Higher Levels Of IL-6 Research Articles

Community-Associated MRSA—Not So Innocent Sibling per Se: A Case Report

Background: Methicillin-resistant S. aureus (MRSA) is a major healthcare burden and is classified as healthcare-associated (HA-MRSA) and community-associated (CA-MRSA). While HA-MRSA is clinically feared, CA-MRSA is often considered less pathogenic. This case report highlights the serious course of illness due to CA-MRSA infection and provides a treatment strategy for the management of such cases. Case description: A 41-year-old male presented with fever and breathlessness for five days. Upon admission, he was provided empirical treatment for atypical infections and vasopressor support for hypotension. His condition deteriorated, necessitating ventilator support. Although the initial tracheal Bio Fire test indicated MRSA, his clinical manifestations did not match MRSA pneumonia symptoms; however, CA-MRSA was confirmed within 12 h. Skin legions developed within 16 h and progressed gradually from ecchymosis, petechial, and palpable purpura to bullous lesions over 72 h. The antibiotic regimen was modified and optimized with the addition of Clindamycin, Vancomycin, and Meropenem–Colistin. Owing to high IL-6 levels, dual vasopressor support, and acute kidney failure, he was started on early (within 12 h) continuous renal replacement therapy (CRRT) with CytoSorb filter (for 3 days) for cytokine removal. IL-6 levels decreased after two days of CytoSorb use. Subsequently, the patient stabilized with reduced dependence on vasopressor and ventilator assistance. Discussion: Early diagnosis of CA-MRSA and management with CRRT using CytoSorb may help improve patient outcomes. To our knowledge, this is the first report of clinical management of CA-MRSA with CytoSorb therapy in India that resulted in positive outcomes.

Improved prognosis prediction of idiopathic pulmonary arterial hypertension using targeted plasma proteomics in disease management

Abstract Background Idiopathic pulmonary arterial hypertension (IPAH), a special subgroup of PAH with unclear etiology, is characterized by rapid progression and poor prognosis underscoring the need for optimization of IPAH management and the accurate prediction of prognosis. However, it is disappointing that specific plasma biomarkers for IPAH management and prognosis are lacking in clinical practice. Up to date, the plasma biomarkers used for assessment of IPAH severity and prognosis are relied solely on indicators such as N-terminal prohormone of brain natriuretic peptide, or brain natriuretic peptide, which could reflect cardiac function but fail to promptly response to the dynamic change of disease condition due to the complexity of IPAH pathogenesis. Purpose We evaluated the prognostic value of plasma proteins in addition to current clinical predictors for prognosis prediction of IPAH. Methods Olink Immune-Response panel was used to measure 92 plasma proteins in a prospective IPAH cohort with 169 patients and a mean follow-up period of 2.4 ± 0.9 years. Six machine learning methods were used to construct predictive models, including plasma proteins-based Olink models, clinical parameters-based clinical models, and integrative models. Results A total of 18 proteins showed differential expression between patients with or without adverse clinical outcomes. Three proteins (STC1, CXADR, and IL6) were strongly correlated with clinical indicators of IPAH severity and their concentrations showed upward trends along with increased risk stratification. Elevated levels of STC1, CXADR, and IL6 are all associated with an increased risk of adverse clinical events, indicated by survival analysis, restricted cubic splines, and multivariable Cox regression analysis (STC1 HR=3.474, 95%CI: 1.129-10.692, P=0.030; CXADR: HR=1.602, 95%CI: 1.074-2.387, P=0.021; IL6: HR=1.883, 95%CI: 1.376-2.576, P<0.001). The inclusion of these three proteins into the predictive model could significantly increase the predictive power on the basis of the clinical model (AUC: 0.746 vs 0.626). Conclusions High levels of STC1, CXADR, and IL6 in plasma were associated with severe clinical phenotype and increased risk of adverse clinical events in patients with IPAH. These plasma proteins could significantly improve the prognostic performance of pre-existing clinical models, facilitating the clinical management of IPAH patients.The predictive efficient of models

Prognostic role of serum cytokines level in non-small cell lung cancer patients with anti-PD-1 and chemotherapy combined treatment.

