Blood Levels Of IL-1β Research Articles

Transcriptomic Changes and Regulatory Networks Associated with Resistance to Mastitis in Xinjiang Brown Cattle.

Xinjiang brown cattle are highly resistant to disease and tolerant of roughage feeding. The identification of genes regulating mastitis resistance in Xinjiang brown cattle is a novel means of genetic improvement. In this study, the blood levels of IL-1β, IL-6, IL-10, TNF-α, and TGF-β in Xinjiang brown cattle with high and low somatic cell counts (SCCs) were investigated, showing that cytokine levels were higher in cattle with high SCCs. The peripheral blood transcriptomic profiles of healthy and mastitis-affected cattle were constructed by RNA-seq. Differential expression analysis identified 1632 differentially expressed mRNAs (DE-mRNAs), 1757 differentially expressed lncRNAs (DE-lncRNAs), and 23 differentially expressed circRNAs (DE-circRNAs), which were found to be enriched in key pathways such as PI3K/Akt, focal adhesion, and ECM-receptor interactions. Finally, ceRNA interaction networks were constructed using the differentially expressed genes and ceRNAs. It was found that keynote genes or mRNAs were also enriched in pathways such as PI3K-Akt, cholinergic synapses, cell adhesion molecules, ion binding, cytokine receptor activity, and peptide receptor activity, suggesting that the key genes and ncRNAs in the network may play an important role in the regulation of bovine mastitis.

ОСОБЕННОСТИ КЛИНИЧЕСКИХ И ЛАБОРАТОРНЫХ ПОКАЗАТЕЛЕЙ У ПАЦИЕНТОВ С ИНФЕКЦИЕЙ SARS-COV-2 В ЗАВИСИМОСТИ ОТ РЕЗУЛЬТАТОВ СЕРОЛОГИЧЕСКОЙ ДИАГНОСТИКИ

To date, over 270 million people have been ill with COVID-19 and more than 2 million have died. Tens of thousands of new cases of the disease are still registered in the world every day, so the assessment of the methods for diagnosing SARS-CoV-2 associated pathology remains highly relevant. The aim of the study was to evaluate the variability of clinical and laboratory parameters in patients with SARS-CoV-2 infection depending on the results of serological diagnostics. Material and methods. 170 patients (88 women, 82 men aged 23 to 90 years) diagnosed with community-acquired interstitial pneumonia following SARS-CoV-2 infection were examined in accordance with the clinical protocol, in 80 of them the blood levels of IL-1β, IL-6, IL-18, CXCL8, and interferon-α were determined. Results. It was found that only in 34.09% of cases a negative PCR result for the presence of the genetic material of SARS-CoV-2 viruses in patients diagnosed with interstitial pneumonia coincided with a negative result of testing for IgG and/or IgM to the viral antigen. A positive PCR result was confirmed by the presence of elevated levels of antibodies in 64.29% of cases. In PCR-positive patients, stage II III respiratory failure was determined significantly more often than in PCR-negative ones (in 40.28% and 16.32% of cases, respectively, p<0.01), and their condition was more often regarded as severe and extremely severe (in 31.94% and 10.0% of cases, respectively, p<0.05). The level of antibodies was associated with the severity of the immune response to a viral infection: the volume of lung damage, the blood level of the pro-inflammatory cytokine IL-18, acute phase inflammation proteins, and the activity of intracellular enzymes were significantly higher in patients with elevated levels of IgG and/or IgM than in patients with negative results of these tests. Conclusions. The determining of IgM and IgG specific to the Spike antigen of the SARS-CoV-2 virus does not duplicate, but complements the molecular genetic study. PCR helps to detect the presence of the genetic material of the virus. Detection of the level of antibodies can be used to make a conclusion about the intensity and stage of the immune response to a viral infection.

FKN/NR Signaling Pathway Regulates Hippocampal Inflammatory Responses: the Survival of Hippocampal Neurons in Diabetic Rats with Chronic Unpredictable Mild Stress.

