk; unlike frailty, adding IL-6 (c-statistic = 0.777; P = 0.02), CRP (c-statistic = 0.728; P = 0.02), or inflammatory index (c-statistic = 0.777; P = 0.02) substantially improved mortality risk prediction. Frailty and markers of inflammation were associated with increased waitlist mortality risk, but only markers of inflammation significantly improved ESRD risk prediction. These findings help clarify the accelerated aging physiology of ESRD and highlight easy-to-measure markers of increased waitlist mortality risk.

Brief Report: Circulating Markers of Immunologic Activity Reflect Adiposity in Persons With HIV on Antiretroviral Therapy.

Obesity alters adipose tissue immunology, and these changes may be reflected in circulating soluble inflammatory biomarker and T-cell subset profiles measured in HIV research studies. We recruited 70 adults with HIV (50% obese) on efavirenz, tenofovir, and emtricitabine, virologic suppression for >2 years, and no rheumatologic or other known inflammatory conditions. We measured fasting plasma levels of several markers of innate immunity and major CD4 and CD8 T-cell subsets. We assessed relationships between measurements of total adiposity [body mass index (BMI), dual-energy X-ray absorptiometry-quantified fat mass index (FMI), and plasma leptin] and the immunologic parameters using covariate-adjusted Spearman's rank correlations. The cohort was 43% women, 54% nonwhite, and median age was 45 years. Higher BMI, FMI, and plasma leptin were consistently associated with higher C-reactive protein, serum amyloid A, and interleukin-6 (P < 0.01 for all), but lower interleukin-10 (P ≤ 0.02 for all). BMI and FMI were positively associated with soluble tumor necrosis factor-α receptor 1 levels (P ≤ 0.02 for both), and a positive correlation approached significance for all 3 body composition measurements with soluble CD163 (P ≤ 0.09 for all). Higher BMI and FMI were associated with lower CD38 expression on CD4 T cells (P ≤ 0.04 for both), but higher CD69 expression (P ≤ 0.01 for BMI and FMI, P = 0.07 for leptin). Greater adiposity is associated with alterations in a limited set of circulating immune markers, potentially reflecting changes known to occur in adipose tissue with treated HIV infection. Measuring total fat mass radiographically did not yield substantively different results compared with BMI.

Immunological recovery in patients with pulmonary tuberculosis after intensive phase treatment.

ObjectivesThis study aimed to examine the change and significance of immune parameters in patients with sputum smear-positive pulmonary tuberculosis (TB) after 2 months of intensive phase anti-TB treatment.MethodsThe immune parameters of 232 cases of sputum smear-positive pulmonary TB were detected before and after 2 months of intensive phase anti-TB treatment and compared with 50 cases from healthy volunteers (controls). The T lymphocyte cell population in peripheral blood was detected using flow cytometry. Serum levels of interleukin (IL)-1β, soluble interleukin-2 receptor, IL-6, and tumour necrosis factor-α were measured by ELISA.ResultsAfter 2 months of intensive phase anti-TB treatment, a reduction in the percentage of CD4+ T cells showed a significant restoration similar to that of controls. Moreover, after intensive anti-TB treatment, serum levels of IL-1β, soluble interleukin-2 receptor, IL-6, and tumour necrosis factor-α were significantly decreased compared with before treatment. Additionally, serum levels of IL-1β and IL-6 showed a diminished recovery compared with controls.ConclusionsOur findings suggest immunological recovery in patients with pulmonary TB after intensive phase treatment. Therefore, serum cytokine levels are considered potential host biomarkers for monitoring the response of treatment for pulmonary TB.