Chemotherapy combined with PD-1 inhibitor treatment has revolutionized the standard of care for patients with NSCLC. However, the benefit is not universal, highlighting the need for precise prediction factors. Given their relationship with the immune system and non-invasive nature, serum cytokines are potential candidates for predicting the clinical effects of chemoimmunotherapy. Our study aims to evaluate the association of serum cytokines with the prognosis of patients with NSCLC treated with chemoimmunotherapy. Levels of 10 serum cytokines were detected in 60 NSCLC patients receiving chemotherapy plus PD-1 inhibitor-based treatment. Of these, dynamic samples from 19 patients were collected at baseline and after two treatment cycles. Their association with patients' clinicopathological characteristics, PFS and OS was described and investigated using survival analysis, cox regression and time-dependent ROC analysis. Preliminary evaluation of changes in cytokine levels associated with treatment response was conducted. Patients with lower baseline levels of serum IL-6, IL-5, IL-8, TNF-α and IL-10 had longer PFS, while patients with higher levels of IL-4 had longer PFS. Patients with lower levels of serum IL-6, IL-8, IL-22, TNF-α and IL-10 had longer OS, while patients with higher levels of IL-4 had longer OS. Multivariate analysis suggested that higher IL-6 and IL-5 levels were associated with poorer PFS, and higher IL-6 levels were associated with dismal OS. Additionally, changes in serum cytokine levels could be associated with treatment response. Our study suggests that serum cytokines, specifically IL-6, IL-5, IL-8, TNF-α, IL-10, and IL-4, are potential prognostic factors for patients with NSCLC receiving chemotherapy plus PD-1 inhibitor treatment.

Characterization of the Biological Variability of the Angiome Biomarkers over Time in Healthy Subjects.

Biomarker analyses are an integral part of cancer research. Despite the intense efforts to identify and characterize biomarkers in cancer patients, little is known regarding the natural variation of biomarkers in healthy populations. Here we conducted a clinical study to evaluate the natural variability of biomarkers over time in healthy participants. The angiome multiplex array, a panel of 25 circulating protein biomarkers, was assessed in 28 healthy participants across 8 timepoints over the span of 60 days. We utilized the intraclass correlation coefficient (ICC) to quantify the reliability of the biomarkers. Adjusted ICC values were calculated under the framework of a linear mixed-effects model, taking into consideration age, sex, body mass index (BMI), fasting status, and sampling factors. ICC was calculated to determine the reliability of each biomarker. HGF was the most stable marker (ICC=0.973), while PDGF-BB was the most variable marker (ICC=0.167). In total, ICC analyses revealed that 22 out of 25 measured biomarkers display good (≥0.4) to excellent (>0.75) ICC values. Three markers (PDGF-BB, TGF-1, PDGF-AA) had ICC values <0.4. Greater age was associated with higher IL-6 (p=0.0114). Higher BMI was associated with higher levels of IL-6 (p=0.0003) and VEGF-R3 (p=0.0045). Of the 25 protein biomarkers measured over this short time period, 22 markers were found to have good or excellent ICC values, providing additional validation for this biomarker assay. This data further supports the validation of the angiome biomarker assay and its application as an integrated biomarker in clinical trial testing.

Effects of normal saline versus lactated Ringer’s solution on organ function and inflammatory responses to heatstroke in rats