Aim To investigate the mechanism via which FKN/CX3CR1 signaling abnormalities mediate N-methyl-D-aspartic acid receptor (NMDA) overexcitation-induced hippocampal neuronal injury in diabetic rats complicated with depression (DD). Methods Sixty rats were randomly divided into 5 groups. The depression-like behaviors of the rats were evaluated by open field test and Morris water maze. The pathological changes of hippocampus in DD rats were observed by HE staining. The blood levels of inflammatory factors (IL-1β, TNF-α, and IL-6) and neurotransmitters (D-serine and glutamic acid) were determined by enzyme-linked immunosorbent assay (ELISA). The expressions of BDNF, A1 receptor (A1R), A2 receptor (A2R), A3 receptor (A3R), calmodulin dependent kinase II (CaMKII), CX3CR1, CX3CL1 (FKN), NR2A, and NR2B proteins were detected by immunohistochemistry and Western-blotting. Results Compared with the normal control group, blood glucose level increased significantly and body weight decreased in T2DM group and T2DMC group. In addition, the number of spontaneous activities significantly decreased and the capability of learning and memory was attenuated in T2DMC group and Chronic Stress group. The blood levels of IL-1β, TNF-α, IL-6, glutamate (Glu), and D-serine significantly increased in each model group. After intervention with CX3CR1 antibody, the expressions of BDNF, CaMK II, A1R, and A3R increased and those of A2R, CX3CR1, FKN, NR2A, and NR2B decreased. Conclusion In the diabetic state, the binding of FKN to CX3CR1 increases, which regulates a variety of adenosine receptors. When it exerts its effect on neurons, the overactivation of NR results in neuronal injury and causes depression.

Treatment Experiences with Intravenous Immunoglobulins, Ixekizumab, Dupilumab, and Anakinra in Netherton Syndrome: A Case Series

Background: Netherton syndrome (NS) is a rare potential life-threatening disorder that causes severe defects to the skin barrier. No effective treatment options are available for patients with NS and current therapy is mostly supportive. The effects of intravenous immunoglobulins (IVIGs), ixekizumab, and dupilumab have scarcely been reported. Additionally, the role of anakinra in patients with NS has never been investigated. Objectives: The objective was to report our experiences of treatment with IVIG, ixekizumab, dupi­lumab, and anakinra in patients with NS. Methods: A retrospective case series, including 5 patients with NS, was performed in a tertiary referral hospital between 2016 and 2021. Patients were treated with IVIG, ixekizumab, dupilumab, and/or anakinra. Long-term experiences with treatment regimens and adverse events requiring medical attention were reported. Results: IVIG, ixekizumab, dupilumab, and anakinra were well tolerated with no severe adverse events. The 2 patients that received IVIG showed clinical response for 6 months and 2.5 years. Ixekizumab was effective in 1 of our patients for 3.5 years, while in another patient ixekizumab lost its effect after 1.5 years. Dupilumab treatment did not result in persistent improvement of NS-related skin symptoms in 1 patient. Anakinra showed physician-assessed clinical response during the first months of treatment in 4 patients with NS. During anakinra treatment, no changes in blood levels of IL-1β, IL-6, and TNF-α levels were measured at routine blood examinations. Conclusions: This case series suggests that the use of IVIG, ixekizumab, dupilumab, and anakinra in NS is safe and moderately effective on the short term. On the long term, a decline in effect was observed. Our experiences may help clinicians and researchers to provide adequate care and develop treatment for these severely affected patients. More international research, especially on the long term, is needed to determine if and which patients benefit most from the emerging therapies for NS.

