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Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150 trans- and 19 cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of the Atypical Chemokine Receptor 1 (ACKR1) acting as scavenger for multiple chemokines and the role of tumor necrosis factor receptor-associated factor 1 (TRAFD1) in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug target cis-MR using 2 independent proteomics datasets paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohn's disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies. The study uses GWAS for 40 circulating cytokines in meta-analyses of 74,783 individuals. With Mendelian randomization, key cytokines like G-CSF/CSF-3 and CXCL9/MIG are identified as potential causal mediators of asthma and Crohn's disease, respectively. [ABSTRACT FROM AUTHOR]

Background: Achalasia is a rare motility disorder of the esophagus often accompanied by immune dysregulation, yet specific underlying mechanisms remain poorly understood. Methods: We utilized Mendelian randomization (MR) to explore the causal effects of cytokine levels on achalasia, with cis-expression/protein quantitative trait loci (cis-eQTLs/pQTLs) for 47 cytokines selected from a genome-wide association study (GWAS) meta-analysis and GWAS data for achalasia obtained from FinnGen. For cytokines significantly linked to achalasia, we analyzed their plasma concentrations and expression differences in the lower esophageal sphincter (LES) using enzyme-linked immunosorbent assay and single-cell RNA sequencing (scRNA-seq) profiling, respectively. We further employed bioinformatics approaches to investigate underlying mechanisms. Results: We revealed positive associations of circulating Eotaxin, macrophage inflammatory protein-1b (MIP1b), soluble E-selectin (SeSelectin) and TNF-related apoptosis-inducing ligand (TRAIL) with achalasia. When combining MR findings with scRNA-seq data, we observed upregulation of TRAIL (OR = 2.70, 95% CI, 1.20–6.07), encoded by TNFSF10, in monocytes and downregulation of interleukin-1 receptor antagonist (IL-1ra) (OR = 0.70, 95% CI 0.59–0.84), encoded by IL1RN, in FOS_macrophages in achalasia. TNFSF10high monocytes in achalasia displayed activated type I interferon signaling, and IL1RNlow FOS_macrophages exhibited increased intercellular communications with various lymphocytes, together shaping the proinflammatory microenvironment of achalasia. Conclusions: We identified circulating Eotaxin, MIP1b, SeSelectin and TRAIL as potential drug targets for achalasia. TNFSF10high monocytes and IL1RNlow macrophages may play a role in the pathogenesis of achalasia. [ABSTRACT FROM AUTHOR]

Whether proinflammatory cytokine dysregulation and cognitive dysfunction are associated with suicidal symptoms in adolescents and young adults with major depressive disorder (MDD) remains uncertain. We assessed the cognitive function and proinflammatory cytokine levels of 43 and 51 patients aged 15–29 years with MDD and severe and mild suicidal symptoms, respectively, as well as those of 85 age- and sex-matched healthy controls. Specifically, we measured serum levels of C-reactive protein, tumor necrosis factor-α (TNF-α), interleukin-2, and interleukin-6 and assessed cognitive function by using working memory and go/no-go tasks. The severity of the patients' suicidal symptoms was based on Item 10 of the Montgomery–Åsberg Depression Rating Scale; scores of ≤ 2 and ≥ 4 indicated mild and severe symptoms, respectively. The patients with MDD and severe suicidal symptoms had higher levels of C-reactive protein (p =.019) and TNF-α (p =.002) than did the patients with mild symptoms or the healthy controls. The number of errors committed on the go/no-go by patients with MDD and severe suicidal symptoms (p =.001) was significantly higher than those by patients with MDD and mild symptoms or by controls. After adjusting for nonsuicidal depressive symptoms, we observed suicidal symptoms to be positively associated with TNF-α levels (p =.050) and errors on the go/no-go task (p =.021). Compared with mild suicidal symptoms, severe symptoms are associated with greater serum levels of proinflammatory cytokines and inferior cognitive function in adolescents and young adults with MDD. [ABSTRACT FROM AUTHOR]

Objective: To evaluate cytokine levels of interleukin (IL)-1β, IL-4, IL-6, IL-17a, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in the gingival crevicular fluid (GCF) of periodontal sites in individuals with Down syndrome (DS) and analyze their relationship with clinical periodontal parameters. Materials and methods: A cross-sectional study was conducted with 49 DS patients and 32 individuals without DS (non-DS group). Periodontal probing depth (PPD), clinical attachment level (CAL), bleeding on probing (BoP), and visible plaque index (VPI) were evaluated. The periodontal sites were classified as shallow, moderate, and deep. GCF was collected in all shallow sites and, when present, in moderate and deep sites for the analysis of cytokine levels. The cytokines, IL-1β, IL-4, IL-6, IL-17a, TNF-α, and IFN-γ, were quantified using the Luminex® automatic analyzer system. Results: The DS group presented greater severity of periodontitis compared to the non-DS group (P = 0.005). The DS group showed a significant direct correlation of IL-1β and an inverse correlation of IFN-γ and IL-14 with all periodontal variables. In the analysis stratified by periodontal pocket depth, we observed a higher level of IFN-γ, IL-17a, IL-1β, and IL-6 in the shallow sites, and IL-17a, IL-1β, and IL-6 in deep pockets of DS group individuals. Multivariate models showed that higher levels of IL-1β, IL-4, IL-6, and IL-17a were associated with Down syndrome even after adjusting for periodontal status, sex, and age. Conclusion: The findings suggest that people with DS have greater periodontal impairment and higher levels of cytokines in GCF, even in sites having clinical periodontal parameters similar to those of individuals without DS. These data reiterate the concept of an altered and less effective immune response in the population with DS in the face of a periodontal microbial challenge. Clinical relevance: Elevated periodontal inflammation burden can be observed with higher cytokine levels in the gingival crevicular fluid of people with Down syndrome, especially IL-1, IL-4, IL-6, and IL-17, regardless of the stage of periodontitis. [ABSTRACT FROM AUTHOR]

We studied interrelationships between behavioral parameters, metabolic processes, and cytokine content in the blood of male and female rats at different stages of postnatal ontogeny after intrauterine stress (mothers were forced to swim in cold water from the 10th to the 16th day of pregnancy). Correlations between behavioral and metabolic parameters in prenatally stressed rats were revealed at an earlier age (day 21 of life) than in controls. In comparison with intact rats, in males exposed to intrauterine stress no relationships between these parameters were revealed at older age, while in females, their direction and character change on day 60 of life. In prenatally stressed males, correlations of the blood levels of IL-6 were revealed: inverse relationships with behavioral parameters on the days 21 and 30 and direct relationships with metabolic parameters on day 60 of life. In prenatally stressed females on day 30 of life, we observed negative correlations between IL-4 levels and metabolic parameters that were absent under normal conditions. Thus, intrauterine stress leads to reorganization of the relationships between the parameters of metabolic and immune processes, which are essential for the purposeful behavior of mammals. The effects of stress seem to depend on the sex of the offspring and stage of postnatal development. [ABSTRACT FROM AUTHOR]

Purpose: This randomized clinical trial aimed to compare the effects of a mucoadhesive formula, containing curcuminoids from Curcuma longa L. and glycerinated extract of Bidens pilosa L. (FITOPROT), associated with photobiomodulation (PBM), and of PBM exclusively, on the incidence of oral mucositis (OM)–induced by radiotherapy (RT) in the head and neck region, and the salivary expression of inflammatory cytokines, in patients with head neck cancer. Methods: Patients were randomly assigned into two intervention groups—FITOPROT + PBM (n = 25) or PBM (n = 27). PBM protocol comprised a wavelength of 660 nm, 25 mW, 0.25 J/point, and daily irradiation from the first until the last day of RT. FITOPROT was gargled twice a day. All patients underwent a preventive oral care program throughout the study. OM degree, salivary concentration of nitrite, and inflammatory (IL-1, TNFα, IL-6, IL-8, and IL-12p70), and anti-inflammatory (IL-10) cytokines were assessed at baseline, and at the 7th, 14th, 21st, and 30th RT sessions. Results: There were no differences in the OM degree between groups, but the RT dose significantly affected the OM. The RT significantly affected the salivary nitrite, TNFα, IL-1β, and IL-10 concentrations. Conclusion: FITOPROT associated with PBM showed limited effects on preventing the incidence of severe OM compared to PBM alone. However, FITOPROT + PBM may be associated with nitrite and cytokine balance, which may contribute to the occurrence of fewer cases of severe OM. Trial registration: Brazilian Clinical Trials database (ReBEC; RBR-9vddmr), registered UTN code: U1111-1193–2066, registered in August 8th, 2017. [ABSTRACT FROM AUTHOR]

