Changes In Cytokine Concentrations Research Articles

A pilot study of thecardiopulmonary effects in healthy volunteers after exposure to high levels of PM2.5 in a New York City subway station.

Subway systems are becoming increasingly common worldwide transporting large populations in major cities. PM2.5 concentrations have been demonstrated to be exceptionally high when underground, however. Studies on the impact of subway PM exposure on cardiopulmonary health in the United States are limited. Healthy volunteers in New York City were exposed to a 2-h visit on the 9th Street Station platform on the Port Authority Trans-Hudson train system. Blood pressure, heart rate variability (HRV), spirometry, and forced impulse oscillometry were measured, and urine, blood spot, and nasal swab biosamples were collected for cytokine analysis at the end of the 2-h exposure period. These endpoints were compared against individual control measurements collected after 2-h in a "clean" control space. In addition to paired comparisons, mixed effects models with subject as a random effect were employed to investigate the effect of the PM2.5 concentrations and visit type (i.e., subway vs. control). Mean PM2.5 concentrations on the platform and during the control visit were 293.6 ± 65.7 (SD) and 4.6 ± 1.9µg/m3, respectively. There was no change in any of the health metrics, but there was a non-significant trend for SDNN to be lower after subway exposure compared to control exposure. Total symptomatic scores did increase post-subway exposure compared to reported values prior to exposure or after the control visit. No significant changes in cytokine concentrations in any specimen type were observed. Mixed-effects models mostly corroborated these paired comparisons. Acute exposures to PM on a subway platform do not cause measurable cardiopulmonary effects apart from reductions in HRV and increases in symptoms in healthy volunteers. These findings match other studies that found little to no changes in lung function and blood pressure after exposure in underground subway stations. Future work should still target potentially more vulnerable populations, such as individuals with asthma or those who spend increased time underground on the subway such as transit workers.

102 Combination and individual vaccines for bovine viral diarrhea virus and infectious bovine rhinotracheitis effects on reproductive cyclicity and immune response

Abstract Vaccines are known to impact both the immune and reproductive systems. The objective of this research was to identify immunological and cyclic differences following vaccination for Bovine Viral Diarrhea Virus (BVDV) and/or Infectious Bovine Rhinotracheitis (IBR). Brahman cows (n = 15) were administered PGF2α to regress corpus lutea on d -3. Animals (d 0) were immunized (2mL, intramuscular injection) with one of three treatments: 1) Modified Live Vaccine (MLV) for BVDV and IBR (BVD+IBR; n = 5), 2) MLV for BVDV only (BVD; n = 5), or 3) sterile saline (CON; n = 5). Blood samples (30 mL/cow) were collected (d -3, 0, 2, 4, 6, 8, 10, and 14) and peripheral blood mononuclear cells (PBMC) were isolated. PBMC were incubated with propidium iodide and antibodies for specific surface cell markers (CD4, CD8, CD25, CD14, CD86, and CD335). An Amnis FlowSight flow cytometer determined cell type percentage. BVDV and IBR antibody concentrations were analyzed in serum samples (d -3, 0, and 14). Plasma samples (d 0, 2, 4, 6, 8, 10, and 14) were evaluated for interferon (IFN)-γ, interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-17A, macrophage inflammatory protein (MIP)-1α, MIP-1β, IL-36RA, interferon-gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF) α, and vascular endothelial growth factor (VEGF) A concentrations by a MagPix multiplex machine using a MILLIPLEX Bovine Cytokine/Chemokine Magnetic Bead Panel. Progesterone (d 0, 2, 4, 6, 8, 10, and 14) and estradiol (d 0) concentrations were determined by RIA. Differences in antibody titers, PBMC populations, and cytokine concentrations were analyzed as repeated measures using PROC MIXED (SASv9.4). Forty percent of BVD+IBR animals experienced abnormal estrus cycles, but no BVD or CON animals did. There was a treatment effect on BVD titer concentration with BVD animals having greater titer concentrations than CON (P = 0.02) but similar concentrations to BVD+IBR (P = 0.18). There was a treatment by time interaction (P < 0.0001) on IBR titers with BVD+IBR animals having greater titer concentrations on d 14 compared with BVD and CON. Treatment had no effect on leukocyte populations (P ≥ 0.1409), but all populations differed over time (P ≤ 0.0045). Antigen presenting cells (CD14+) and natural killer cells (CD335+) were affected by a treatment and time interaction (P ≤ 0.0479). BVD animals had increased CD14+ cells on d 2, 4, 8, and 14 compared with CON, but CON had a greater CD335+ cell population compared with BVD and BVD+IBR on d 10. There tended to be or was a significant treatment by day interaction for IL-1α (P = 0.08), IL-1b (P = 0.03), IL-10 (P = 0.06), IFN-γ (P = 0.05), IP-10 (P = 0.02), MIP-1α (P = 0.02), MIP-1 b (P = 0.01), TNFα (P = 0.01), and VEGFA (P = 0.03). IL-1a, IL-10, IL-1b, and MIP-1 b increased in BVD+IBR from d 0 to 4 or 6 then decreased but not in CON or BVD. Increased VEGFA was observed in CON compared with BVD and BVD+IBR animals. Overall, BVD+IBR resulted in abnormal cycles and changes in cytokine concentrations and leukocyte populations. USDA is an equal opportunity provider and employer.