Quercetin ameliorates XIAP deficiency–associated hyperinflammation

AbstractXIAP (X-linked inhibitor of apoptosis) deficiency is a rare inborn error of immunity. XIAP deficiency causes hyperinflammatory disease manifestations due to dysregulated TNF (tumor necrosis factor)-receptor signaling and NLRP3 (NOD- [nucleotide-binding oligomerization domain], LRR- [leucine-rich repeat] and pyrin domain-containing protein 3) inflammasome function. Safe and effective long-term treatments are needed and are especially important to help prevent the need for high-risk allogeneic hematopoietic cell transplantation. Here we evaluated inflammasome inhibitors as potential therapeutics with a focus on the natural flavonoid antioxidant quercetin. Bone marrow (BM)-derived macrophages were derived from XIAP-deficient or wild-type (WT) mice. Human monocytes were obtained from control or XIAP-deficient patients. Cells were stimulated with TLR (Toll-like receptor) agonists or TNF-α ± inhibitors or quercetin. For in vivo lipopolysaccharide (LPS) challenge experiments, XIAP-deficient or WT mice were fed mouse chow ± supplemental quercetin (50 mg/kg per day exposure) for 7 days followed by a challenge with 10 ng/kg LPS. IL-1β (interleukin-1β) and IL-18 were measured by ELISA (enzyme-linked immunosorbent assay). In murine studies, quercetin prevented IL-1β secretion from XIAP knockout cells following TLR agonists or TNF-α stimulation (P < .05) and strongly reduced constitutive production of IL-18 by both WT and XIAP-deficient cells (P < .05). At 4 hours after in vivo LPS challenge, blood levels of IL-1β and IL-18 were significantly decreased in mice that had received quercetin-supplemented chow (P < .05). In experiments using human cells, quercetin greatly reduced IL-1β secretion by monocytes following TNF-α stimulation (P < .05). Our data suggest that quercetin may be an effective natural therapeutic for the prevention of XIAP deficiency-associated hyperinflammation. Clinical trials, including careful pharmacokinetic and pharmacodynamic studies to ensure that effective levels of quercetin can be obtained, are warranted.

Hippocampal Cytokine Release in Experimental Epileptogenesis-A Longitudinal In Vivo Microdialysis Study.

Background: Inflammation, particularly cytokine release, contributes to epileptogenesis by influencing the cerebral tissue remodeling and neuronal excitability that occurs after a precipitating epileptogenic insult. While several cytokines have been explored in this process, release kinetics are less well investigated. Determining the time course of cytokine release in the epileptogenic zone is necessary for precisely timed preventive or therapeutic anti-inflammatory interventions. Methods: Hippocampal extracellular levels of six cytokines and chemokines (IL-1β, IL-6, IL-10, CCL2, CCL3, and CCL5) were quantified at various time points during epileptogenesis in a rat model of mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) using microdialysis (MD). Results: The analysis of microdialysates demonstrated consistent elevation at all time points during epileptogenesis for IL-1β and IL-10. IL-10 release was maximal on day 1, IL-1β release peaked at day 8. No correlation between local hippocampal IL-1β concentrations and IL-1β blood levels was found. Conclusion: The release kinetics of IL-1β are consistent with its established pro-epileptogenic properties, while the kinetics of IL-10 suggest a counter-regulatory effect. This proof-of-concept study demonstrates the feasibility of intraindividual longitudinal monitoring of hippocampal molecular inflammatory processes via repetitive MD over several weeks and sheds light on the kinetics of hippocampal cytokine release during epileptogenesis.

Effect of Repeated Stress Exposures on the Blood Cytokine Profile in Rats with Different Behavioral Parameters.

Changes in the blood cytokine profile were studied in rats with different behavioral patterns in the open-field test during chronic stress on the model of daily 4-h immobilization over 8 days. The level of proinflammatory cytokines IL-1α and IFNγ in behaviorally active and passive animals changed insignificantly under these experimental conditions. Repeated stress exposures were accompanied by a progressive decrease in the plasma level of IL-2 and IL-5 in passive rats; these changes were most pronounced on day 8 of the study. Active animals were characterized by a tendency toward reduction of IL-2 content, but significant decrease in IL-5 concentration on days 3 and 8 of restraint stress. Blood levels of IL-1β and IL-6 in rats remained practically unchanged after single immobilization, but progressively increased during further stress exposures and reached maximum on day 8 of stress. The content of the anti-inflammatory cytokine IL-4 in rats was constant, but blood concentration of IL-10 increased during repeated stress exposures. These changes were most pronounced on day 8 in passive animals and on days 3 and 8 of restraint stress in active animals. These data indicate that the direction of variations in the blood cytokine profile of rats under conditions of chronic stress depends on the baseline parameters of behavior and frequency of stress exposures.