Lichen simplex chronicus (LSC) presents a challenge in dermatology due to its elusive pathogenic mechanisms. While associations between circulating inflammatory cytokines and LSC were observed, the definitive causal dynamics remain to be elucidated. Our study used a two-sample Mendelian randomization (MR) approach to investigate causal relationships. We applied a suite of MR methodologies, including IVW, Weighted Median, MR-Egger, Weighted Mode, Simple Mode, MR-PRESSO, and the Steiger test, to ensure robust causal inference. Our analysis confirmed the causal impact of genetically determined cytokine levels on LSC risk, particularly MMP-10 (OR = 0.493, P = 0.004) and DNER (OR = 0.651, P = 0.043) in risk attenuation. We also found a positive causal correlation between GDNF levels (OR = 1.871, P = 0.007) and LSC prevalence. Notably, bidirectional causality was observed between DNER and LSC. Consistency across various MR analyses and sensitivity analyses confirmed the absence of horizontal pleiotropy, validating the causal estimates. This pioneering MR investigation unveils a novel genetically anchored causal relationship between the circulating levels of MMP-10, DNER, and GDNF and LSC risk. Although further validation is requisite, our findings augment the understanding of cytokine mediation in LSC and underscore prospective avenues for research. [ABSTRACT FROM AUTHOR]

While several studies have examined the role of T cells and related cytokines in the development of chronic spontaneous urticaria (CSU), there is a limited amount of research focusing on the changes in cytokine levels during omalizumab treatment. The primary objective of this study was to investigate the inflammatory cytokine profile (including IL-4, IL-5, IL-10, IL-13, IL-17, IL-31, IL-33, and TNFα) among CSU patients undergoing to omalizumab treatment. Plasma levels of cytokines were measured using ELISA. Measurements were taken before CSU treatment, at the 3rd and 6th months of omalizumab treatment, and once in the control group. The severity of the patients’ disease was assessed using the weekly Urticaria Activity Score(UAS7), and disease control was evaluated using the Urticaria Control Test(UCT). Thirty-one CSU patients and 56 age- and gender-matched healthy controls were included. Plasma levels of IL-4 and IL-33 were significantly lower in patients with CSU compared to healthy controls (p = 0.001; p = 0.038, respectively). During omalizumab treatment, IL-4 levels showed a significant increase in the 3rd month compared to baseline (p = 0.01), and IL-5 levels significantly decreased in the 6th month compared to both the 3rd month and baseline (6th month vs. baseline; p = 0.006, 6th month vs. 3rd month; p = 0.001). One potential mechanism of action for omalizumab may involve its regulatory effects on type 2 inflammatory cytokines in CSU patients. This finding partially explains the efficacy of anti-IL-4/13 treatments in chronic spontaneous urticaria. Further investigations on drugs targeting type 2 inflammatory cytokines in CSU are warranted. [ABSTRACT FROM AUTHOR]

Background: Cluster headache is characterized by activation of the trigeminovascular pathway with subsequent pain signalling in the meningeal vessels, and inflammation has been suggested to play a role in the pathophysiology. To further investigate inflammation in cluster headache, inflammatory markers were analysed in patients with cluster headache and controls. Methods: We performed a case–control study, collecting cerebrospinal fluid and serum samples from healthy controls, cluster headache patients in remission, active bout, and during an attack to cover the dynamic range of the cluster headache phenotype. Inflammatory markers were quantified using Target 48 OLINK cytokine panels. Results: Altered levels of several cytokines were found in patients with cluster headache compared to controls. CCL8, CCL13, CCL11, CXCL10, CXCL11, HGF, MMP1, TNFSF10 and TNFSF12 levels in cerebrospinal fluid were comparable in active bout and remission, though significantly higher than in controls. In serum samples, CCL11 and CXCL11 displayed decreased levels in patients. Only one cytokine, IL-13 was differentially expressed in serum during attacks. Conclusion and interpretation: Our data shows signs of possible neuroinflammation occurring in biological samples from cluster headache patients. Increased cerebrospinal fluid cytokine levels are detectable in active bout and during remission, indicating neuroinflammation could be considered a marker for cluster headache and is unrelated to the different phases of the disorder. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a malignant hematological neoplastic disease. Autocrine or paracrine cytokines released by leukemic cells regulate the proliferation of AML cells. It is uncertain whether cytokines can indicate whether patients with AML are in remission with chemotherapy. The goal of this study was to evaluate the levels of Th1/Th2/Th17 cytokines in AML patients before and after chemotherapy to determine whether the cytokine levels could predict disease remission after chemotherapy. It was found that the levels of IL-5, IL-6, IL-8, IL-10, TNF-α, TNF-β, IL-17F, and IL-22 were significantly increased at the time of AML diagnosis in patients who achieved remission after two chemotherapy treatments (P < 0.05). After chemotherapy, the cytokine levels were reduced in patients with remission, while the levels of IL-6 and IL-8 were raised in patients without remission (P < 0.05). A comparison of cytokine levels before and after chemotherapy in patients who achieved remission showed areas under the curve (AUCs) of 0.69 for both IL-6 and IL-8. In addition, a comparison of the remission and non-remission groups after chemotherapy showed an AUC of 0.77 for IL-6. We then calculated the cutoff value using receiver operating characteristic curves. Values of IL-6 < 9.99 and IL-8 < 8.46 at the time of diagnosis were predictive of chemotherapy success and remission, while IL-6 > 14.89 at diagnosis suggested that chemotherapy would not be successful and remission would not be achieved. Multifactorial analysis showed that age, Neu, IL-6, and IL-8 were independent risk factors for AML prognosis, and IL-6 (OR = 5.48, P = 0.0038) was superior to age (OR = 3.36, P = 0.0379), Neu (OR = 0.28, P = 0.0308), IL-8 (OR = 0.0421, P = 0.0421). In conclusion, IL-6 levels were found to be predictive of the likelihood of remission. [ABSTRACT FROM AUTHOR]

In this study, we assess the impact of photodynamic therapy (PDT) using aluminum phthalocyanine tetrasulfonate (AlPcS4) on the viability and cellular stress responses of MCF-7 breast cancer cells. Specifically, we investigate changes in cell viability, cytokine production, and the expression of stress-related genes. Experimental groups included control cells, those treated with AlPcS4 only, light-emitting diode (LED) only, and combined PDT. To evaluate these effects on cell viability, cytokine production, and the expression of stress-related genes, techniques such as 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, enzyme-linked immunosorbent assays (ELISA), and real-time quantitative PCR (RT‒qPCR) were employed. Our findings reveal how PDT with AlPcS4 modulates mitochondrial activity and cytokine responses, shedding light on the cellular pathways essential for cell survival and stress adaptation. This work enhances our understanding of PDT's therapeutic potential and mechanisms in treating breast cancer. [ABSTRACT FROM AUTHOR]

Background and objective: Psychological stress has been identified in some observational studies as a potential factor that may modify and affect periodontal diseases, but there are no similar data for peri-implantitis. The aim of this study was to determine the relationship between interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)α inflammatory cytokines and the psychological stress-related markers, glucocorticoid receptor-α (GRα), and salivary α-amylase (sAA) gene expression levels in saliva samples obtained from healthy implants and peri-implantitis patients. Materials and methods: The study included a total of 50 systemically healthy subjects. Peri-implant clinical parameters were recorded and psychological stress level was evaluated with the hospital anxiety and depression scale (HAD) and state-trait anxiety inventory (STAI) questionnaire forms. Following the evaluations, the patients were divided into 4 groups according their stress and clinical status (Ia, Ib, IIa, IIb). IL-1β, IL-6, IL-10, IFNα, GRα, sAA gene expression levels in the saliva samples were quantified by quantitative polymerase chain reaction (qPCR). Results: In the group of peri-implantitis who had a high score in stress level assessment scales, significantly higher IL-1β, IL-6, sAA expression levels were observed (p < 0.001). The IL-10 gene expression levels were lower in the groups with a high score in the stress level assessment scales (p < 0.001). GRα gene was expressed at lower levels in the group of peri-implantitis who had a high score in stress level assessment scales but the difference was not statistically significant (p = 0.065). Conclusion: The study findings suggest that psychological stress may increase the inflammation associated with peri-implantitis by affecting cytokine expression levels. Clinical relevance: To prevent peri-implantitis or reduce its prevalence, it could be beneficial to evaluate stress levels and identify individuals experiencing stress. [ABSTRACT FROM AUTHOR]