Changes in cytokine concentrations during passage through a granulocyte and monocyte adsorption column in a porcine lipopolysaccharide-induced inflammation model

BackgroundSepsis 3 definitions have shifted the focus from nonspecific inflammation to sepsis as an organ dysfunction caused by a dysregulated host response to infection. Neutrophils have become therapeutic targets because of their intimate but complex involvement in sepsis. We conducted ex vivo and animal experiments to apply a granulocyte and monocyte adsorption column, which is clinically used for inflammatory bowel disease, in sepsis. In this study, the biocompatibility was evaluated in sepsis-like hypercytokinemia.MethodsSix female outbred pigs were anesthetized. Extracorporeal direct hemoperfusion (DHP) with an Adacolumn or a sham column was initiated after lipopolysaccharide (LPS) administration. The DHP was performed for 2 h at a blood flow rate (QB) of 30 or 60 mL/min. Blood samples were collected before and during the DHP (30, 60, 90, and 120 min). The percentage change in white blood cell count, platelet count, and cytokine concentration was compared between the Adacolumn and sham columns.ResultsThe percentage change in white blood cells were 96 (95–98)% and 106 (101–108)% in the Adacolumn and sham groups, respectively, at QB = 60 mL/min (p < 0.01). The percentage change in platelets were 95 (90–96)% and 97 (93–99)% in the in the Adacolumn and sham groups, respectively, at QB = 60 mL/min (not significant; n.s.). At QB = 60 mL/min, the percentage change in tumor necrosis factor-α, interleukin (IL)-6, and IL-10 were 92 (81–106)%, 95 (93–102)%, and 98 (95–100)%, respectively, for the Adacolumn and 100 (95–102)%, 98 (87–104)%, and 97 (93–99)%, respectively, for the sham column. The percentage change in white blood cell counts, platelet counts, and all cytokines at QB = 30 and 60 mL/min showed similar trends.ConclusionThe biocompatibility of the Adacolumn was evaluated using a porcine LPS-induced inflammation model. No decrease in platelet counts or significant cytokine production was observed, suggesting that the Adacolumn could be safely used in patients with sepsis with QB = 30–60 mL/min for 2 h. However, production of mediators other than cytokines remains unknown and requires further investigation.

Effect of serum concentrations of IL-6 and TNF-α on brain structure in anorexia nervosa: a combined cross-sectional and longitudinal study

Previous studies of brain structure in anorexia nervosa (AN) have reported reduced gray matter in underweight patients, which largely normalizes upon weight gain. One underlying biological mechanism may be glial cell alterations related to low-grade inflammation. Here, we investigated relationships between brain structure as measured by magnetic resonance imaging and serum concentrations of two pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor alpha) cross-sectionally in 82 underweight adolescent and young adult female patients (mean age 16.8 years; 59 of whom were observed longitudinally after short-term weight restoration; mean duration 2.8 months), 20 individuals long-term weight-recovered from AN (mean age 22.7 years) and 105 healthy control (HC) participants (mean age 17.2 years). We measured cortical thickness, subcortical volumes and local gyrification index, a measure of cortical folding. In contrast to most previous studies of cytokine concentrations in AN, we found no cross-sectional group differences (interleukin-6: p = 0.193, tumor necrosis factor alpha: p = 0.057) or longitudinal changes following weight restoration (interleukin-6: p = 0.201, tumor necrosis factor alpha: p = 0.772). As expected, widespread gray matter reductions (cortical thickness, subcortical volumes, cortical folding) were observed in underweight patients with AN compared to HC. However, we found no evidence of associations between cytokine concentrations and structural brain measures in any participant group. Furthermore, longitudinal changes in cytokine concentrations were unrelated to changes in gray matter. In conclusion, we did not identify any association between (sub-)inflammatory processes and structural brain changes in AN. Future studies are needed to elucidate which other factors besides nutritional status may contribute to brain morphological alterations.

Bone Marrow Cytokines Concentrations in Myelodysplastic Neoplasms: Its Correlation with the Immune Populations and Clonal Hematopoiesis