Functional analysis of gut microbiota and immunoinflammation in children with autism spectrum disorders

Background and AimsRecent evidence implicates gut microbiota (GM) and immune alterations in autism spectrum disorders (ASD). We assess GM profile and peripheral levels of immunological, neuronal and bacterial molecules in ASD children and controls. Alarmin HMGB1 was explored as a non-invasive biomarker to monitor gastrointestinal (GI) symptoms. MethodsThirty ASD children and 14 controls entered into the study. GM metagenomic analysis was performed for 16 ASD patients and 7 controls. GM functional profile was assessed by GO term analysis. Blood levels of IL-1β, TNFα, TGFβ, IL-10, INFγ, IL-8, lipopolysaccharide, Neurotensin, Sortilin1 and GSSG/GSH ratio were analyzed in all subjects by ELISA. Fecal HMGB1 was analyzed by Western blot. ResultsWe observed a significant decrease in bacterial diversity. Furthermore, 82 GO terms underrepresented in ASD. Four of them pointed at 3,3 phenylpropionate catabolism and were imputable to Escherichia coli (E. coli) group. Serum levels of TNFα, TGFβ, NT, and SORT-1 increased in ASD patients. Fecal levels of HMGB1 correlated with GI sign severity in ASD children. ConclusionsWe suggest that a decrease of E. coli might affect the propionate catabolism in ASD. We report occurrence of peripheral inflammation in ASD children. We propose fecal HMGB1 as a non-invasive biomarker to detect GI symptoms.

Association between baseline pro-inflammatory cytokines and brain activation during social exclusion in patients with vulnerability to suicide and depressive disorder

BackgroundNeuroimaging studies suggest that social distress and suicidal vulnerability share common cerebral bases. Moreover, increased peripheral inflammatory activity is involved in both social distress and suicidal behavior. ObjectiveTo evaluate, in suicidal and non-suicidal individuals, the association between the activation of specific cerebral regions (anterior cingulate, insula and orbitofrontal cortex) during experimental social exclusion and the baseline blood levels of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) and of the anti-inflammatory cytokine interleukin-2 (IL-2). MethodsIn total, 101 euthymic women were recruited: 42 suicide attempters (SA), 40 affective controls (AC), and 19 healthy controls (HC). During functional MRI (fMRI), they performed the Cyberball game, a validated social exclusion task. Blood levels of IL-1β, IL-6, TNF-α and IL-2 were measured prior to fMRI. The activation of insula, orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) during the explicit social exclusion (ESE) vs social inclusion (INC) conditions of the Cyberball game was analyzed in function of the baseline cytokine levels. ResultsIL-1β was negatively associated with right OFC activation (p = 0.01) in ESE vs. INC, whereas IL-2 was positively associated with activation of the right ACC (p = 0.02), insula (p = 0.002) and OFC (p = 0.004) in ESE vs. INC. These associations remained significant after controlling for group, indicating that they were independent of the suicidal status. ConclusionBaseline IL-1β and IL-2 blood levels are differentially associated with cerebral activation involved in the perception of social exclusion, independently of suicidal behavior. Our results may help to better understand the role of basal inflammation in social distress and its link with mood disorder pathophysiology.

Efficacy of Xuebijing Injection () on Cardiopulmonary Bypass-Associated Pulmonary Injury: A Prospective, Single-center, Randomized, Double Blinded Trial.

To evaluate the efficacy of Xuebijing Injection (, XBJ) on the lung injury induced by cardiopulmonary bypass (CPB). Fifty patients undergoing CPB were randomized to either the saline group or XBJ group according to a random number table (25 cases in each group). The patients in the saline group received saline and patients in XBJ group received XBJ at 12 h prior to the operation, at the beginning of the operation, and at 12 h after the second injection. The PaO2/FiO2 at extubation 3 days post-operation, duration of ventilation in the intensive care unit (ICU), and lengths of stay in the ICU and hospital were recorded. The levels of inflammatory mediators including interleukin (IL)-1β, IL-8, IL-10, and C-reactive protein (CRP) in bronchoalveolar lavage fluid (BALF) and plasma were measured. The neutrophil count and elastase neutrophil elastase in BALF were also measured. In addition, adverse events were monitored. The PaO2/FiO2 in the XBJ group was higher than that in the saline group from 12 to 72 h post-operation (all P<0.05). The blood levels of IL-1β, IL-8, and CRP in the XBJ group from 12 to 72 h were all significantly lower than those in the saline group (all P<0.05). In contrast, the level of the anti-inflammatory cytokine IL-10 was significantly higher in the XBJ group than in the saline group (P<0.05). In addition, 4 patients presented with atelectasis in the saline group and none in the XBJ group. Ten patients experienced mild acute respiratory distress syndrome (ARDS) during hospitalization, and 5 patients with mild ARDS were in the XBJ group (P<0.05). XBJ shows protective potential against lung injury in patients who undergo CPB surgery, possibly through the downregulation of inflammatory mediators, reduction in neutrophil infiltration, and upregulation of IL-10 (Trial registry: ChiCTR-TRC-14004628).