Objective: Occupational exposure to pesticides is a known risk for disrupting cellular immune response in flower workers due to their use of multiple chemical products, poor work conditions, and inadequate protection. Recently, the analysis of pesticide use patterns has emerged as an alternative to studying exposure to mixtures of these products. This study aimed to evaluate the association between exposure to different patterns of pesticide use and the cytokine profile of flower workers in the State of Mexico and Morelos, Mexico. Methods: A cross-sectional study was carried out on a population of 108 flower workers. Serum levels of IL-4, IL-5, IL-6, IL-8, IL-10 cytokines were analyzed by means of multiplex analysis, and TNF-α and IFN-γ using an ELISA test. Pesticide use patterns were generated by principal components analysis. Results: The analysis revealed that certain patterns of pesticide use, combining insecticides and fungicides, were associated with higher levels of pro-inflammatory cytokines, particularly IL-6 and IFN-γ. Conclusion: These findings indicate that pesticides may possess immunotoxic properties, contributing to increased inflammatory response. However, further comprehensive epidemiological studies are needed to establish a causal relationship. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are promising for clinical studies owing to their self-renewal, multipotency, trophic, and immunomodulatory properties. This study aimed to investigate the cytokine levels of human umbilical cord blood (CB) and Wharton's Jelly-(WJ) derived MSCs relevant to immune modulation on different passage levels in vitro. Umbilical CB MSCs were isolated using the ficoll-paque gradient method, and WJ-MSCs were isolated by the explant method. After isolation, the MSCs were characterized using flow cytometry. The supernatant cytokine levels (interferon-gamma (IFN-γ), interleukin 4 (IL-4), interleukin 17 (IL-17)) of MSCs at each passage were evaluated using the ELISA assay. MSCs exhibited different cytokine levels with each passage number. In WJ-MSC culture supernatants, IL-17 levels significantly increased at P4 and P5 compared to the first passage (p < 0.005), while the other passages showed a decrease. IFN-γ levels increased at passage P1 and P4 and decreased at other passages (p < 0.005). IL-4 levels significantly increased only at passage P3 (p < 0.005). In CB-MSC culture supernatants, IL-17 and IL-4 cytokines decreased compared to P0, while IFN-γ cytokine increased from P0 (p < 0.005). The changing ratio of cytokine levelsfor both CB-MSCs and WJ-MSCs were similarly maintained from early to late passages. More research is needed to understand the immunomodulatory functions of MSCs. [ABSTRACT FROM AUTHOR]

Introduction: Cytokines are key players in the development of both type 1 diabetes (T1D) and cardiovascular disease (CVD). Offspring of women with T1D are known to have an increased risk of early-onset CVD. We studied whether an increased risk of CVD can be observed in the cytokine profile among young adult offspring of women with T1D. Methods: This cross-sectional case–control study included 67 offspring of women with T1D (cases) and 79 control participants (controls). At an age of 18–23 years, they participated in a clinical assessment including laboratory tests and questionnaires. Cytokine levels were analyzed from venous blood samples after 10 h fasting using Quansys biosciences Q-Plex™ High Sensitivity Human Cytokine Array. Results: Circulating cytokine levels were in general similar between the groups. The circulating levels of interferon-γ (1.78 [IQR 1.20, 2.36] pg/mL versus 2.57 [IQR 1.50, 3.89] pg/mL) (p = 0.006) were lower in cases than controls. Conclusion: The findings did not support our hypothesis that serum cytokine profile, determined in early adulthood, was associated with a more adverse CVD risk profile in offspring of women with T1D. Further studies are warranted to find out whether cytokines could serve as early biomarkers of CVD development or whether changes in the cytokine levels over years could be used to monitor CVD progression in offspring of women with T1D. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer accounts for 30% of all female cancers in the US. Cytomegalovirus (CMV), a herpesvirus that establishes lifelong infection, may play a role in breast cancer. CMV is not oncogenic, yet viral DNA and proteins have been detected in breast tumors, indicating possible contribution to tumor development. CMV encodes cmvIL-10, a homolog of human cellular IL-10 (cIL-10) with potent immunosuppressive activities. We investigated the relationship between CMV infection, cytokines, and breast cancer. Methods: We evaluated CMV serostatus and cytokine levels in plasma of women with benign breast disease (n = 38), in situ carcinoma (n = 41), invasive carcinoma, no lymph node involvement (Inv/LN−; n = 41), and invasive with lymph node involvement (Inv/LN+; n = 37). Results: Fifty percent of the patient samples (n = 79) were CMV seropositive. There was no correlation between CMV status and diagnosis (p = 0.75). For CMV+ patients, there was a trend toward higher CMV IgG levels in invasive disease (p = 0.172). CmvIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN− and Inv/LN+ groups (p = 0.020). Similarly, cIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN− and Inv/LN+ groups (p = 0.043). The results were quite different in CMV− patients where cIL-10 levels were highest in Inv/LN− compared to benign, in situ, or Inv/LN+ (p = 0.019). African American patients were significantly associated with CMV+ status (p = 0.001) and had lower cmvIL-10 levels than Caucasian patients (p = 0.046). Conclusion: No association was observed between CMV IgG and diagnosis, but CMV infection influences cytokine production and contributes to altered cytokine profiles in breast cancer. [ABSTRACT FROM AUTHOR]

Vitamin D3 deficiency is associated with an increased risk of dementia. An association between vitamin D3 deficiency and subjective cognitive complaints in geriatric patients has been previously reported. This study aimed to evaluate the effects of two doses of vitamin D3 on spatial memory (using the Radial Maze) and cytokine levels [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10)] on 2-, 6-, 13-, 22-, and 31-month-old male Wistar rats. Animals were supplemented with vitamin D3 at doses of 42 IU/kg and 420 IU/kg for 21 days. A radial maze test was performed to evaluate spatial memory. After the behavioral test, the frontal cortex and hippocampus were dissected for enzyme immunoassay analyses to measure the cytokine levels (TNFα, IL-1β, IL-6, and IL-10). Our results showed that vitamin D3 supplementation reversed spatial memory impairment at the supplemented doses (42 and 420 IU/kg) in 6-, 13-, and 22-month-old animals and at a dose of 420 IU/kg in 31-month-old animals. The lower dose (42 IU/kg) regulates both pro- and anti-inflammatory cytokines mainly in the frontal cortex. Our results suggest that vitamin D3 has a modulatory action on pro- and anti-inflammatory cytokines, since older animals showed increased cytokine levels compared to 2-month-old animals, and that vitamin D3 may exert an immunomodulatory effect on aging. [ABSTRACT FROM AUTHOR]

Exploration of cytokine levels in systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF) is needed to find common and diverse biomolecular pathways. Circulating levels of 87 cytokines were compared amongst 19 healthy controls and consecutive patients with SSc-ILD (n = 39), SSc without ILD (n = 29), and IPF (n = 17) recruited from a Canadian centre using a log-linear model adjusted for age, sex, baseline forced vital capacity (FVC), and immunosuppressive or anti-fibrotic treatment at time of sampling. Also examined was annualized change in FVC. Four cytokines had Holm's corrected p-values less than 0.05. Eotaxin-1 levels were increased approximately two-fold in all patient categories compared to healthy controls. Interleukin-6 levels were eight-fold higher in all ILD categories compared to healthy controls. MIG/CXCL9 levels increased two-fold more in all but one patient category compared to healthy controls. Levels of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, (ADAMTS13) were lower for all categories of patients compared to controls. No substantial association was found for any of the cytokines with FVC change. Observed cytokine differences suggest both common and diverse pathways leading to pulmonary fibrosis. Further studies evaluating longitudinal change of these molecules would be informative. [ABSTRACT FROM AUTHOR]

Neuroinflammation plays an important role in epileptogenesis, however, most studies are performed using pharmacological models of epilepsy, while there are only few data available for non-invasive, including genetic, models. The levels of a number of pro-inflammatory cytokines were examined in the Krushinsky–Molodkina (KM) rat strain with high audiogenic epilepsy (AE) proneness (intense tonic seizure fit in response to loud sound) and in the control strain "0" (not predisposed to AE) using multiplex immunofluorescence magnetic assay (MILLIPLEX map Kit). Cytokine levels were determined in the dorsal striatum tissue and in the brain stem. Background levels of IL-1β, IL-6, and TNF-α in the dorsal striatum of the KM rats were significantly lower than in the rats "0" (by 32.31, 27.84, and 38.87%, respectively, p < 0.05, 0.05, and 0.01), whereas no inter-strain differences in the levels of these metabolites were detected in the brain stem in the "background" state. Four hours after sound exposure, the TNF-α level in the dorsal striatum of the KM rats was significantly lower (by 38.34%, p < 0.01) than in the "0" rats. In the KM rats, the dorsal striatal levels of IL-1β and IL-6 were significantly higher after the sound exposure and subsequent seizure fit, compared to the background (35.29 and 50.21% increase, p < 0.05, 0.01, respectively). In the background state the IL-2 level in the KM rats was not detected, whereas after audiogenic seizures its level was 14.01 pg/ml (significant difference, p < 0.01). In the KM rats the brain stem levels of IL-1β and TNF-α after audiogenic seizures were significantly lower than in the background (13.23 and 23.44% decrease, respectively, p < 0.05). In the rats of the "0" strain, the levels of cytokines in the dorsal striatum after the action of sound (which did not induce AE seizures) were not different from those of the background, while in the brain stem of the "0" strain the levels of IL-1β were lower than in the background (40.28%, p < 0.01). Thus, the differences between the background levels of cytokines and those after the action of sound were different in the rats with different proneness to AE. These data suggest involvement of the analyzed cytokines in pathophysiology of the seizure state, namely in AE seizures. [ABSTRACT FROM AUTHOR]