CLINICAL EXPERIENCE WITH ETANERCEPT IN THE TREATMENT OF PATIENTS WITH ANKYLOSING SPONDYLITIS

Etanercept (ETC), a soluble tumor necrosis factor-α (TNF-α) receptor, was registered for the treatment of spondyloarthritis in the Russian Federation in 2009. By now, results of prolonged treatment with this drug have been obtained in patients with ankylosing spondylitis (AS). Objective: to evaluate the efficiency and tolerability of long-term therapy with ETC in patients with AS. Subjects and methods. The follow-up included 60 patients with a documented diagnosis of AS (the 1984 New York criteria) and/or axial spondyloarthritis (the 2009 ASAS criteria), high activity (BASDAI >4), who received long-term (at least a year) regular therapy with subcutaneous ETC 50 mg weekly. Its effect was evaluated using the ASAS criteria. Results and discussion. ETC was the first TNF-α inhibitor used in 29 (48%) patients, including 22 (76%) patients who achieved partial remission; 7 (24%) patients who showed ASAS40 improvement. One patient was observed to have hepatotoxicity (alanine aminotransferase elevation to 72 U/l), therefore the drug was discontinued. 31 (52%) patients were switched to ETC after infliximab (n=24) or adalimumab (n=7) due to their poor tolerance and/or loss of effect. At the same time, ETC became the second anti-TNF-α drug in 21 (35%) patients and the third one in 10 (17%). During the therapy, 21 (68%) patients switched to ETC were noted to have ASAS40 improvement; 9 (29%) patients had partial remission. The insufficient effect of the drug was observed only in one patient (3%), in whom ETC was the third TNF-α inhibitor. The tolerability of ETC was generally satisfactory after switching from anti-TNF-α monoclonal antibodies (mAbs). Three patients developed de novo psoriasis that required therapy discontinuation in one patient; another male patient developed uveitis for the first time. In one female patient with AS associated with Crohn’s disease with loss of mAb effect, ETC became the third anti-TNF-α drug, during therapy with which there was no exacerbation of Crohn’s disease. The drug was well tolerated and highly effective in 8 patients, in whom ETC treatment was initiated at the age of 60 years and older: 6 (75%) achieved partial remission, 2 (25%) had ASAS40 improvement. Nine patients with previous and/or latent tuberculosis had no exacerbation of this disease during ETC therapy. Conclusion. During regular therapy with ETC, more than half of patients (52%) achieved partial remission according to the ASAS criteria, while this was more frequently achieved when the drug was used for the first time (76%) than when mAbs were switched to ETC (29%). Discontinuation of the latter due to adverse events was required only in 2 (3%) patients.

THE ROLE OF GENETIC VARIATION SINGLE NUCLEOTIDE POLYMORPHISM T45G AND SINGLE NUCLEOTIDE POLYMORPHISM G276T OF THE ADIPONECTIN GENE IN FATTY LIVER PATHOMECHANISM ON OBESE MALE SUBJECT

Objective: The aim of this study was to observe the role of genetic variation T45G and G276T of adiponectin gene in pathomechanism of fatty liver on obese subjects.Methods: An observational study with case–control design was conducted on 94 obese male subjects (50 subjects are obese male with fatty liver and 44 subjects are obese male without fatty liver). The research is taken place in Prodia Clinical Laboratory Makassar to determine genetic variation single nucleotide polymorphism (SNP) T45G (Genotype TT, thyroglobulin [TG], and GG) and SNP G276T (Genotype GG, GT, and TT) of adiponectin gene, technique of polymerase chain reaction-restriction fragment length polymorphism was used. The level of adiponectin, soluble tumor necrosis factor-α receptor 2 (sTNF-αR2), and insulin serum were measured by enzyme-linked immunosorbent assay method, meanwhile, fatty liver was detected by ultrasonography.Results: The result of the study showed genetic variation, T45G of adiponectin gene was genotype TT 62.8 %, genotype TG 30.9%, and genotype GG 6.3%; meanwhile, genetic variation G276T of adiponectin gene was genotype GG 43.6%, genotype GT 38.3 %, and genotype TT 18.1 %. There was no significant correlation of genetic variation T45G as well as G276T of adiponectin gene, to the level of adiponectin serum (&gt;0.05). Insulin resistance was more frequent on genotype TT genetic variation T45G of adiponectin gene as compare to that on TG+GG (p=0.069). Genotype TT on genetic variation T45G of adiponectin gene was significant correlated with fatty liver (p=0.010). Genotype TG+TT on genetic variation G276T of adiponectin gene was more likely to have insulin resistance and fatty liver than that of genotype GG. Allele T carrier on genetic variation T45G and G276T of adiponectin gene had a higher chance to have insulin resistance and fatty liver as compare to that of allele G carrier. The odds ratio of having fatty liver insulin resistance is 5.3, genotype TT on genetic variation T45G of adiponectin gene is 3.8, low level of adiponectin is 3.4, and high level of sTNF-αR2 is 3.3.Conclusion: Genotype TT on genetic variation T45G of adiponectin gene has a role in fatty liver on obese subjects. Genotype TG+TT on genetic variation G276T of adiponectin gene was more high frequent to have fatty liver compare to that on genotype GG. Allele T carrier on genetic variation T45G of adiponectin gene had higher frequency on the occurrence of insulin resistance than that on allele G carrier. Insulin resistance has the highest influence as compare to genotype TT on genetic variation T45G of adiponectin gene, low level of adiponectin serum, high level of sTNF-αR2 serum in the pathomechanism of fatty liver in obese subjects.

Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells

Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-α (sTNF-α) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-α (tmTNF-α) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-α at high levels in breast cancer tissues and tmTNF-α expression positively correlated with resistance to anthracycline chemotherapy. Alteration of tmTNF-α expression changed the sensitivity of primary human breast cancer cells and breast cancer cell lines to doxorubicin (DOX). Overexpression of N-terminal fragment (NTF) of tmTNF-α, a mutant form with intact intracellular domain of tmTNF-α to transmit reverse signals, induced DOX-resistance. Mechanistically, the tmTNF-α/NTF-ERK-GST-π axis and tmTNF-α/NTF-NF-κB-mediated anti-apoptotic functions were required for tmTNF-α-induced DOX-resistance. In a xenograft mouse model, the combination of tmTNF-α suppression with chemotherapy significantly enhanced the efficacy of DOX. Our data indicate that tmTNF-α mediates DOX-resistance through reverse signaling and targeting tmTNF-α may be beneficial for the treatment of DOX-resistant breast cancer.

Low-grade Inflammatory Marker Profile May Help to Differentiate Patients With LADA, Classic Adult-Onset Type 1 Diabetes, and Type 2 Diabetes.

To test whether differences in serum concentrations of adiposity-related low-grade inflammatory mediators could help to differentiate patients with latent autoimmune diabetes in adults (LADA), classic adult-onset type 1 diabetes, and type 2 diabetes. This cross-sectional study involved 75 patients with LADA, 67 with classic adult-onset type 1 diabetes, and 390 with type 2 diabetes. Serum concentrations of adiponectin, soluble tumor necrosis factor-α receptor 2 (sTNFRII), interleukin-6, hs-CRP, and total leukocyte number were measured. To evaluate the differences of these markers among diabetes types, we performed logistic regression models and evaluated area under the receiver-operating characteristic curve (AUCROC) values. The profile of innate immunity-related inflammatory markers correlated with metabolic syndrome components. LADA versus classic adult-onset type 1 diabetes was independently related to sTNFRII (odds ratio [OR] 1.9 [95% CI 1.01-3.97]; P = 0.047) and hs-CRP levels (OR 0.78 [95% CI 0.62-0.96]; P = 0.019), and a higher number of total leukocytes lowered the risk of LADA compared with type 2 diabetes (OR 0.98 [95% CI 0.97-0.99]; P = 0.036). The logistic regression model including explanatory biomarkers explained 35% of the variation for LADA versus classic adult-onset type 1 diabetes (AUCROC 0.83 [95% CI 0.74-0.92]; P < 0.001) and 15% of the variation for LADA versus type 2 diabetes (AUCROC 0.73 [95% CI 0.70-0.80]; P < 0.001). Inflammatory, adiposity, and immune-related markers could help to differentiate a LADA diagnosis from that of classic adult-onset type 1 diabetes, and also LADA from that of type 2 diabetes, along with islet autoantibody positivity.