The source of fat in a high fat diet affects systemic inflammatory markers and modulates gene expression in intestinal, hepatic and adipose tissues of growing pigs.

Abstract While high fat diets have been associated with increased level of inflammation and metabolic health impairment, new evidences show that the source of fat plays an important role on these outcomes. In order to investigate the specific role of dairy fats on metabolic health, a model of growing pigs was used. A total of 40 pigs aged 6 weeks were fed a low fat diet, or high fat diets (17.5% fat) containing either lard only, a combination of lard and butter (butter: 4.5% fat; lard: 13% fat) or a combination of lard and cheddar cheese (cheddar: 4.5% fat; lard: 13% fat) for 10 weeks. After 5 and 10 weeks, blood samples were collected to determine hyperlipidemia and inflammatory markers level. After 10 weeks, pigs were euthanized to collect intestinal, hepatic and adipose tissues to measure the expression of a selection of genes involved in inflammation, oxidative stress and energy metabolism by qPCR. Blood levels of IL-1β and TNF-α were decreased in pigs fed either butter or cheddar compared to the lard-only high fat diet (P &amp;lt; 0.05), while no changes were observed in the level of blood lipids. To visualize the impact of dairy fats on gene expression, a Heatmap of gene expression was drawn and showed that both butter and cheddar affected gene expression in jejunum, while butter specifically modulated the gene expression in liver and fat tissues, and cheddar specifically changed gene expression in colon. In conclusion, replacement of lard for dairy fats in a high fat diet protects from systemic inflammation and changes gene expression in pig intestinal, hepatic and adipose tissues.

Oral Infections and Cytokine Levels in Patients with Alzheimer's Disease and Mild Cognitive Impairment Compared with Controls.

Background Oral infections are prevalent in the adult population. Their impact includes the implication as a risk factor for Alzheimer's disease (AD), altering its progression. One of the potential mechanisms involves immune mediators such as circulating cytokines. Objective The goal of the present study was to investigate the prevalence of oral infections and blood levels of IL-1β, TNF-α, and IL-6 in patients with AD, mild cognitive impairment (MCI), and controls. Methods Sixty-five elderly were evaluated (25 AD, 19 MCI, and 21 controls) by the following methods: Mini Mental State Exam, Questionnaire of Functional Activities, periodontal and oral evaluation, and blood concentrations of IL-1β, TNF-α and IL-6. Results Patients with AD had high serum IL-6 levels (p = 0.029), and patients with periodontitis had high serum TNF-α levels (p = 0.005). There was an association between IL-6 and TNF-α in patients with AD/MCI and periodontitis (p = 0.023). Conclusion The increased levels of TNF-α and IL-6 in this study suggests their implication in the overlapping mechanisms between oral infections and AD. Longitudinal studies are necessary for further investigation.

Periodontal disease and inflammatory blood cytokines in patients with stable coronary artery disease.

ABSTRACTPeriodontal disease has been associated with elevations of blood cytokines involved in atherosclerosis in systemically healthy individuals, but little is known about this association in stable cardiovascular patients. The aim of this study was to assess the association between periodontal disease (exposure) and blood cytokine levels (outcomes) in a target population of patients with stable coronary artery disease (CAD). Material and Methods This cross-sectional study included 91 patients with stable CAD who had been under optimized cardiovascular care. Blood levels of IL-1β, IL-6, IL-8, IL-10, IFN-γ, and TNF-α were measured by Luminex technology. A full-mouth periodontal examination was conducted to record probing depth (PD) and clinical attachment (CA) loss. Multiple linear regression models, adjusting for gender, body mass index, oral hypoglycemic drugs, smoking, and occurre:nce of acute myocardial infarction were applied.Results CAD patients that experienced major events had higher concentrations of IFN-γ (median: 5.05 pg/mL vs. 3.01 pg/mL; p=0.01), IL-10 (median: 2.33 pg/mL vs. 1.01 pg/mL; p=0.03), and TNF-α (median: 9.17 pg/mL vs. 7.47 pg/mL; p=0.02). Higher numbers of teeth with at least 6 mm of CA loss (R2=0.07) and PD (R2=0.06) were significantly associated with higher IFN-γ log concentrations. Mean CA loss (R2=0.05) and PD (R2=0.06) were significantly related to IL-10 concentrations. Elevated concentrations of TNF-α were associated with higher mean CA loss (R2=0.07).Conclusion Periodontal disease is associated with increased systemic inflammation in stable cardiovascular patients. These findings provide additional evidence supporting the idea that periodontal disease can be a prognostic factor in cardiovascular patients.