Background: Myelodysplastic neoplasms (MDS) are a clonal, heterogenic disease of the hematopoietic stem cell. Pathophysiology is mainly related to intrinsic myeloid abnormalities, epigenetic changes and immune system deregulation that leads to changes in the bone marrow microenvironment. MDS patients have shown broad and heterogenic changes in cytokine concentrations compared to controls. An elevation of pro-apoptotic and inflammatory cytokines and chemokines has been described. Nevertheless, the role of inflammatory soluble factors is still poorly understood. We aim to describe cytokine concentrations in the bone marrow of MDS patients and how it correlates with the immune population and clonal hematopoiesis. Methods: We prospectively analyzed 60 bone marrow plasma samples. Forty-four MDS patients without RS or 5q deletion, 8 healthy donors (HD) and 9 cytopenia of unknown significance (CUS). Cytokine/chemokine concentration were analyzed with ThermoFisher commercial kit ProcartaPlexTM Multiplex immunoassay of 32-PLEX (EGF/eotaxin/FGF-2/G-CSF/GM-CSF/HGF/INFalpha/ IFNgamma/IL-1alpha,/IL1-b/IL-10/IL-12/IL-13/IL-15/IL-17a/IL-1RA/IL-2/IL-22 /IL3 /IL-4/IL-5/IL-6/IL-7/IL-8/IL-9), carried out by Luminex® platform. Furthermore, we analyzed NK subpopulations differentiating an immature population (CD56 brigthCD16 −) from a mature one (CD56 dimCD16+). Lymphocyte T sub-populations were studied in PB samples determined as CD45+CD3+ and the different expression of the following monoclonal antibodies CD4/CD8/CCR7/CD45RA/CD27/CD28/CD25/CD127/CXCR3/CXCR6. The analysis was performed, by flow cytometry, on fresh samples, following a membrane staining protocol with 10-colors/3 lasers. Finally, molecular analysis was performed by NGS using the Oncomine Myeloid Research Assay included 40 genes. Results: A total of 60 subjects were included (median age was 71 years-old and 35% were female). Auto-immune disease was present in 6.6% (Figure 1). Regarding chemokines, CCL11 a pro-inflammatory chemokine was increased in MDS (59.73pg/ml) compared to CUS (41.24pg/ml) and HD (22.63pg/ml), also CXCL9, with a complex role in tumor progression, being 29.08pg/ml in MDS, 17.14pg/ml in CUS and 1.13pg/ml in HD. On the other hand, CCL2 and CCL4 showed lower concentrations in MDS vs HD but higher than CUS (Figure 2). Interleukins analysis showed, IL-1RA higher concentrations in MDS (139.9pg/ml), than HD (36.4pg/mL) and no detection in CUS. IL- 2 was detected only in HD (7.61pg/mL) and IL-3 showed greater concentrations in HD and CUS (20.75pg/ml) compared to MDS (13.84pg/ml). IL-6 did not showed differences among the three groups; in 18.3% subjects (11/60) concentrations were ≥10pg/ml and 8 were MDS. IL-8, a pro-inflammatory/proangiogenic cytokine, showed increased concentrations in only 23% subjects (14/60); 13 were MDS. Regarding growth factors, we observed EGF only in HD (28.16%), whilst HGF and VEGF-A showed higher concentrations in MDS. Mature NK sub-populations were increased in CUS (76.16%) vs MDS (11.58%), (p=0.006) and HD (10.66%), (p=0.01). Moreover, CD8+ T lymphocytes between CUS 49.79% vs MDS 14.29% and HD 1.68 (p=0.05) and Th2 in MDS of 22.71% vs CUS 17.5 (p=0.031) without differences to HD 22.54%. Forty-six MDS subjects presented ≥3 somatic mutations, those presented higher concentrations of CCL11 (73.56pg/mL), HGF (497.7pg/mL), CCL2 (95.3pg/ml) and VEGF-A (506pg/mL). Interestingly, we found that among CUS subjects 66.6% (6/9) presented mutations, 2 DMT3A (VAF &amp;lt; 5%), 1 IDH1 (VAF 3.7%), 1 SRSF2 (VAF 38.9%), 1 TET2 (VAF 39.5%), 1 ZRSR2 (VAF 35%), 1 PHF6 (VAF 39.8%). Finally, regarding IPSS-R risk, we observed higher concentrations of inhibitory proteins like IL-10 and cytokines involved in the regulation of tumor microenvironment like CXCL10 or CCL2 in HR-MDS, while in LR-MDS we observed a more cytotoxic and inflammatory profile (Figure 2). Conclusions: Our study describes a heterogenic background of MDS. Suggesting an increase in some cytokines related to cell recruitment, migration, and proliferation in the bone marrow of MDS and an exhaustive and inhibitory environment in those patients with high-risk characteristics, pointing out the important role of immune subpopulations and environment in the clonal progression.

A description of the elevation of pericardial cortisol: cortisone ratio in patients with tuberculous pericarditis.

Pulmonary tuberculosis is an inflammatory disease associated with an elevated cortisol/cortisone ratio at the site of infection and an array of cytokine changes. Tuberculous pericarditis is a less common but more lethal form of tuberculosis and has a similar inflammatory process in the pericardium. As the pericardium is largely inaccessible, the effect of tuberculous pericarditis on pericardial glucocorticoids is largely unknown. We wished to describe pericardial cortisolcortisone ratio in relation to plasma and saliva cortisol/cortisone ratios and the associated changes in cytokine concentrations. The median (interquartile range) of plasma, pericardial, and saliva cortisol concentration was 443 (379-532), 303 (257-384), and 20 (10-32) nmol/L, respectively, whereas the median (interquartile range) of plasma, pericardial, and saliva cortisone concentrations was 49 (35-57), 15.0 (0.0-21.7), and 37 (25-55) nmol/L, respectively. The cortisol/cortisone ratio was highest in pericardium with median (interquartile range) of 20 (13-445), followed by plasma of 9.1 (7.4-12.1) and saliva of 0.4 (0.3-0.8). The elevated cortisol/cortisone ratio was associated with elevated pericardial, interferon gamma, tumor necrosis factor-alpha, interleukin-6, interleukin-8, and induced protein 10. Administration of a single dose of 120 mg of prednisolone was associated with the suppression of pericardial cortisol and cortisone within 24h of administration. The cortisol/cortisone ratio was highest at the site of infection, in this case, the pericardium. The elevated ratio was associated with a differential cytokine response. The observed pericardial cortisol suppression suggests that 120 mg of prednisolone was sufficient to evoke an immunomodulatory effect in the pericardium.