Chronic inflammation is persistent disease caused by unregulated activation of Nf-kb pathway and production of pro-inflammatory cytokines, induced by accumulation of reactive oxygen species above thresholds. The purpose of this study was to evaluate the anti-oxidant, anti-lipidemia, inhibition Nf-kb pathway, and reduction of pro-inflammatory cytokine activities of Ixeris dentata extract (IDE) to demonstrate its inhibitory ability against chronic inflammatory in RAW264.7. Polyphenol content, radical scavenging activity, and lipase activity inhibition of IDE were 9.2 ± 0.2 GAE mg/g dry matter, 84.7%, and 72.4%, respectively, showing high effects against anti-oxidant and lipolysis inhibitory. Furthermore, anti-inflammatory effects of IDE on LPS-induced RAW 264.7 were investigated, and expression of inflammatory genes such as Cox-2, Inos, Tnf-α, Il-6, Nf-kb, and Il-1β were decreased by 36.5%–83.4%. Studies have confirmed that IDE has excellent antioxidant, lipolysis inhibitory, and anti-inflammatory effects, and Ixeris dentata can be used as natural ingredients for food and medicine to prevent. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to assess levels of biomarkers associated with inflammation and tissue destruction in peri-implant crevicular fluid (PICF) of implants provided with customized or standard healing abutments during early implant healing. Materials and methods: Thirty implants were placed in 22 patients with partial posterior edentulism. Subsequently, test group implants (n=15) received one-piece titanium abutments that were fabricated using computer-aided design/computer-aided manufacturing (CAD/CAM). Control group implants (n=15) were provided with standard abutments. PICF collection and standardized periapical radiographs were carried out at suture removal one week later, following crown delivery after 3 months and at 6 months. Expression of C-reactive protein (CRP), interferon-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12A, IL-17A, macrophage inflammatory protein (MIP)-1α, matrix metalloproteinase (MMP)-13, osteopontin, osteoactivin, Receptor Activator of NF-κB (RANK), and TGF-β were analyzed using a multiplex ELISA kit. Results: Both groups showed a significant decrease in protein expression of CRP, IL-1β, IL-6, IL-8, MIP-1α, osteopontin, osteoactivin, and TGF-β, while MMP-13 levels increased during the observation period. A rise in OPG and RANK levels was detected among customized abutments. Expression of CRP was higher, whereas IL-1β, IL-1α, and MIP-1α were decreased in control compared to test group implants after 6 months. Marginal bone loss did not depend on abutment modality. Conclusions: Both abutment types showed distinctive temporal expression of inflammatory biomarkers during 6 months following implant placement. Trial registration: ISRCTN98477184, registration date 18/05/2022 Clinical relevance: Customized healing abutments exert similar effects on inflammation during early implant healing compared to standard healing abutments. [ABSTRACT FROM AUTHOR]

Animal and human data indicate variable effects of interferons in treating coronavirus infections according to inflammatory status and timing of therapy. In this sub-study of the MIRACLE trial (MERS-CoV Infection Treated with a Combination of Lopinavir–Ritonavir and Interferon β-1b), we evaluated the heterogeneity of treatment effect of interferon-β1b and lopinavir–ritonavir versus placebo among hospitalized patients with MERS on 90-day mortality, according to cytokine levels and timing of therapy. We measured plasma levels of 17 cytokines at enrollment and tested the treatment effect on 90-day mortality according to cytokine levels (higher versus lower levels using the upper tertile (67%) as a cutoff point) and time to treatment (≤ 7 days versus > 7 days of symptom onset) using interaction tests. Among 70 included patients, 32 received interferon-β1b and lopinavir–ritonavir and 38 received placebo. Interferon-β1b and lopinavir–ritonavir reduced mortality in patients with lower IL-2, IL-8 and IL-13 plasma concentrations but not in patients with higher levels (p-value for interaction = 0.09, 0.07, and 0.05, respectively) and with early but not late therapy (p = 0.002). There was no statistically significant heterogeneity of treatment effect according to other cytokine levels. Further work is needed to evaluate whether the assessment of inflammatory status can help in identifying patients with MERS who may benefit from interferon-β1b and lopinavir–ritonavir. Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843). [ABSTRACT FROM AUTHOR]

Aims: Natural killer (NK) cells are important innate cytotoxic lymphocytes and can contribute to the immune response through the synthesis and secrete proinflammatory cytokines. In the present study, we assessed and compared the proportion of NK cells in peripheral blood lymphocytes, various cytokine levels and metabolic parameters in type 2 diabetes mellitus (T2DM), prediabetes and normal glucose tolerance (NGT). Methods: Individuals with 57 T2DM, 58 prediabetes and 60 NGT were enrolled. Fasting plasma glucose, 2-h postload glucose, fructosamine, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein and triglyceride levels were assessed on an automatic biochemical analyzer. Various cytokine levels in the serum including IL-2, IL-5, IL-6, IL-10, IL-12p70, and IFN-γ were assessed using ELISA kits. Proportion of NK cells in peripheral blood lymphocytes was assessed by flow cytometry. Results: The proportion of NK in lymphocytes from prediabetes was significantly increased compared with that obtained from T2DM, while the data was significantly decreased compared with that obtained from NGT. Significant increases in fasting plasma glucose, postprandial plasma glucose and triglycerides were observed in prediabetes compared with NGT.IL-12p70 level was significantly lower in prediabetes and T2DM compared with NGT. IL-6 and IFN-γ levels in prediabetes were significantly lower than those in NGT and T2DM patients, in addition IL-6 level in T2DM patients was significantly higher compared to NGT. The trend of IL-10 level was opposite to that of IL-6. Conclusions: The decreased proportion of NK cells in peripheral blood lymphocytes following some cytokine levels (IL-12p70, IL-6,IL-10 and IFN-γ) was likely involved in the development of T2DM and prediabetes. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the changes in vitreous inflammatory and angiogenic cytokine levels, primarily interleukin-(IL)-6, following intravitreal injection of the 0.19 mg fluocinolone acetonide (FAc, ILUVIEN®) implant in patients with diabetic macular edema. Methods: A single-center phase IV study involving 12 patients' eyes with diabetic macular edema. Vitreous fluid samples were obtained prior to intravitreal injection of the fluocinolone acetonide implant and then again over a 6-month period. Vitreous samples were examined using a cytometric bead array to measure IL-6, IL-8, IP-10, MCP-1, VEGF, and CD54. PIGF and PEDF were measured using an enzyme-linked immunosorbent assay. Changes in the cytokine and chemokine expression patterns were analyzed. Clinical parameters such as BCVA and center point thickness (CPT) were also examined. Results: There were mean reductions in all parameters between baseline and month 6. Significant changes (p < 0.05 versus baseline) were observed in the expression of IL-6, IP-10, MCP-1, and CD54 following the administration of fluocinolone acetonide implant. VEGF and PIGF increased at month 1 before declining at month 6, though this trend was not significant. CPT decreased rapidly between screening and the first follow-up visit, and this decrease was sustained. BCVA remained relatively stable throughout. Conclusion: This study demonstrated changes in vitreous inflammatory and angiogenic cytokine levels following intravitreal injection of the FAc implant in patients with diabetic macular edema. Data show that the fluocinolone acetonide implant led to rapid and sustained reductions of some inflammatory cytokines with improvement of the overall clinical picture. [ABSTRACT FROM AUTHOR]

Rationale and objective: In this study, we hypothesized that the chronic use of clozapine affects cytokine expression and has a greater effect on female patients than on male patients. The aims of this study were to detect (1) whether serum cytokine levels were altered in patients with chronic schizophrenia after clozapine treatment compared with age- and sex-matched healthy controls, (2) whether there was a gender difference in serum cytokine levels after clozapine treatment, and (3) whether there was a correlation between serum cytokine levels and clozapine daily dosage in patients with schizophrenia. Methods: Forty-nine inpatients with schizophrenia treated with clozapine and fifty-three sex- and age-matched healthy controls were recruited. The patients' psychiatric symptoms were measured by the Positive and Negative Syndrome Scale (PANSS). Blood samples from both patients and healthy controls were collected. Serum IL-1β, IL-2, IL-6, IL-17, IFN-γ, and TNF-α levels were measured in duplicate by sandwich enzyme-linked immunosorbent assay. Results: We found that chronic clozapine treatment in patients with schizophrenia resulted in the abnormal expression of serum cytokines, such as IL-2, IL-6, IL-17, and TNF-α, compared with the healthy controls. In addition, there was a gender difference in the abnormal expression of cytokines between male and female patients with schizophrenia. In the female group, IL-2 serum levels were lower than those in the male group. Interestingly, there was a positive correlation between serum IL-2 levels and the daily clozapine dosage in female patients with schizophrenia. Conclusion: Findings from our study have shown clear evidence that clozapine had a greater effect on immune function in female patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Purpose: Although uniportal video-assisted thoracoscopic surgery (VATS) has been widely used, the associated postoperative pain is still severe. Currently, a variety of regional anesthesia methods have been used to relieve postoperative pain. In our study, we wanted to evaluate the effectiveness of ultrasound-guided erector spinae plane block (ESPB) as a postoperative analgesia after uniportal VATS. Methods: Eighty patients scheduled to undergo uniportal VATS were randomly divided into Group ESP and Group C. In Group ESP, the patients underwent ultrasound-guided ESPB under general anesthesia before surgery, while Group C was set as blank control group without ESPB. The primary outcome was the sufentanil dose within 24 h after surgery. The secondary outcomes mainly included postoperative pain scores at 2, 4, 8, and 24 h evaluated using a numeric rating scale (NRS), intraoperative opioid dosage, levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in the plasma, side effect profile, and length of postoperative hospital stay. Results: Postoperative sufentanil consumption (32.5 ± 6.3 μg vs. 42.8 ± 7.6 μg, P < 0.001) was significantly lower in Group ESP than in Group C. Intraoperative sufentanil consumption was significantly lower in Group ESP than in Group C (P < 0.001). The postoperative NRS score and levels of inflammatory cytokines were significantly lower in Group ESP than in Group C (P < 0.05). Conclusions: Ultrasound-guided ESPB decreased the consumption of sufentanil both postoperatively and intraoperatively for patients undergoing uniportal VATS and appeared to be an effective treatment option. [ABSTRACT FROM AUTHOR]