Oral Infections and Cytokine Levels in Patients with Alzheimer's Disease and Mild Cognitive Impairment Compared with Controls.

Oral infections are prevalent in the adult population. Their impact includes the implication as a risk factor for Alzheimer's disease (AD), altering its progression. One of the potential mechanisms involves immune mediators such as circulating cytokines. The goal of the present study was to investigate the prevalence of oral infections and blood levels of IL-1β, TNF-α, and IL-6 in patients with AD, mild cognitive impairment (MCI), and controls. Sixty-five elderly were evaluated (25 AD, 19 MCI, and 21 controls) by the following methods: Mini Mental State Exam, Questionnaire of Functional Activities, periodontal and oral evaluation, and blood concentrations of IL-1β, TNF-α and IL-6. Patients with AD had high serum IL-6 levels (p = 0.029), and patients with periodontitis had high serum TNF-α levels (p = 0.005). There was an association between IL-6 and TNF-α in patients with AD/MCI and periodontitis (p = 0.023). The increased levels of TNF-α and IL-6 in this study suggests their implication in the overlapping mechanisms between oral infections and AD. Longitudinal studies are necessary for further investigation.

Effect of Histone Acetylation on N-Methyl-D-Aspartate 2B Receptor Subunits and Interleukin-1 Receptors in Association with Nociception-Related Somatosensory Cortex Dysfunction in a Mouse Model of Sepsis.

Whole-body inflammation (i.e., sepsis) often results in brain-related sensory dysfunction. We previously reported that interleukin (IL)-1 resulted in synaptic dysfunction of septic encephalopathy, but the underlying molecular mechanisms remain unknown, as do effective treatments. Using mice, we examined immunohistochemistry, co-immunoprecipitation, enzyme-linked immunosorbent assay, and behavior analyses, and investigated the role of the N-methyl-D-aspartate 2B subunit (NR2B) of NMDA receptor, IL-1 receptor, and histone acetylation in the pathophysiology underlying sensory dysfunction induced by lipopolysaccharide (LPS). Mice groups of sham-operated, LPS, LPS with an NR2B antagonist, or LPS with resveratrol (a histone acetylation activator) were analyzed. We found that LPS increased NR2B and interleukin-1 receptor (IL-1R) immunoreactivity. The expression of Iba1, a marker for microglia and/or macrophages, increased more significantly in the brain than in the spinal cord, implicating NR2B and IL-1R in brain inflammation. Immunoprecipitation with NR2B and IL-1R revealed related antibodies. Blood levels of IL-1β (i.e., the IL-1R ligand) increased, though not significantly, suggesting that inflammation peaked at 20 h. Behavioral assessments of central (CNS) and peripheral sensory (PNS) function indicated that LPS delayed CNS but not PNS escape latency. Finally, NR2B antagonist or resveratrol in the lateral ventricle antagonized the effects of LPS in the brain and improved animal survival. In summary, histone acetylation may control expression of NR2B and IL-1R, alleviating inflammation-induced sensory neuronal dysfunction caused by LPS.

Interleukin-1β Promoter Polymorphism Enhances the Risk of Sleep Disturbance in Alzheimer's Disease.