Tumor necrosis factor receptor in Egyptian patients with bipolar disorder during mania: a case–controlled study

Background The role of inflammation has received increasing attention as a potential pathophysiological mechanism in bipolar disorder (BD). Objective To compare the level of soluble tumor necrosis factor-α receptor 1 (sTNFR1) in manic state of BD with healthy controls and investigate the relation between its level and the severity of BD. Patients and methods Serum levels of sTNFR1 were measured with enzyme-linked immunosorbent assay techniques in 44 patients with BD-I during the manic episode and 88 healthy controls recruited from Kasr Al Ainy Hospital, Cairo University. The severity of the manic symptoms was assessed using Young Mania Rating Scale. Results The level of sTNFR1 was higher in patients with BD-I, with the most recent episode manic, than in healthy control. Patients with BD-I, with the most recent episode manic, with psychotic features had higher levels of sTNFR1 than those without psychotic features. sTNFR1 level correlated with Young Mania Rating Scale scores. Conclusion High level of sTNFR1 may be considered as state marker in manic episodes in patients with BD-I. The more severe the disease, the higher the level of sTNFR1.

Interrelationships between Infliximab and Recombinant Tumor Necrosis Factor-α in Plasma Using Minimal Physiologically Based Pharmacokinetic Models.

The soluble cytokine tumor necrosis factor-α (TNF-α) is an important target for many therapeutic proteins used in the treatment of rheumatoid arthritis. Biologics targeting TNF-α exert their pharmacologic effects through binding and neutralizing this cytokine and preventing it from binding to its cell surface receptors. The magnitude of their pharmacologic effects directly corresponds to the extent and duration of free TNF-α suppression. However, endogenous TNF-α is of low abundance, so it is quite challenging to assess the free TNF-α suppression experimentally. Here we have applied an experimental approach to bypass this difficulty by giving recombinant human TNF-α (rhTNF-α) to rats by s.c. infusion. This boosted TNF-α concentration enabled quantification of TNF-α in plasma. Free rhTNF-α concentrations were measured after separation from the infliximab-rhTNF-α complex using Dynabeads Protein A. The interrelationship of infliximab and TNF-α was assessed with minimal physiologically based pharmacokinetic models for TNF-α and infliximab with a target-mediated drug disposition component. Knowledge of TNF-α pharmacokinetics allows reliable prediction of the free TNF-α suppression with either free or total TNF-α concentration profiles. The experimental and modeling approaches in our study may aid in the development of next-generation TNF-α inhibitors with improved therapeutic effects.

Effect of the menopausal transition and physical activity energy expenditure on inflammatory markers: a MONET group study.

Menopausal transition is usually associated with changes in body composition and a decrease in physical activity energy expenditure. Adipose tissue, especially visceral fat, is an important source of inflammatory markers, which contributes to the development of a proinflammatory state. Conversely, high levels of physical activity and exercise have an anti-inflammatory effect. This study aimed to investigate the impact of menopausal transition and physical activity on inflammatory makers. One hundred two healthy premenopausal women participated in a 5-year longitudinal study. The present secondary analyses were performed on 58 participants with a full set of data (age: 49.6 ± 1.7 y; body mass index: 23.3 ± 2.4 kg/m). Measures included body composition, waist circumference, fasting glucose and insulin levels, insulin sensitivity, plasma lipid levels, cardiorespiratory fitness, physical activity energy expenditure, and inflammatory markers. Repeated measure analyses revealed, after the 5-year follow-up, significant increases in ferritin, interleukin-8 (IL-8), and soluble tumor necrosis factor-α receptor 1 and 2 (sTNFR1 and sTNFR2) (P < 0.001), and a significant decrease in serum high-sensitive C-reactive protein (P < 0.05). Positive correlations were observed between change (year 5 to baseline) in waist circumference and changes in high-sensitive C-reactive protein, orosomucoid (ORM), haptoglobin, and apolipoprotein B (ApoB) levels (0.26 ≤ r ≤ 0.34; P < 0.05), and between change in peripheral fat and changes in ORM, ApoB, sTNFR2 (0.28 ≤ r ≤ 0.39; P < 0.05). On the contrary, negative correlations were found between change in physical activity energy expenditure and changes in ORM as well as ApoB (r = -0.35 and r = -0.36, respectively; P < 0.05). No significant correlations were found between change in cardiorespiratory fitness, glucose, insulin, insulin sensitivity and changes in inflammatory markers. Multiple regression analyses showed that changes in physical activity energy expenditure and waist circumference together explained 23% of the individual variance of change in ORM (P < 0.05). Also, change in physical activity energy expenditure explained 15% (P < 0.05) of the variance of change in ApoB. Fat mass change explained 15% (P < 0.05) of the variance of change in IL-8, and finally change in peripheral fat explained 15% of variance of change in sTNFR2 (P < 0.05). The present study indicates that the menopausal transition is accompanied by an increase in inflammatory markers, namely ferritin, IL-8, sTNFR1, and sTNFR2. The increase in IL-8 and sTNFR2 with menopause could be explained, in part, by changes in fat mass and peripheral fat, respectively.