We investigated the effect of hydroxychloroquine (HCQ) as an add-on treatment to immunosuppressants on the expression of proinflammatory cytokines in patients with systemic lupus erythematosus. Serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6, IL-8, vascular endothelial growth factor (VEGF)-A, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and interleukin 1 receptor antagonist (IL-1ra) were measured immediately before and 3 months after treatment with oral HCQ. Among the 51 patients enrolled in the study, HCQ treatment led to significantly reduced serum levels of TNF-α, IL-6, IL-8, VEGF-A, IL-1ra, and IL-2 (p < 0.0001; p = 0.0006; p = 0.0460, p = 0.0177; p < 0.0001; p = 0.0282, respectively) and to decreased (but not significantly) levels of MIP-1α (p = 0.0746). No significant changes were observed in the serum MCP-1 levels before and after HCQ administration (p = 0.1402). Our results suggest that an add-on HCQ treatment modulates the expression of proinflammatory cytokines even in systemic lupus erythematosus patients with low disease activity. [ABSTRACT FROM AUTHOR]

Purpose: To determine the correlation between aqueous humor cytokine levels and the prognostic value of anti-vascular endothelial growth factor (VEGF) therapy for treating macular edema resulting from retinal vein occlusion (RVO-ME). Methods: This prospective study included 47 RVO-ME and 32 senile cataract cases. Aqueous humor collection was performed in patients with RVO-ME before intravitreal injection of ranibizumab and in patients before cataract surgery. VEGF, monocyte chemotactic protein 1 (MCP-1), interleukin (IL)-8, IL-6, basic fibroblast growth factor (b-FGF), and tumor necrosis factor-α (TNF-α) levels were measured in the aqueous humor. Central retinal thickness (CRT) was measured before ranibizumab treatment and during each follow-up visit. The recovery rate following ranibizumab treatment was calculated as (CRTBT—CRTAT1W)/CRTBT, in which CRTBT was the CRT measured before treatment and CRTAT1W was measured 1 week after treatment. The recurrence time of RVO-ME was recorded. Results: VEGF, MCP-1, IL-8, and IL-6 levels in the aqueous humor of patients with RVO-ME were significantly higher compared with control and were positively correlated with the CRTBT. Ranibizumab significantly reduced CRT, and VEGF levels positively correlated with the recovery rate. The mean recurrence time of RVO-ME was 43.5 days. IL-6 levels negatively correlated with the recurrence time of ME. Conclusion: VEGF, MCP-1, IL-8, and IL-6 levels were significantly increased in patients with RVO-ME and were positively correlated with ME. Higher VEGF levels were indicative of CRT recovery, and higher IL-6 levels were indicative of ME recurrence after ranibizumab treatment. [ABSTRACT FROM AUTHOR]

Introduction: Anti-tumor necrosis factor (anti-TNF) agents are commonly used in treatment of axial spondyloarthritis (axSpA), but clinical and radiological improvement is not achieved in all patients. We aimed to investigate the impact of anti-TNFs on inflammatory and noninflammatory parameters in patients with axSpA. Methods: In this longitudinal study, 30 biologic naïve axSpA patients with high disease activity and 30 healthy controls were enrolled. All patients were treated with anti-TNF agents for 6 months. ASDAS-CRP, BASDAI, BASFI, BASMI, patient and physician global assessments were evaluated. C-reactive protein, COX2, TNF-α IL-6, IL-17, IL-22, IL-23, IL-33, sclerostin, dickkopf-1, and noggin levels were evaluated at baseline and at 6 months of anti-TNF treatment. Results: At baseline, axSpA patients had significantly higher median (IQR) TNF-α levels, 34.4 (31.4–37.03) vs. 18.1 (12.1–28.4) pg/ml (p < 0.001), and lower DKK1, 446.7 (356.9–529.3) vs. 1088.7 (951.7–1244.4) pg/ml, and sclerostin, 312.4 (140.8–412.7) vs. 412.3 (295.4–512.8) pg/ml, compared to healthy controls (all p < 0.001). The median (IQR) serum levels of IL-17, IL-22, and IL-33 increased significantly after 6 months of anti-TNF treatment, from 93.3 (85.1–104.8) to 102.1 (86.6–114.6) pg/ml (p = 0.026), 159.2 (151.9–178.4) to 183.5 (156.3–304.6) pg/ml (p = 0.033), and 127.8 (106.6–186.1) to 147.06 (128.5–213.4) pg/ml (p = 0.016), respectively. Sclerostin and DKK-1 levels increased significantly after anti-TNF treatment from 312.4 (140.8–412.7) to 405.1 (276.3–452.5) pg/ml (p = 0.018) and 446.7 (356.9–529.3) to 881.3 (663.1–972.2) pg/ml (p < 0.001), while there was no significant change in noggin level. Conclusions: Many inflammatory cytokines increase after anti-TNF treatment and noggin is not affected by anti-TNF treatment in AxSpA. Noggin might be a therapeutic target in patients with axSpA. Key Points: • Anti-TNF therapy is not sufficient for complete blockage of the inflammatory process in axial spondyloarthritis. • The increase in IL-17, IL-22, and IL-33 may decrease the efficiency of anti-TNF therapy. • Noggin might be a therapeutic target as a complementary or alternative approach to anti-TNF therapy in axial spondyloarthritis. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effects of balneological outpatient treatment (hydrotherapy and peloidotherapy) on clinical status and serum cytokine levels in patients with chronic low back pain (CLBP). Seventy-four patients with CLBP who accepted to participate to the study were randomly divided into two groups. The study group was given ten sessions (in 2 weeks) of hydrotherapy, peloidotherapy, and home exercise, while the control group was given only home exercise. All patients were assessed before and at the end of therapy, at the 1st and 3rd months. The primary outcomes were pain intensity on the visual analog scale (VAS) (VAS-pain, VAS-rest, VAS-exercise) and Oswestry Disability Index (ODI). The secondary outcome measures included patient's and physician's global assessment (VAS-PGA), (VAS-DGA), finger-to-floor distance (FFD), modified Schober test, Short Form-36 (SF-36), and the use of analgesic drug. Venous blood samples were drawn from all patients before/1st day and after therapy/12th day to measure serum interleukin (IL)-6 and IL-10 levels. Significant improvement was observed in the study group in VAS-pain, VAS-rest, VAS-exercise, VAS-PGA, VAS-DGA, ODI, and SF-36 parameters after treatment and improvement maintained for 3 months. In the control group, significant improvement was observed in VAS-pain, VAS-exercise, VAS-PGA, VAS-DGA, and ODI scores on the 12th day and continued for 3 months. Decrease in pain, pain during rest and exercise, modified Schober test, VAS-PGA, VAS-DGA, ODI scores, and the increase in SF-36 pain and general health scores showed superiority in favor of the study group in all evaluations. There was a significant increase in IL-10 values from baseline at the end of treatment in the study group. The use of non-steroidal anti-inflammatory drug (NSAID) was significantly lower in the study group compared with the use of NSAID in the control group in the 3rd month. Balneological outpatient treatment improved clinical status in CLBP patients. Although no significant correlation was clearly determined between IL-10 levels and pain score, this effect might be related to the observed increase in the anti-inflammatory cytokine IL-10 levels that was observed only in the study group. [ABSTRACT FROM AUTHOR]

Recent studies suggest immune function dysregulation in depression and anxiety disorders. Elevated pro-inflammatory cytokines may be a marker for immune system dysregulation. No study assessed the correlation between the levels of cytokines in children and adolescents with depression/anxiety disorders and their parents. In this study, 92 children and adolescents (mean age 13.90 ± 2.41 years) with depression and/or anxiety disorders were treated with fluoxetine. Blood samples were collected before initiation of treatment. One hundred and sixty-four of their parents (mean age 50.6 ± 6.2 years) and 25 parents of healthy children (mean age 38.5 ± 6.2 years) also gave blood samples. Plasma levels of three pro-inflammatory cytokine (TNF-α, IL-6, IL-1β) were measured by enzyme linked immunosorbent assays (ELISA) and compared between depressed/anxious children and their parents. We also compared cytokine levels between parents of children with depression/anxiety and control parents. Mothers of depressed children had higher TNF-α levels than mothers of controls. No significant difference was detected in the fathers. A positive correlation was found between the IL-1β levels of the depressed/anxious boys and their mothers. No such correlation was observed in the fathers. Our conclusions are that higher levels of proinflammatory cytokines may indicate immune system activation in mothers in response to the distress associated with having depressed/anxious offspring. The correlation between IL-1β levels in the mothers and their depressed/anxious children may indicate familial vulnerability to depression and anxiety. Our observation highlights the need for a better understanding of sexual dimorphism in inflammatory responses to stress. [ABSTRACT FROM AUTHOR]