Association of Peripheral Inflammatory Biomarkers and Growth Factors Levels with Sex, Therapy and Other Clinical Factors in Schizophrenia and Patient Stratification Based on These Data.

Multiple lines of evidence are known to confirm the pro-inflammatory state of some patients with schizophrenia and the involvement of inflammatory mechanisms in the pathogenesis of psychosis. The concentration of peripheral biomarkers is associated with the severity of inflammation and can be used for patient stratification. Here, we analyzed changes in serum concentrations of cytokines (IL-1β, IL-2, IL-4, IL-6, IL-10, IL-21, APRIL, BAFF, PBEF/Visfatin, IFN-α, and TNF-α) and growth/neurotrophic factors (GM-CSF, NRG1-β1, NGF-β, and GDNF) in patients with schizophrenia in an exacerbation phase. IL-1β, IL-2, IL-4, IL-6, BAFF, IFN-α, GM-CSF, NRG1-β1, and GDNF increased but TNF-α and NGF-β decreased in schizophrenia compared to healthy individuals. Subgroup analysis revealed the effect of sex, prevalent symptoms, and type of antipsychotic therapy on biomarker levels. Females, patients with predominantly negative symptoms, and those taking atypical antipsychotics had a more pro-inflammatory phenotype. Using cluster analysis, we classified participants into "high" and "low inflammation" subgroups. However, no differences were found in the clinical data of patients in these subgroups. Nevertheless, more patients (17% to 25.5%) than healthy donors (8.6% to 14.3%) had evidence of a pro-inflammatory condition depending on the clustering approach used. Such patients may benefit from personalized anti-inflammatory therapy.

Histotripsy ablation for the treatment of feline injection site sarcomas: a first-in-cat in vivo feasibility study

Purpose Feline soft tissue sarcoma (STS) and injection site sarcoma (fISS) are rapidly growing tumors with low metastatic potential, but locally aggressive behavior. Histotripsy is a non-invasive focused ultrasound therapy using controlled acoustic cavitation to mechanically disintegrate tissue. In this study, we investigated the in vivo safety and feasibility of histotripsy to treat fISS using a custom 1 MHz transducer. Materials and Methods Three cats with naturally-occurring STS were treated with histotripsy before surgical removal of the tumor 3 to 6 days later. Gross and histological analyses were used to characterize the ablation efficacy of the treatment, and routine immunohistochemistry and batched cytokine analysis were used to investigate the acute immunological effects of histotripsy. Results Results showed that histotripsy ablation was achievable and well-tolerated in all three cats. Precise cavitation bubble clouds were generated in all patients, and hematoxylin & eosin stained tissues revealed ablative damage in targeted regions. Immunohistochemical results identified an increase in IBA-1 positive cells in treated tissues, and no significant changes in cytokine concentrations were identified post-treatment. Conclusions Overall, the results of this study demonstrate the safety and feasibility of histotripsy to target and ablate superficial feline STS and fISS tumors and guide the clinical development of histotripsy devices for this application.

Mechanical High-Intensity Focused Ultrasound (Histotripsy) in Dogs With Spontaneously Occurring Soft Tissue Sarcomas.

Histotripsy is a non-invasive focused ultrasound therapy that uses controlled acoustic cavitation to mechanically disintegrate tissue. To date, there are no reports investigating histotripsy for the treatment of soft tissue sarcoma (STS). This study aimed to investigate the in vivo feasibility of ablating STS with histotripsy and to characterize the impact of partial histotripsy ablation on the acute immunologic response in canine patients with spontaneous STS. A custom 500 kHz histotripsy system was used to treat ten dogs with naturally occurring STS. Four to six days after histotripsy, tumors were surgically resected. Safety was determined by monitoring vital signs during treatment and post-treatment physical examinations, routine lab work, and owners' reports. Ablation was characterized using radiologic and histopathologic analyses. Systemic immunological impact was evaluated by measuring changes in cytokine concentrations, and tumor microenvironment changes were evaluated by characterizing changes in infiltration with tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) using multiplex immunohistochemistry and differential gene expression. Results showed histotripsy ablation was achievable and well-tolerated in all ten dogs. Immunological results showed histotripsy induced pro-inflammatory changes in the tumor microenvironment. Conclusion & Significance: Overall, this study demonstrates histotripsy's potential as a precise, non-invasive treatment for STS.

Age‐related changes in clinically relevant biomarkers in a Beagle model of Alzheimer’s disease.