Sleep alleviates Alzheimer’s disease (AD)-related neuropathological processes, whereas sleep disturbance in AD patients is associated with elevated peripheral inflammatory cytokine levels. In the present study, we assessed interleukin (IL)-1β and APOEε4 polymorphisms for association with susceptibility of sleep disturbances in AD patients. A total of 123 pretreated AD patients and 120 age-, gender- and education level-matched healthy controls were recruited for two consecutive full-night polysomnography and measurement of Epworth Sleepiness Scale (ESS) scores for sleep-wake disturbance. Their genomic DNA was analyzed for IL-1β and APOEε4 SNPs using ligase detection reaction (LDR) technology. Blood levels of IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) were measured using ELISA after lipopolysaccharide (LPS) stimulation. The odds ratio and 95% confidence interval for genotype-specific risk were calculated using an unconditional logistic regression model and adjusted by age, gender, educational levels, body mass index (BMI), and activities of daily living (ADL). Compared to the non-APOEε4/ε4 genotype, APOEε4/ε4 significantly increased the risk of AD (APOEε4/ε4 vs. non-APOEε4/ε4, adjusted OR = 4.33, 95% CI = 1.33–14.10, p = 0.015). Compared to the IL-1β CC genotype (-31), the TT genotype significantly increased the risk of AD (TT vs. CC, adjusted OR = 1.72, 95% CI = 1.13–2.61, p = 0.010). AD patients carrying the APOEε4 allele and the IL-1β TT genotype showed less time in bed, longer sleep latency and REM latency, more awakenings, and a lower SWS percentage than those carrying CC/CT combined genotypes. In addition, blood IL-1β levels were significantly greater in AD patients carrying both the APOEε4 allele and the IL-1β-31TT genotype than in those carrying the APOEε4 allele and the -31 TC or CC genotype. In conclusion, this study provides the first evidence indicating that the IL-1β-31TT genotype and homozygous APOEε4 combined are associated with increased risk of developing AD with sleep disturbance.

Effects of an Immunostimulant Containing Propionibacterium acnes (EqStim) on Cell-Mediated Immunity and Nasal Shedding of Respiratory Pathogens Using a Model of “Weaning” Stress in Foals

Weaning of foals is a stressful event, and often, times can be associated with negative health consequences, including reduced immunity and increased susceptibility to gastrointestinal and respiratory disorders. Thus, a possible preventative immunomodulator of weaning-associated stress was studied in 21 pony foals (205 days ± 5 day old). Of these, n = 11 received the immunostimulant EqStim and n = 10 received a saline control on days −7, −3, and 0 (day of weaning). During these time points, as well as days 3, 7, 14, and 21, after weaning measurements were determined for the following parameters: clinical parameters as well as plasma cortisol concentrations, immune function using flow cytometry for protein determination and real-time polymerase chain reaction (PCR) for gene expression, and pathogen detection using nasal swabs (NSs) and PCR. Results showed an overall time effect of weaning for most parameters: decreased rectal temperature, increased nasal discharge and NS PCR detection of Streptococcus equi subsp. zooepidemicus, increased serum cortisol levels, and both decreased and increased production of cytokines (lymphocyte production interferon gamma and tumor necrosis factor alpha (TNF-α) and whole blood levels of IL-1β, TNF-α, and IL-10). In addition, there was an effect of treatment on cortisol concentrations and peripheral blood mononuclear cell production of IL-1β. Data suggest that, regardless of treatment, the weaning process produces significant changes in clinical and immunologic measures in foals. Although treatment with the immunostimulant EqStim had no effect on the incidences of nasal shedding of respiratory pathogens or other clinical parameters, it did appear to modulate rises in cortisol after weaning and possibly enhance innate immunity.

Bronchopulmonary dysplasia: Biomarkers, lung function, and clinical course

The paper presents an investigation of airway resistance with bronchodilator response and time course of changes in the levels of proinflammatory (IL-1β) and anti-inflammatory (IL-4, IL-10) cytokines and the indirect marker of fibrosis — matrix metalloproteinase 3 (MMP3) in order to specify their role in the immunopathogenesis and course of bronchopulmonary dysplasia. 15 healthy full-term infants aged 3 to 20 months and 39 premature infants (a study group) with bronchopulmonary dysplasia were examined. The infants of the study group were divided into 3 subgroups: 1) 11 babies of less than 55 weeks postconceptual age; 2) 11 infants of 55–75 weeks postconceptual age; 3) 17 ones of 76–141 weeks conceptual age. Airway resistance and bronchodilator response were investigated using the Rint method; oxygen saturation and the presence of RS virus in nasal secretions were determined. An enzyme immunoassay was used to estimate the blood levels of IL-1β, IL-4, IL-10, and MMP3. It was ascertained that the increased level of IL-10 were more common in Subgroup 1 and that of MMP3 in Subgroup 2 as compared to the group of healthy infants. As this takes place, a 10‑fold and more increase in IL-10 levels in the infants from Group 3 (the old group) is a poor prognostic factor. The infants in Subgroups 1 and 2 showed higher Rint and more marked bronchodilator response, suggesting respiratory failure. Conclusions. As the infant grows, there are decreases in the frequency of exacerbations and in the magnitude of bronchodilator response and an increase in saturation, but the proportion of infants with greater responsiveness remains high and fails to reach the values observed in healthy babies. Immunological heterogeneity and mosaicism of changes in the levels of biomarkers of bronchopulmonary dysplasia suggest that there may be different inflammatory phenotypes in this disease.