Prognostic and predictive plasma cytokines and angiogenic factors (CAF) in patients (pts) with advanced non-clear cell renal cell carcinoma treated with first-line sunitinib or everolimus: Results from the ESPN trial.

e16112Background: There is a need for markers to guide treatment selection in non-clear cell renal cell carcinoma (nccRCC). We found that soluble tumor necrosis factor-α receptor-I (sTNFR-I) and in...

Soluble Tumor Necrosis Factor-α Receptor 2 in Urine Is a Potential Biomarker for Noninvasive Diagnosis of Malaria During Pregnancy.

Background. During pregnancy, the placenta is inaccessible for diagnosis of placental malaria (PM), but soluble tumor necrosis factor-α receptors (sTNFR) are elevated in the plasma of women with PM.Methods. In this study, sTNFR-1 and sTNFR-2 were quantified in urine of pregnant and nonpregnant Cameroonian women who were positive or negative for malaria by blood-smear microscopy.Results. We found that levels of both sTNFR in urine were higher in pregnant compared with nonpregnant women, but malaria-positive pregnant women excreted substantially more sTNFR-1 (P = .005) and sTNFR-2 (P < .001) than malaria-negative pregnant women. The amount of sTNFR-1(rs = 0.784, P < .001) and sTNFR-2 (rs = 0.816, P < .001) in urine correlated with parasitemia, even in afebrile pregnant women. Urine sTNFR-2 predicted maternal malaria with an area under curve of 0.892 (95% confidence interval, .787–.898). At cutoff concentrations of 9.8 ng and 13.6 ng of sTNFR-2 per mL urine, the sensitivity/specificity were 82.6%/87.0% and 78.3%/95.7%, respectively.Conclusions. The sTNFR-2 in noninvasive urine samples may be useful for diagnosis of malaria during pregnancy.

Preliminary Report of Inflammatory Markers, Oxidative Stress, and Insulin Resistance in Adolescents of Different Ethnicities.

Higher fasting glucose and hemoglobin A1C levels are seen more often in African American (AA) and Hispanic (H) youth, even after adjusting for body mass index (BMI), pointing to other factors that might be promoting abnormal glucose tolerance, such as inflammatory mediators. Our study compared markers of inflammation and oxidative stress in adolescents of different ethnicities. This was a cross-sectional cohort study of healthy Caucasian (C), H, and AA adolescents. Fasting urine for F2-isoprostanes and plasma for adiponectin, soluble vascular cell adhesion molecule (s-VCAM 1), interleukins (ILs), and tumor necrosis factor-α were collected and analyzed. Insulin resistance was measured by homeostasis model assessment of insulin resistance (HOMA-IR). Multivariable regression analyses were used to assess the effect of the biomarkers on HOMA-IR. Seventy adolescents were enrolled (26 C, 20 A, and 24 H); 32 were male (46%) and 27 (39%) were obese. Exploratory analysis showed that for every 1 U increase in BMI z-score, IL-8 rose by 0.53 (0.05, 1.00), P = 0.03. On regression analyses, for every unit increase in BMI z-score, HOMA-IR increased by 0.67 U (P = 0.001); for every unit increase in IL-8, HOMA-IR decreased by 0.21 U (P = 0.04). None of the other biomarkers was significantly associated with HOMA-IR. Higher insulin resistance was associated with increasing BMI z-scores and lower IL-8. This pilot study demonstrates the need to further evaluate inflammatory markers as an independent risk factor for the development of diabetes and to explore if there is a cause and effect relationship between IL-8 and insulin resistance. This could prove valuable for early identification of insulin resistance and as targets for intervention.