AbstractBackgroundCanine aging is associated with cognitive decline linked to several neuropathological changes that parallel those reported in Alzheimer’s disease including deposition of amyloid‐β, cerebral amyloid angiopathy, dystrophic neurites, reduced neurogenesis, neuronal loss, activated microglia and astrogliosis. Dogs also demonstrate domain specific cognitive decline with short‐term working memory and executive function impacted early in canine aging. One contributing factor of Alzheimer’s disease is neuroinflammation, including activation of microglia and astrocytes, which are also seen in canine brain aging. Microglia bind to soluble amyloid‐β oligomers and fibrils by various receptors including toll‐like receptors (TLR2, TLR4, TLR6 and TLR8), which is postulated to be part of the neuroinflammatory process in Alzheimer’s disease. Toll like receptor activation leads to downstream production and release of pro‐inflammatory cytokines through the NFκB signaling pathway. Activated astrocytes accumulate around senile plaques and release cytokines, and other cytotoxic molecules, when exposed to amyloid‐b, further contributing to the neuroinflammatory response. The current study sought to investigate whether concentrations of the following cytokines varied by age in canine biofluids; IL‐6, TNFα, IL‐8, IL‐10, and IL‐12.MethodConcentrations of the aforementioned cytokines in cerebrospinal fluid and plasma from three age groups of dogs were evaluated in the current study. The young aged group included samples from dogs under 6 years of age. The middle age group included samples from dogs between 6 and 10 years of age. The aged or senior group included samples from dogs greater than 10 years of age.Results and ConclusionThe results of the study will be presented, and we hypothesize that age‐related changes in cytokine concentrations may be used as a potential clinically relevant biomarker for evaluating the effects of putative Alzheimer’s disease therapeutics targeting neuroinflammation, particularly when used in conjunction with neuropsychological cognitive assays.

Effect of Remote Ischaemic Conditioning on the Inflammatory Cytokine Cascade of COVID-19 (RIC in COVID-19): a Randomized Controlled Trial

PurposePatients hospitalized with COVID-19 may develop a hyperinflammatory, dysregulated cytokine “storm” that rapidly progresses to acute respiratory distress syndrome, multiple organ dysfunction, and even death. Remote ischaemic conditioning (RIC) has elicited anti-inflammatory and cytoprotective benefits by reducing cytokines following sepsis in animal studies. Therefore, we investigated whether RIC would mitigate the inflammatory cytokine cascade induced by COVID-19.MethodsWe conducted a prospective, multicentre, randomized, sham-controlled, single-blind trial in Brazil and South Africa. Non-critically ill adult patients with COVID-19 pneumonia were randomly allocated (1:1) to receive either RIC (intermittent ischaemia/reperfusion applied through four 5-min cycles of inflation (20 mmHg above systolic blood pressure) and deflation of an automated blood-pressure cuff) or sham for approximately 15 days. Serum was collected following RIC/sham administration and analyzed for inflammatory cytokines using flow cytometry. The endpoint was the change in serum cytokine concentrations. Participants were followed for 30 days.ResultsEighty randomized participants (40 RIC and 40 sham) completed the trial. Baseline characteristics according to trial intervention were overall balanced. Despite downward trajectories of all cytokines across hospitalization, we observed no substantial changes in cytokine concentrations after successive days of RIC. Time to clinical improvement was similar in both groups (HR 1.66; 95% CI, 0.938–2.948, p 0.08). Overall RIC did not demonstrate a significant impact on the composite outcome of all-cause death or clinical deterioration (HR 1.19; 95% CI, 0.616–2.295, p = 0.61).ConclusionRIC did not reduce the hypercytokinaemia induced by COVID-19 or prevent clinical deterioration to critical care.Trial RegistrationClinicalTrials.gov Identifier: NCT04699227.

Probiotic Therapy with Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis Results in Infarct Size Limitation in Rats with Obesity and Chemically Induced Colitis

In this study, we investigated the effect of three different probiotics, namely, a combination of Lactobacillus acidophilus (LA-5) and Bifidobacterium animalis subsp. lactis (BB-12), Saccharomyces boulardii, and Enterococcus faecium L3 on myocardial infarct size in rats with diet-induced obesity (DIO) and chemically-induced colitis (CIC). Potential associations between the effects of probiotics on myocardial ischemia-reperfusion injury and gut microbiome patterns as well as the serum levels of pro- and anti-inflammatory cytokines, lipopolysaccharide, and short chain fatty acids were also studied. Intragastric administration of lyophilized Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis at a dose of 1.2 × 108 CFU/mL for 15 days resulted in myocardial infarct size reduction in rats with DIO, CIC, and antibiotic-induced dysbiosis. This cardioprotective effect was associated with specific changes in cytokine concentrations, namely reduced levels of IL-1β, TNF-α, IL-2, and IL-8. At the same time, the use of Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis was accompanied by a significant reduction in lipopolysaccharide level, suggesting normalization of intestinal epithelial barrier permeability. However, the cardioprotective effect of Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis is not secondary to improved healing of the intestinal mucosa in CIC, as evidenced by the lack of difference in histopathological scores.

Serum cytokines predict efficacy and toxicity, but are not useful for disease monitoring in lung cancer treated with PD-(L)1 inhibitors.