CHANGES IN THE PARAMETERS OF BLOOD LIPIDS AND CYTOKINES IN PATIENTS WITH PRIMARY OSTEOARTHRITIS DURING TREATMENT WITH ARTHRA

Objective: to study the time course of changes in the cytokine profile, the parameters of lipid peroxidation (LPO), antioxidant defense, and lipid spectrum during Arthra therapy in patients with primary osteoarthritis (POA). Subjects and methods. The study was conducted in 26 POA patients (aged 39.5+5.4 years) with knee and hip joint lesions in the absence of synovitis. The efficiency of treatment was evaluated by pain intensity and WOMAC index. The levels of proinflammatory cytokines, lipids, LPO primary and intermediate products, and antioxidant defense were compared in patients with PAO prior to and 12 and 24 weeks after Arthra therapy. Results. Positive changes in articular manifestations were determined after 24 weeks of therapy, by using the WOMAC scale. The mean concentration of C-reactive protein (CRP) was halved in the patients 24 weeks following the start of Arthra therapy. The blood levels of IL-1β, IL-6, IL-18, TNF-α decreased just after 12 weeks of therapy as compared to the baseline level and continued to decline by the end of the therapy. There were reductions in LPO primary and intermediate products in serum and red blood cells. There was activation of antiradical protection (increases in serum and red blood cell catalase activities and serum antioxidant activity and a decrease in the number of hemolyzed red blood cells). After a course of therapy, there were reduced blood concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol in patients with POA. Conclusion. The POA patients treated with Arthra displayed improvements in LPO profile and antioxidant defense and lower blood concentrations of cholesterol and LDL cholesterol along with a decline in the levels of the blood cytokines IL-1β, IL-6, IL-18, TNF-α, and CRP.

Abstract B35: Serum inflammatory biomarkers of acute and persistent fatigue in a preclinical breast cancer treatment model

Abstract Aims: Cancer treatment related fatigue (CTRF) is a debilitating symptom of cancer chemotherapy. The acute CTRF that occurs during chemotherapy can become persistent lasting for weeks, month, or years after treatment has ended. Although, treatment-related increases in IL-1β and TNF-α have been implicated in CTRF, the role that these cytokines play in CTRF is unclear. The aim of this study was to determine the relationship between chemotherapy-induced IL-1β and TNF-α production and acute and persistent CTRF in a pre-clinical mouse model. Methods: Blood levels of IL-1β, TNF-α and several other inflammatory biomarkers were measured in acutely fatigued, non-fatigued, and persistently fatigued mice following administration of cytoxan-adriamycin-5-fluorouracil (CAF), a commonly used adjuvant chemotherapy regimen for the treatment of breast cancer, by assessing changes in voluntary wheel running activity as a proxy for fatigue. Results: Fatigued mice showed increased blood levels of IL-1β, TNF-α as well as several other inflammatory markers including, IL-5, IL-6, IL-7, IL-9, IP-10, G-CSF, KC, MCP-1 and MIP-1β. Importantly, serum levels of these fatigue associated biomarkers were not significantly increased in non-fatigued CAF treated mice. CAF-treated mice with persistent fatigue had elevated serum levels of IL-6, IL-17, and MIP-1α. Conclusions: This study advances the science of symptom management by providing evidence that treatment induced increases in IL-1β and TNF-α play a role in acute CTRF. Similar temporal analyses between serum inflammatory biomarkers in the clinical setting may lead to a better understanding of the role of immune dysfunction in the etiology of acute and persistent fatigue. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B35