Cytokine release syndrome (CRS) is a great challenge for the application of anti-CD19 CAR-T cell therapy. The aim of this study was to investigate the effect of knocking down interferon gamma (IFN-γ) by shRNA as a potential strategy to reduce the cytokine storms. A newly designed short hairpin interference RNA of IFN-γ (shIFN-γ) in CD19CAR gene was constructed. Several cellular model systems of approach using Nalm-6 cell lines including Nalm-6CD19pos and Nalm-6CD19neg with or without monocytes and endothelial cells were used to analyze the different levels of cytokines after shIFN-γ-anti-CD19CAR-T cell targeted therapy. The activity of this novel CD19CAR-T was evaluated both in vitro and in NSG mouse model. The killing efficacy of shIFN-γ-anti-CD19CAR-T at the E:T ratio of 2:1 was similar to that of regular anti-CD19CAR-T at the E:T ratio of 1:1. The IFN-γ level in the shIFN-γ-anti-CD19CAR-T cell group was (2673.1 ± 307.4) pg/ml at the E:T ratio of 2:1 which was significantly lower than that ((8261.5 ± 345.5) pg/ml) in the regular anti-CD19CAR-T group at the E:T ratio of 1:1. Cytotoxicity experiments in vitro showed significantly reduced concentrations of IFN-γ, IL-6 and TNFα in the shIFN-γ-anti-CD19CAR-T cell group compared to regular anti-CD19CAR-T cell group. Both regular anti-CD19CAR and shIFN-γ-CD19CAR-T exerted bystander killing effect in vitro. We conclude that shIFN-γ-anti-CD19CAR-T cells can reduce the generation of cytokine storms without significantly compromising their therapeutic efficacy in the preclinical setting. In mouse model, 3 × 106 shIFN-γ-anti-CD19CAR-T cells/mouse generated the similar killing efficacy to that with 2 × 106 regular anti-CD19CAR-T cells/mouse. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to use umbilical cord mesenchymal stem cells (UCMSCs) loaded with graphene oxide (GO) granular lubricant to treat knee osteoarthritis (KOA) animal models and to analyze their effect on cytokine levels in the articular cavity. Methods: Twenty-four New Zealand rabbit models of KOA were established by the modified Hulth and cartilage injury method, and they were assigned to the blank group, the GO group, the UCMSC group, and the GO + UCMSC group, each group containing six animal models. The GO and UCMSC groups were treated by a single intra-articular injection. The treatment was started one month after surgical modeling, and the observation period was eight weeks. The expression levels of nitric oxide (NO), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), glycosaminoglycan (GAG), and collagen-II (COL-II) in serum and articular fluid after treatment were compared to analyze the efficacy. Results: The GO granular lubricant caused no significant improvement in the intra-articular environment of the knee joint, and UCMSCs caused a certain degree of improvement in the inflammatory environment. The improvement results of NO, IL-6, TNF-α, GAG, and COL-II were the best in the GO + UCMSC group, but the improvement results of inflammatory cytokine levels in serum and articular fluid were not consistent, especially the differences in NO, IL-6, and TNF-α were greater. Conclusion: UCMSCs loaded with the GO granular lubricant can reduce the inflammatory level and improve the level of biochemical environment in the articular cavity, and thus promote cartilage repair. [ABSTRACT FROM AUTHOR]

We aimed to investigate the relationship between non-perfusion on ultra-widefield angiography (UWF FA) and aqueous cytokine levels and central macular thickness (CMT) in eyes with branch retinal vein occlusion (BRVO). Thirty-five eyes with treatment-naïve BRVO were included. Non-perfusion area (NPA) for partial and complete ischemia was manually segmented and the ischemic index (ISI) for each was calculated using stereographically projected UWF FA for four different retinal zones. Partial and complete ischemia had different regional predominance. Partial ischemia was predominant in the posterior regions, while complete ischemia was predominant in the periphery. And partial ischemic area, located posterior to far periphery, showed significant correlation with central macular thickness and concentrations of angiogenic and inflammatory cytokines, while complete ischemic area showed no correlation with any of the parameters. Taken together, partial but not complete ischemia, particularly in the more posterior retina, was associated with higher cytokine levels and more severe macular edema in eyes with BRVO. These findings would help us to better understand the different clinical significance of ischemia in BRVO depending on the severity and regional distribution. [ABSTRACT FROM AUTHOR]

We investigated the relationship between aqueous cytokine levels, changes in ocular blood flow, and morphological and functional improvements after intravitreal ranibizumab injection (IRI) in treatment-naïve eyes with center-involving diabetic macular edema (DME). Thirty-three eligible patients with DME (33 eyes) were recruited. At the first IRI, we collected a sample of aqueous humor from each eye and measured levels of the cytokines/chemokines. Mean blur rate (MBR) was used to evaluate retinal and choroidal flow by laser speckle flowgraphy at the time of the first IRI and 1 month later. One month after IRI, both retinal and choroidal MBR had significantly decreased from baseline. The reduction ratio of the retinal MBR was significantly correlated with aqueous levels of monocyte chemotactic protein (MCP)-1 and interleukin-8, and with reduction of central macular thickness, but not with improvement of best corrected visual acuity. The reduction ratio of choroidal MBR showed no statistical correlation with any cytokine levels or changes in clinical parameters. We conclude that IRI reduces both retinal and choroidal blood flow in treatment-naïve DME. Reduction of retinal blood flow correlated with regression of morphological pathology, which is regulated by the initial aqueous levels of some cytokines. [ABSTRACT FROM AUTHOR]

Plasmodium infection causes inflammation in the host. A combination of herbs like Azadirachta indica and Curcuma longa may have beneficial effect in remediating inflammation in malaria disease. The aim of this study is to investigate the immunomodulatory and synergistic effects of the association of Azadirachta indica and Curcuma longa in experimental Plasmodium berghei infection. Fifty male Swiss mice were infected with chloroquine susceptible (NK 65) strain of Plasmodium berghei intraperitoneally. Parasitemia was confirmed using microscopy and the animals were grouped (n = 5), treated once daily and orally for 7 days with 200 and 400 mg/kg of A. indica and C. longa methanol extracts. Four hundred milligrams per kilogram A. indica was combined with the two doses of C. longa methanol extract and fractions. Negative control was treated with 10 mL/kg 5% (v/v) dimethyl sulfoxide (DMSO, vehicle) while positive control was treated with artemether–lumefantrine (10 mg/kg) and normal control not infected with parasites was treated with distilled water only. Animals were sacrificed on day 7, and blood serum was obtained. Serum immunoglobulins G (IgG) and immunoglobulin M (IgM), C-reactive protein (CRP), tumour necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) were assayed using ELISA techniques. Combination of A. indica and C. longa significantly increased (P < 0.05) IgG and TNF-α than separate treatment while IgM increased albeit insignificantly (P < 0.05); CRP and IL-1β decreased significantly relative to control (P < 0.05) while IL-6 levels was modulated both in separate and combined therapy. Separate administration and combinations of A. indica and C. longa have immunomodulatory effects in malaria-infected mice. [ABSTRACT FROM AUTHOR]

In patients with moderate-to-severe and severe psoriasis and high efficacy of therapy (PASI≥75) with signaling pathway inhibitors (apremilast, tofacitinib), cytokine spectra in the skin and blood plasma were studied using xMAP technology at baseline and on weeks 14 and 26 of treatment. Comparison of cytokine levels in psoriatic lesional skin and plasma samples of patients treated with apremilast or tofacitinib revealed statistical difference only for IFNγ level (р<0.05) at week 26. [ABSTRACT FROM AUTHOR]

Elevated proinflammatory cytokines and decreased antiinflammatory cytokines are important in the context of perinatal health, and immune dysregulation has been found among perinatal women with low socioeconomic status (SES). Data examining psychological factors that may contribute to cytokines in pregnancy are lacking. Of importance, these associations may be most evident among women with low SES. This study examined the moderating role of SES on associations among presence of meaning in life and repetitive negative thinking with cytokine levels among 67 pregnant women. A cumulative SES index was calculated using income, education, perceived social class, and receipt of governmental support. Measures included the Perseverative Thinking Questionnaire, Meaning in Life Questionnaire, and serum interleukin (IL)-6 as well as IL-4. Using PROCESS, moderation analyses showed significant interactions between psychological factors and SES in predicting serum cytokines. In the context of high SES only, greater repetitive negative thinking was associated with higher levels of the proinflammatory cytokine IL-6 (p = 0.056) while greater meaning in life was associated with higher levels of the antiinflammatory cytokine IL-4 (p = 0.02). Findings from this study suggest that the benefits of these psychological factors on cytokine levels may be most readily observable among women with greater economic stability. Identifying psychological factors that positively contribute to biological functioning in women experiencing heightened economic distress will be crucial in addressing SES-related disparities in perinatal health. [ABSTRACT FROM AUTHOR]