PD-(L)1 inhibitors (IO) have improved the prognosis of non-small-cell lung cancer (NSCLC), but more reliable predictors of efficacy and immune-related adverse events (irAE) are urgently needed. Cytokines are important effector molecules of the immune system, whose potential clinical utility as biomarkers remains unclear. Serum samples from patients with advanced NSCLC receiving IO either alone in the first (1L, n=46) and subsequent lines (n=50), or combined with chemotherapy (ICT, n=108) were analyzed along with age-matched healthy controls (n=15) at baseline, after 1 and 4 therapy cycles, and at disease progression (PD). Patients were stratified in rapid progressors (RP, progression-free survival [PFS] <120 days), and long-term responders (LR, PFS >200 days). Cytometric bead arrays were used for high-throughput quantification of 20 cytokines and other promising serum markers based on extensive search of the current literature. Untreated NSCLC patients had increased levels of various cytokines and chemokines, like IL-6, IL-8, IL-10, CCL5, G-CSF, ICAM-1, TNF-RI and VEGF (fold change [FC]=1.4-261, p=0.026-9x10-7) compared to age-matched controls, many of which fell under ICT (FC=0.2-0.6, p=0.014-0.002), but not under IO monotherapy. Lower baseline levels of TNF-RI were associated with longer PFS (hazard ratio [HR]= 0.42-0.54; p=0.014-0.009) and overall survival (HR=0.28-0.34, p=0.004-0.001) after both ICT and IO monotherapy. Development of irAE was associated with higher baseline levels of several cytokines, in particular of IL-1β and angiogenin (FC=7-9, p=0.009-0.0002). In contrast, changes under treatment were very subtle, there were no serum correlates of radiologic PD, and no association between dynamic changes in cytokine concentrations and clinical outcome. No relationship was noted between the patients' serologic CMV status and serum cytokine levels. Untreated NSCLC is characterized by increased blood levels of several pro-inflammatory and angiogenic effectors, which decrease under ICT. Baseline serum cytokine levels could be exploited for improved prediction of subsequent IO benefit (in particular TNF-RI) and development of irAE (e.g. IL-1β or angiogenin), but they are not suitable for longitudinal disease monitoring. The potential utility of IL-1/IL-1β inhibitors in the management and/or prevention of irAE in NSCLC warrants investigation.

SHORT DURATION OF UPPER EXTREMITY LYMPHEDEMA CORRELATES WITH A FAVORABLE CYTOKINE RESPONSE AFTER LYMPH NODE TRANSFER SURGERY

Vascularized lymph node transfer surgery (VLNT) can provide benefit to lymphedema patients. Cytokines may play a role in the development of lymphedema and in the regeneration of lymphatic vessels after VLNT. Our primary aim was to investigate whether the VLNT patients have a specific cytokine profile. Our secondary aim was to see whether the preoperative lymphedema or severity affects the postoperative cytokine response. Wound exudate was gathered from 18 patients undergoing VLNT on the first and sixth postoperative day (POD). The concentrations of IL-10, TNF-α, TGF-β1 and VEGF-C were analyzed using enzymelinked immune-sorbent assays. A general score was generated to assess the benefit of the surgery. The changes in cytokine concentrations (1st POD-6th POD) were correlated with the pre- and postoperative lymphedema related factors. A shorter duration of lymphedema preoperatively correlated with an increase in the concentration of IL-10 and TNF-β during the first six PODs (IL-10: r=0.495, p=0.051; TNF-α: r=0.737, p=0.006) and a decrease in the concentration of TGF-ß1 (r= -0.613, p=0.020). The increase of the concentration of TNF-α during the first six PODs also correlated with a greater total general score (r=0.775, p=0.005) and hence indicated a better response to the surgery. The patients with a shorter duration of lymphedema preoperatively had a more favorable cytokine response during the first six PODs after VLNT.

Change in Ocular Surface Staining during Eyelid Warming Is Related to Tear Cytokine Levels.

Purpose To investigate the changes in the tear cytokine profile of patients with meibomian gland dysfunction (MGD) treated with eyelid warming and to correlate these changes with clinical parameters for dry eye disease (DED). Methods Seventy patients with MGD were included and treated with the warming of eyelids. Of these, 61 still used the treatment three months after baseline, while 48 completed the whole treatment period of six months. The concentrations of 39 cytokines in the tear fluid were measured at baseline and after three and six months of treatment. All participants were examined with tests for DED, including tear film break-up time (TBUT), ocular surface staining (OSS), and the self-reporting Ocular Surface Disease Index (OSDI). Changes in cytokine concentrations were assessed from baseline to three months, from three to six months, and from baseline to six months. Correlation analyses were performed between changes in the cytokine concentrations and changes in TBUT, OSS, and OSDI during the same time intervals. Results No significant changes were found in the concentrations of the 39 cytokines during any of the three treatment intervals. However, several correlations were detected between changes in the level of cytokines and OSS from baseline to three months of treatment. Decreasing concentrations of granulocyte chemotactic protein 2 (GCP-2/CXCL6, mean effect 2.36, p=0.042), interleukin 10 (IL-10, mean effect 1.04, p=0.045), and IL-16 (mean effect 1.36, p=0.035) were associated with decreasing OSS. Decreasing concentrations of granulocyte macrophage colony-stimulating factor (GM-CSF, mean effect −2.98, p=0.024), IL-8 (IL-8/CXCL8, mean effect −1.35, p=0.026), and macrophage migration inhibitory factor (MIF, mean effect −2.44, p=0.033) were related to increasing OSS. Conclusions Warming of eyelids did not change the concentration of cytokines in the tear fluid of patients with MGD significantly. However, alterations in the level of several cytokines were associated with changes in the OSS. This finding indicates a close connection between tear cytokines and OSS in MGD patients treated with eyelid warming.