BackgroundHeatstroke is a life-threatening condition characterized by severe hyperthermia and multiple organ dysfunction. Both normal saline (NS) and lactated Ringer’s solution (LR) are commonly used for cooling and volume resuscitation in heatstroke patients; however, their specific impacts on patient outcomes during heatstroke management are poorly understood. Given that the systemic inflammatory response and multiple-organ damage caused by heat toxicity are the main pathophysiological features of heatstroke, the aim of this study was to evaluate the effects of NS and LR on the production of inflammatory cytokines and the functional and structural integrity of renal and cardiac tissues in a rat model of heatstroke.MethodsFifty-five male Sprague‒Dawley rats were randomly divided into four groups: cold NS or LR infusion postheatstroke (4 ℃, 4 ml/100 g, over 10 min) and NS or LR infusion without heatstroke induction (control groups). Vital signs, arterial blood gases, inflammatory cytokines, and renal and cardiac function indicators, such as serum creatinine and cTnI, were monitored after treatment. Tissue samples were analysed via HE staining, electron microscopy, and fluorescence staining for apoptosis markers, and protein lysates were used for Western blotting of pyroptosis-related proteins.ResultsCompared with LR-treated heatstroke rats, NS-treated heatstroke rats presented lower mean arterial pressures, worsened metabolic acidosis, and higher levels of IL-6 and TNF-α in both the serum and tissue. These rats also presented increased serum creatinine, troponin, catecholamines, and NGAL and reduced renal clearance. Histological and ultrastructural analyses revealed more severe tissue damage in NS-treated rats, with increased apoptosis and increased expression of NLRP3/caspase-1/GSDMD signalling molecules. Similar differences were not observed between the control groups receiving either NS or LR infusion. One NS-treated heatstroke rat died within 24 h, whereas all the LR-treated and control rats survived.ConclusionsNS resuscitation in heat-exposed rats significantly promotes metabolic acidosis and the inflammatory response, leading to greater functional and structural organ damage than does LR. These findings underscore the necessity of selecting appropriate resuscitation fluids for heatstroke management to minimize organ damage and improve outcomes.

Electroacupuncture attenuates depressive-like behaviors in poststroke depression mice through promoting hippocampal neurogenesis and inhibiting TLR4/NF-κB/NLRP3 signaling pathway.

The aim of this study was to investigate the impact and underlying molecular mechanisms of electroacupuncture on mice with poststroke depression (PSD). Mice were randomly allocated into sham, PSD, and electroacupuncture groups. Mice in the PSD and electroacupuncture groups underwent middle cerebral artery occlusion (MCAO) surgery following with sedentary behavior. Electroacupuncture targeting Zusanli (ST36) acupoint was performed 24 h after MCAO for 4 weeks in electroacupuncture group. The sucrose preference test, forced swimming test, open field test, tail suspension test, elevated plus maze, Catwalk analysis, RNA sequencing, Nissl staining, Golgi staining, TUNEL staining, Edu labeling, and doublecortin staining were performed. Lymphocyte subsets in peripheral blood and the levels of IL-1β, IL-6, TNF-α, and expression of Iba1/CD86, Iba1/NLRP3, TLR4/p38/NF-κB/NLRP3 pathways in the hippocampus were detected. Electroacupuncture effectively protected against the development of depression-like symptoms. The number of granulosa cells and doublecortin-positive cells in the dentate gyrus (DG) were significantly decreased in PSD group, which were significantly upregulated ( P < 0.01) by electroacupuncture. Electroacupuncture also significantly reduced ( P < 0.05) TUNEL-positive cells in the DG and CA1. RNA-seq revealed that electroacupuncture may exert antidepressant effect by regulating the inflammation mediated by TLR4/NF-κB/NLRP3 pathway in hippocampus. Electroacupuncture remarkably elevated ( P < 0.01) the ratio of CD4+ to CD8+ T cells and percentage of CD3-CD49b+ cells in CD45+CD49b+ cells in the peripheral blood. Electroacupuncture significantly reduced ( P < 0.05) the high levels of IL-1β, IL-6, TNF-α, iba1, TLR4, p-p38, p-NF-κB, and NLRP3 and sedentary behavior. Electroacupuncture was observed to mitigate depression symptoms and increase hippocampal neurogenesis in mice with PSD, possibly by inhibiting TLR4/p38/NF-κB/NLRP3 pathways and improving the microglia-mediated inflammatory microenvironment in the hippocampus.