Introduction: Ankylosing spondylitis (AS) is a lifelong condition where spinal inflammation causes chronic back pain and restriction of spinal function. While proinflammatory cytokines participate in the disease process, their relation with disease activity, spinal function, and quality of life is less well understood. Methods: Cross-sectional study of serum levels of four inflammatory cytokines (IL-6, TNF, IL-23, and IL-17A) in AS patients not on biologics. Disease characteristics and simultaneous spinal function tests and patient-reported health measures (Bath Functional Index (BASFI), Dougados Functional Index (DFI), Modified Health Assessment Questionnaire (MHAQ), and routine laboratory parameters were recorded. The composite ASDAS-CRP score was used to classify disease activity as absent, low, or high. Results: In 164 AS patients (age 46 years, 70.1% males, 90.9% HLAB27 positive, ASDAS-CRP 1.8), disease activity was classified as inactive in 14%, low in 54%, and high in 31%. ASDAS-CRP correlated well with MHAQ, DFI, BASFI, and spinal mobility across patients with low and high disease activity (all p < 0.05). Cytokine levels did not correlate with ASDAS-CRP, ESR, BASFI, or spinal mobility scores and were comparable between patients with no, low, or high disease activity regardless of gender or disease duration (all p > 0.2). Conclusions: A large proportion of AS not on biologics have active disease far into the disease course. This impacts negatively on quality of life, work ability, and spinal mobility. Serum cytokine levels are poor markers for these central disease features in AS management. Funding: Abbott Norway AS and Arthritis Foundation of Western Australia. [ABSTRACT FROM AUTHOR]

Introduction: Osteonecrosis of the jaw (ONJ) occurring after invasive dental treatment often adversely affects patients' activities of daily living. Long-term administration of strong anti-bone resorptive agents such as bisphosphonates prior to invasive dental treatment is considered an ONJ risk factor; however, pathological mechanisms underlying ONJ development remain unclear. Materials and Methods: We developed an ONJ mouse model in which a tooth is extracted during treatment with the bisphosphonate zoledronate. Results: We observed induction of apoptosis in osteocytes, resulting in formation of empty lacunae in jaw bones at sites of tooth extraction but not in other bones of the same mice. We also observed elevated levels of inflammatory cytokines such as TNFα, IL-6 and IL-1 in jaw bone at the extraction site relative to other sites in zoledronate-treated mice. We also report that treatment in vitro with either zoledronate or an extract from Porphyromonas gingivalis, an oral bacteria, promotes expression of inflammatory cytokines in osteoclast progenitor cells. We demonstrate that gene-targeting of either TNFα, IL-6 or IL-1 or treatment with etanercept, a TNFα inhibitor, or a neutralizing antibody against IL-6 can antagonize ONJ development caused by combined tooth extraction and zoledronate treatment. Conclusions: Taken together, the cytokine storm induced by invasive dental treatment under bisphosphonate treatment promotes ONJ development due to elevated levels of inflammatory cytokine-producing cells. Our work identifies novel targets potentially useful to prevent ONJ. [ABSTRACT FROM AUTHOR]

Kynurenine 3-monooxygenase (KMO) regulates the levels of neuroactive metabolites in the kynurenine pathway (KP), dysregulation of which is associated with Huntington's disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites, and has been found to ameliorate disease-relevant phenotypes in several HD models. Here, we crossed KMO knockout mice to R6/2 HD mice to examine the effect of KMO depletion in the brain and periphery. KP genes were dysregulated in peripheral tissues from R6/2 mice and KMO ablation normalised levels of a subset of these. KP metabolites were also assessed, and KMO depletion led to increased levels of neuroprotective kynurenic acid in brain and periphery, and dramatically reduced neurotoxic 3-hydroxykunurenine levels in striatum and cortex. Notably, the increased levels of pro-inflammatory cytokines TNFa, IL1β, IL4 and IL6 found in R6/2 plasma were normalised upon KMO deletion. Despite these improvements in KP dysregulation and peripheral inflammation, KMO ablation had no effect upon several behavioural phenotypes. Therefore, although genetic inhibition of KMO in R6/2 mice modulates several metabolic and inflammatory parameters, these do not translate to improvements in primary disease indicators—observations which will likely be relevant for other interventions targeted at peripheral inflammation in HD. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium (M.) tuberculosis-caused immunopathology is characterized by aberrant expression of plasma cytokines in human tuberculosis. Disease severity and long-term anti-mycobacterial treatment are potentially influenced by immunopathology and normalization of plasma cytokine levels during therapy may indicate treatment efficacy and recovery. Study design and methods: In this study, we analyzed the concentrations of selected plasma cytokines (i.e., IL-6, IP-10, IL-10, IL-22, IFNγ, GM-CSF, IL-8) and M. tuberculosis sputum burden in patients with tuberculosis (n = 76). Cytokine levels were compared to healthy contacts (n = 40) and changes under treatment were monitored (i.e., 6 and 16 weeks after treatment start). According to differences in M. tuberculosis sputum burden and conversion, tuberculosis patients were classified as paucibacillary as well as 'rapid' or 'slow' treatment responders. A subgroup of tuberculosis patients had fatal disease courses. Results: Six of seven cytokines were significantly higher in tuberculosis patients as compared to contacts and four of these (i.e., IL-6, IP-10, IL-10, and IL-22) were detectable in the majority of tuberculosis patients. IL-6 showed the strongest discriminating capacity for tuberculosis disease and in combination with IL-10 concentrations efficiently classified paucibacillary tuberculosis cases as well as those with fatal disease outcome. In addition, IL-6 and IP-10 levels decreased significantly after 6 weeks of treatment and analyses of subgroups with differential treatment response showed delayed decline of IL-6 levels in slow treatment responders. Conclusions: Combinations of different plasma cytokine (namely, IL-6, IL-10, and IP-10) efficiently classified tuberculosis patients with differential mycobacterial burden and especially IL-6 qualified as a biomarker candidate for early treatment response. [ABSTRACT FROM AUTHOR]

Background: Diabetes induces bone alterations accompanied by altered cytokine expression patterns. These alterations lead to modified fracture healing, contributing to musculoskeletal fragility in the elderly. Aims: We evaluated the inflammatory immune response in diabetic patients during fracture healing relative to clinical and radiographic assessments. Methods: Fifty patients of both sexes with fragility fractures were studied: 30 diabetics (group A, mean age 73.4 ± 11.2 years) and 20 normoglycemic controls (group B, mean age 75.1 ± 16.9 years). Two subgroups comprised those with hip or wrist fragility fractures (25 and 16 patients, respectively). We evaluated serum concentrations of tumor necrosis factor α, interleukins 4 and 8, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor, and epidermal growth factor (EGF) before and at 4 and 8 weeks after surgery. We also determined the Radiographic Union Score for Hips and the Radius Union Scoring System score and applied the Physical Activity Scale for the Elderly test at the same time points. Each patient underwent bone densitometry. Results: MCP-1 and EGF levels were higher in group A than in group B at 4 weeks after surgery ( p > 0.05). Radiographic evaluation showed lower scores in group A ( p < 0.05). The main difference between the groups was evident 4 weeks after surgery. Changes in the serum concentrations of chemotactic and angiogenic factors could explain the radiographically proved impaired fracture healing in diabetic patients. Conclusions: Fragility fracture healing is impaired in diabetic patients. Radiographic and molecular patterns confirmed that the most compromised fracture-healing phase is at 4 weeks after surgery, during callus mineralization. [ABSTRACT FROM AUTHOR]

Lumbar intervertebral disc (IVD) herniation causes severe low back pain (LBP), which results in substantial financial and emotional strains. Despite the effectiveness of discectomy, there is no existing treatment for post-operative LBP induced by progressive IVD degeneration. Two key factors of LBP are intradiscal inflammation, indicated by tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), and sensory nerve ingrowth into the inner layer of the annulus fibrosus, triggered by nerve growth factor/high-affinity tyrosine kinase A (TrkA) signalling. In an animal models of discectomy, the bioresorbable ultra-purified alginate (UPAL) gel with an extremely low-toxicity has been effective in acellular tissue repair. We aimed to investigate whether UPAL gel can alleviate LBP using a rat nucleus pulposus (NP) punch model and a rabbit NP aspirate model. In both models, we assessed TNF-α and IL-6 production and TrkA expression within the IVD by immunohistochemistry. Further, histological analysis and behavioural nociception assay were conducted in the rat model. UPAL gel implantation suppressed TNF-α and IL-6 production, downregulated TrkA expression, inhibited IVD degeneration, and reduced nociceptive behaviour. Our results suggest the potential of UPAL gel implantation as an innovative treatment for IVD herniation by reducing LBP and preventing IVD degeneration after discectomy. [ABSTRACT FROM AUTHOR]