Pharmacological Regulation of the Inflammatory Response under Mesh Implant Prosthetics in the Treatment of Patients with External Abdominal Hernias

Introduction. Seromas and hematomas of the implantation area are among the most common complications in prosthetic repair of a hernia defect with a mesh implant. The adequate tissue inflammation response to prosthesis implantation is achieved by the local protective role of pro-inflammatory cytokines. With suppression of the body's immune system combined with existing comorbidities, mesh implants result in even greater suppression of the immune system, which is manifested by an inadequate inflammatory response, both local and systemic, leading to the development of complications.Previously, the authors studied the effect of pyrimidine preparation "Xymedon" (INN - hydroxyethyldimethyldihydropyrimidine) on the systemic inflammatory process after prosthetic repair of anterior abdominal wall hernias. Based on the results of the interim study, it was hypothised: Regulation of the inflammation response to prosthesis implantation in hernioplasty manifested by changes in cytokine concentration in the blood can reduce postoperative complications. The aim of the study was to reduce the number of postoperative complications in prosthetic hernioplasty by regulating inflammatory reactions that occur after mesh implants.Materials and methods. Experimental part of the study. The experiment involved 66 rats, both sexes, pure line, which were implanted with mesh prostheses. Animals in group I (n=33) the control one - received 1 ml of 0,9% sodium chloride solution, i.e. received no specific treatment. Animals in group II (n=33) - the main one - received "Ximedon" 21 mg/day as pharmacological support. Blood sampling to determine inflammation markers was performed on the 5th day after the intervention. Animals were withdrawn from the experiment and the implantation site was taken for histological and histomorphometric investigations on the 5th day of the study. The study was carried out in the SPF vivarium at the laboratory of the Center for Genetic Collections of Laboratory Animals, Lobachevsky State University of Nizhny Novgorod. The study consisted of 4 series of experiments (2018-2021). Clinical part of the study. Prospectively (2018 - February 2022), we analyzed clinical outcomes of 101 patients with prosthetic repair (by Liechtenstein, TAPP, eTAR, "sublay") of an aponeurosis hernia defect of the anterior abdominal wall who received treatment in the City Clinical Hospital №7 named after E.L. Berezow. Patients of the "control" group (n=33) received only conventional treatment; patients of the "Ximedon" group (n=68) received 0.5 mg of ximedon 3 times a day for 10 days orally from the first day after the operation. Blood sampling was carried out on the 5th day after surgery. The data obtained were processed and structured using Microsoft Excel 2019 (64 bit), and statistical values were calculated in StatSoft Statistica 12,5 (64 bit).Results. Xymedon has a significant effect on the increase in the area of ​​the vessels of the implantation area in the experiment. Its use is associated with a lower level of C-reactive protein and blood IL-6 on day 5 in the experimental group compared to the control group. In the clinical study ximedon has a significant effect on the cytokine concentration in the blood: C-reactive protein, TNF-a, interleukins 6, 8 and 10. In the experimental study the dynamic of C-reactive protein, blood interleukins 6 and 10 does not significantly differ from the clinical one. In the clinical study, xymedon intake was associated with fewer postoperative complications. Conclusion. The studies performed allow us to consider "ximedon" as a means of pharmacological support for prosthetic repair in external abdominal hernias due to a significant reduction in postoperative complications provided by the ability to regulate inflammation reactions and stimulate reparative regeneration.

Changes in the Synovial Fluid Cytokine Profile of the Knee Between an Acute Anterior Cruciate Ligament Injury and Surgical Reconstruction

Background: Changes in the intra-articular inflammatory state during the immediate period after an acute anterior cruciate ligament (ACL) rupture are not well defined. Purpose: To evaluate changes in the concentration of select proinflammatory and anti-inflammatory synovial fluid cytokines during the interval between an ACL injury and surgical reconstruction. Study Design: Descriptive laboratory study. Methods: In patients with an acute ACL injury, a synovial fluid sample was obtained from the injured knee during the initial office visit within 2 weeks of the inciting traumatic event. An additional synovial fluid sample was collected at the time of ACL reconstruction just before the surgical incision. Synovial fluid samples from both the acute injury and the surgery time points were processed with a protease inhibitor, and the concentrations of 10 cytokines of interest were measured using a multiplex magnetic bead immunoassay. The primary outcome was the change in cytokine concentrations between time points. Results: A total of 20 patients with a mean age of 30.2 ± 8.3 years were included. The acute injury synovial fluid samples were collected at 6.6 ± 3.8 days after the injury. The surgical synovial fluid samples were collected at 31.6 ± 15.6 days after the acute injury samples. Based on a series of linear mixed-effects models to control for the effect of concomitant meniscal injuries and by-patient variability, there was a statistically significant increase in the concentrations of RANTES and bFGF and a statistically significant decrease in the concentrations of IL-6, MCP-1, MIP-1β, TIMP-1, IL-1Ra, and VEGF between time points. Conclusion: This study demonstrates the ongoing alterations in the intra-articular microenvironment during the initial inflammatory response in the acute postinjury period. We identified 6 synovial fluid cytokines that significantly decreased and 2 that significantly increased between the first clinical presentation shortly after the injury and the time of surgery 1 month later. Clinical Relevance: This study describes the molecular profile of the inflammatory changes between the time of an acute ACL injury and the time of surgical reconstruction 1 month later. A greater understanding of the acute inflammatory response within the knee may be helpful in identifying the optimal timing for a surgical intervention that balances the risk of chondral damage with the likelihood of successful, well-healed reconstruction.

Inflammation-Triggered Supramolecular Nanoplatform for Local Dynamic Dependent Imaging-Guided Therapy of Rheumatoid Arthritis.

The aging of population has resulted in a significant increase in the prevalence of rheumatoid arthritis (RA), which is a persistent and recurrent synovial inflammation caused by abnormal immune activation. Herein, the authors designed an inflammation‐triggered disassembly (ITD) nanoplatform by a supramolecular assembly method, which controls the decomposition and drug release through changes in cytokine concentrations and redox potentials during the onset of arthritis, and its dual‐targeted synergistic effect on collagen‐induced arthritis (CIA) rats resulted in higher cell death rate and immunosuppressive rate. Meanwhile, they propose the local dynamic dependent imaging (LDDI) technology to diagnose the disease status, which may produce corresponding changes with the fluctuation of inflammatory activity and improve the accuracy of dual‐target therapy by monitoring the synovial changes through in situ photoactivation of the second near infrared light (NIR‐II). Very importantly, histological analysis shows that ITD strategy relieved joint destruction and cartilage degeneration and its clinical score is similar to that of the healthy group. Their work provides an effective strategy for the early diagnosis and treatment of acute and chronic inflammation diseases, which can interfere to abnormal immune activation, rather than affecting the normal function of immune system.

Anti-inflammatory Effect of Ketamine: A Double-Blind Placebo-Controlled Randomised Study

Considering the rapid antidepressant action of ketamine, we aimed to investigate its anti-inflammatory effect. As part of a randomised double-blind placebo-controlled study plasma samples from 31 healthy remitted depressed were collected before and 1.5 hours after ketamine (0.5 mg/kg) and saline (placebo) administration in a two-period cross-over design. Meso Scale Discovery was used to measure cytokines concentrations. Significant interaction effect between the treatment and time were found for IL-1beta (F=8.35, p=0.008), TNF-alpha (F=5.17, p=0.032), IFN-gamma (F=8.78, p=0.006) and GM-CSF (F=5.19, p=0.031). Following ketamine administration, there was a significant decrease in the levels of IFN-gamma (p<0.001) and GM-CSF (p=0.021); but not after placebo infusion (p>0.05). Delta for changes in cytokine concentration in response to ketamine showed statistical significance for IL-1beta, TNF-alpha, and IFN-gamma (p<0.05), and a trend for GM-CSF (p=0.072). Ketamine exhibits anti-inflammatory properties by the effect on the major proinflammatory cytokines including IL-1beta, TNF-alpha, IFN-gamma and GM-CSF. Ketamine could be useful for treatment resistant depression or suicidal thoughts, and our findings suggest that rapid changes in inflammatory markers to be studied as potential mediators of these effects, especially in patients with higher levels of inflammation.

An Exploratory Study Demonstrating That Salivary Cytokine Profiles Are Altered in Children With Small Area Thermal Injury.

Serum can be used to investigate changes in cytokine concentration following burn injury in children; however, for children receiving treatment in an outpatient setting, blood is not routinely collected and therefore cannot be used for monitoring. The aim of this study was to investigate the use of saliva as a noninvasive tool for predicting burn outcomes by measuring the concentration of salivary cytokines in children with small area burns. A multiplex cytokine assay was used to measure 17 cytokines in the saliva of pediatric patients with burns (n = 20) and healthy controls (n = 20). After the removal of cytokines that had >30% of samples below the assay lower detection limit, six cytokines including IL-1β, IL-4, IL-7, IL-8, MCP-1, and TNFα were analyzed for association with burns. IL-1β and IL-4 were found to be significantly elevated in the pediatric burn patients compared to healthy controls. Interestingly, IL-1β was also significantly elevated in scald burns, compared to contact burns. In addition, biologically meaningful differences in cytokine concentration were identified in patients with different burn characteristics, which warrant further investigation. This exploratory study provides evidence that cytokines can be detected in the saliva of children and that salivary cytokine profiles differ between healthy controls and children with burns. Overall, this study demonstrates the value of saliva for the investigation of cytokines and its potential application in pediatric diagnostics, specifically in situations where blood collection is not appropriate.