The exercise effects on behavioral tests, hippocampal and cortical oxidative stress, and hippocampal inflammatory cytokines of lipopolysaccharide (LPS) administered rats were investigated. The rats were divided into four groups (N = 8): (1) control; (2) moderate training (MT, 15 m/min, 30 min/day, 9 weeks); (3) LPS (1 mg/kg LPS) and (4) LPS + MT (1 mg/kg LPS; 15 m/min, 30 min/day, 9 weeks). LPS was injected 2 h before the behavioral experiments during the last week of training. Finally, the rats' brain were removed for biochemical assessments. LPS increased escape latency and traveled distance to reach the platform in Morris water maze (MWM) test (P < 0.05–P < 0.001). In the passive avoidance (PA) test, LPS decreased the latency to enter the dark compartment and the time spent in the light compartment and increased the time spent in the dark compartment (P < 0.01–P < 0.001), while MT improved the rats performances in MWM and PA tests (P < 0.01–P < 0.001). Additionally, LPS increased tumor necrosis factor α (TNF-α), interleukin 1 beta (IL-1β) and C-reactive protein levels in the hippocampal tissues, malondialdehyde (MDA) and nitric oxide metabolite in hippocampal and cortical tissues, and decreased thiol contents and catalase (CAT) and superoxide dismutase (SOD) activity in hippocampal and cortical tissues compared to the control group (P < 0.01-P < 0.001); while moderate training decreased the levels of TNF-α, IL-1β and MDA; increased thiol contents, and SOD and CAT activity in the LPS + MT compared to the LPS group (P < 0.001). These results indicated that moderate training improved LPS-induced learning and memory impairments by attenuating the hippocampal cytokine levels and brain oxidative damage. [ABSTRACT FROM AUTHOR]

Smoking affects several disease processes. Epidemiological studies have previously found a negative association between primary Sjögren’s syndrome (pSS) and smoking. The aim of this study was to examine whether markers of disease activity and cytokine expression in pSS patients differ between ever and never smokers. Fifty-one consecutive pSS patients and 33 population controls were included in the study. Clinical and standard laboratory parameters were registered. Serum cytokines (IL-1β, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-18, IL-33, IFN-α, IFN-γ, TNF-α, EGF, BAFF, Fas-ligand, RANTES, TGF-β1) were assessed. A positive lip biopsy was less prevalent among ever smoking patients compared to never smokers (81 vs 100%; p = 0.03). However, except for TNF-α, which was higher in ever smokers, no differences in cytokine levels were found when comparing ever and never smoking pSS patients. Furthermore, no significant differences were found between ever and never smoking patients in the ESSDAI total score, IgG levels, or complement levels. However, IL-6, IL-12, IL-17 and IL-18 were significantly increased in pSS patients compared to controls. In this study, a negative association between ever smoking and positive lip biopsy was found, confirming previous reports. Expected differences in cytokine levels compared to controls were noted, but no major differences were found between ever and never smoking pSS patients. Taking into account the negative association between pSS diagnosis and smoking in epidemiological studies, possible explanations include a local effect of smoking on salivary glands rather than systemic effects by cigarette smoke. [ABSTRACT FROM AUTHOR]

The interferon regulatory factor 9 ( IRF9) gene is a member of the IRF family and has been shown to play functionally diverse roles in the regulation of the immune system. Previous study revealed the IRF9 gene resides within the reported quantitative trait locus (QTLs) for cytokine levels. The aims of this study were to identify genomic variants in IRF9 and to test the association between the variants and cytokine levels in pig. A synonymous single-nucleotide polymorphism ( c.459A > G) was identified in exon 4 of the IRF9 gene. Association analysis in 300 piglets (Landrace, n = 68; large white, n = 158; and Songliao black, n = 74) showed that this variant was significantly associated with the level of interferon (IFN)-γ and the ratio of IFN-γ to IL-10 in serum ( P < 0.05). Relative quantification of messenger RNA (mRNA) revealed that spleen had the highest expression level and individuals with genotype AA had higher expression than those with genotype AG. Transfection-based mRNA stability assay analysis further showed that the mutant allele G could reduce the RNA stability of IRF9. These findings suggest that the SNP ( c.459A > G) could be a causative mutation for the association between IRF9 and the serum cytokine levels in swine. [ABSTRACT FROM AUTHOR]

To analyze the value of cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-6, IL-8, IL-10) as predictors of mortality at 30 days in octogenarians and nonagenarians hospitalized in an internal medicine unit for community-acquired pneumonia (CAP). An observational, analytical, retrospective cohort study was conducted in the Department of Internal Medicine at Alicante General University Hospital between January 2014 and December 2015. Blood samples were frozen at − 80 °C, and cytokines were measured by ELISA. We included 115 patients, of whom 54% were men, with a mean age of 86.4 (standard deviation 4.5) years. There is a moderate correlation between IL-10 levels and CURB-65 score (p < 0.001) and a weak correlation with creatinine levels (p = 0.012) and urea levels (p = 0.032). Forty-five (39.1%) patients died within 30 days. In a multivariate analysis, the variables associated with mortality at 30 days were the following: age (adjusted odds ratio [ORa] 1.134, 95% confidence interval [CI] 1.02, 1.26), male sex (ORa 2.85, 95% CI 1.14, 7.14), IL-8 of 19 pg/mL or more (ORa 4.09, 95% CI 1.67, 10.01), and IL-10 of 11.29 pg/mL or more (ORa 4.00, 95% CI 1.58, 10.12). High IL-8 and IL-10 levels were shown to predict 30-day mortality in elderly patients with CAP. The inflammatory response in these patients seems to condition their prognosis. Further research in this line would provide more understanding about the physiopathological mechanisms and potential therapeutic targets for improving survival. [ABSTRACT FROM AUTHOR]

Background: Matrix metalloproteinase-12 (MMP-12) and Tissue inhibitor of metalloproteinase-4 (TIMP-4) play important roles in the pathophysiology of chronic obstructive pulmonary disease (COPD). Subjects of many previous studies were patients with severe and very severe COPD. However, there are comparatively few studies on patients with mild-to-moderate COPD. Our aim was to measure MMP-12 and TIMP-4 levels and to compare its levels in various materials in patients with mild-to-moderate acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We also compared which of the two materials of these biomarkers was better correlated with disease severity and DODE index. Methods: A total of 39 patients with AECOPD and 25 control subjects were enrolled in our study. MMP-12 and TIMP-4 in different respiratory samples were detected by ELISA. Results: Expression levels of MMP-12 in bronchoalveolar lavage fluid (BALF) and exhaled breath condensate (EBC) and TIMP-4 in BALF were significantly higher in AECOPD patients than that in healthy subjects (P < 0.001). However, there was no significant difference in TIMP-4 level in EBC of AECOPD patients compared to healthy subjects (P = 0.0527). The levels of MMP-12 in BALF and EBC and TIMP-4 in BAFL of AECOPD patients were significantly correlated with FEV1% predicted (P < 0.001). However, in AECOPD patients, there was no significant correlation between TIMP-4 levels in EBC and BODE index (r = 0.4175, P = 0.0559). Conclusion: During mild-to-moderate AECOPD, the levels of MMP-12 and TIMP-4 in BALF were better correlated with FEV1% predicted and BODE index than that in EBC, indicating that they may be new target interventions for pharmacology to prevent and/or treat AECOPD. [ABSTRACT FROM AUTHOR]

Objectives: Magnetic resonance imaging (MRI) is a standardized method for assisting joint diagnosis. To validate the reliability of different imaging-based grading systems, this study examined (1) the associations between grading systems for osseous change, joint effusion, and the Wilkes classification of temporomandibular joint (TMJ) disorders and (2) the correlation between cytokines in synovial fluid and imaging-based joint scores. Materials and methods: Twenty-seven patients, who routinely received numeric rating scale (NRS) and MRI assessment before TMJ arthrocentesis, were enrolled. Each joint was evaluated through the grading criteria for severity of osseous change and joint effusion by blinded observers using MRI. ImageJ was employed for classifying joint effusion. Joint synovial fluid, collected through arthrocentesis, was examined for cytokine expression by using a Luminex multiplex assay. All data were analyzed using the Pearson correlation analysis. Results: The Wilkes classification was strongly correlated with osseous change scores, but not with joint effusion scores. Joint effusion scores significantly correlated with NRS scores, but not with the Wilkes classification and osseous change scores. Compared with osseous change scores, joint effusion scores had a higher correlation with the levels of inflammatory cytokines (interleukin (IL)-8 and soluble IL-6 receptor (sIL-6R)) and with anti-inflammatory cytokines (soluble tumor necrosis factor receptors I and II (sTNF-RI/II)). Conclusions: In patients with TMJ disorders, MRI grades are strongly correlated with NRS scores and levels of cytokines (IL-8, sIL-6R, and sTNF-RI/II) in the synovial fluid. Clinical relevance: Joint effusion scoring can be a reliable and valid indicator for pathological assessment of TMJ disorders. [ABSTRACT FROM AUTHOR]