Assessment of immune status markers during occupational lead exposure

The immune system is sensitive to the effects of environmental factors, and according to numerous studies, lead has an immunotoxic effect. At the same time, there is evidence of the multidirectional nature of the impact of lead on the immune system, determined by the degree of exposure to this heavy metal, which makes it current to study changes in immunological markers in workers of a modern lead recycling plant, taking into account levels and complexity of exposure. In the era of personalized medicine, monitoring the potential influence of occupational factors exposure on the immune system can facilitate a personalized approach to the prevention of work-related health conditions. The aim of the study: to evaluate changes in immune status markers among employees of lead recycling plant. The main group – 62 men working at a lead recycling plant, the control group – 47 men not exposed to occupational factors. Laboratory examination included a determination of the lead blood level, a clinical blood test, the serum levels of IL- 1â, IL- 10, IL- 8, MCP-1, C3 and C4 complement components, IgA, IgM, IgG. In the main group, compared to the control group, a higher number of neutrophils, lymphocytes, monocytes, higher levels of IL-8, C3 and C4 components of the complement system, and lower levels of IgM were detected. In the main group, the following changes in markers were significantly more often detected in comparison with reference values: an increase in the C3 component of complement (51.6% in the main group compared to 12.5% in the control group), decreased IgG (24.2% compared to 6.2%) and increased IgA (22.6% compared to 6.2%). Associations were identified between the lead blood level and the number of lymphocytes, the level of IgG, between work experience in contact with lead and the level of MCP-1 and C3 complement components. The results of the studies revealed the presence of changes in the immune status markers of workers at a lead recycling plant, which demonstrate a proinflammatory effect of lead and an influence on the humoral immune status. The identified changes in immunological parameters may underlie the mechanisms of formation of pathological conditions associated with lead exposure, which determines the relevance of continuing research to assess dynamic changes in immunological parameters and develop a system for monitoring the immune status of workers exposed to lead and its compounds to optimize preventive measures.

Cardiovascular and kidney diseases are positively associated with neuroinflammation and reduced brain-derived neurotrophic factor in patients with severe COVID-19

Even though respiratory dysfunctions are the primary symptom associated with SARS-CoV-2 infection, cerebrovascular events, and neurological symptoms are described in many patients. However, the connection between the neuroimmune profile and the lung's inflammatory condition during COVID-19 and its association with the neurological symptoms reported by COVID-19 patients still needs further exploration. The present study characterizes the SARS-CoV-2 infectivity profile in postmortem nervous and lung tissue samples of patients who died due to severe COVID-19, and the pro-inflammatory factors present in both nervous and lung tissue samples, via a proteomic profiling array. Additionally, Brain-Derived Neurotrophic Factor (BDNF) levels and intracellular pathways related to neuroplasticity/neuroprotection were assessed in the samples. Out of the 16 samples analyzed, all samples but 1 were positive for the viral genome (genes E or N2, but only 3.9% presented E and N2) in the olfactory brain pathway. The E or N2 gene were also detected in all lung samples, with 43.7% of the samples being positive for the E and N2 genes. In the E/N2 positive brain samples, the Spike protein of SARS-CoV-2 co-localized with TUJ-1+ (neuron-specific class III beta-tubulin) and GFAP+ (glial fibrillary acidic protein) astrocytes. IL-6, but not IL-10, expression was markedly higher in most nervous tissue samples compared to the lung specimens. While intracellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), macrophage migration inhibitory factor (MIF), and plasminogen activator inhibitor 1 (PAI-1) were increased in lung samples from SARS-Cov-2 patients, only MIF and IL-18 were detected in nervous tissue samples. Correlation analysis suggested that high levels of IL-6 are followed by increased levels of IL-10 in the brain, but not in lung samples. Our analysis also demonstrated that the presence of comorbidities, such as cardiovascular disease, hypertension, and hypothyroidism, is associated with neuroinflammation, while chronic kidney conditions predict the presence of neurological symptoms, which correlate with lower levels of BDNF in the brain samples. Our results corroborate the hypothesis that a pro-inflammatory state might further impair neural homeostasis and induce brain abnormalities found in COVID-19 patients.

Role of Interleukins in Pancreatic Cancer: A Literature Review.

This review article summarizes the pathophysiological aspects of interleukins (ILs) including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, and IL-10 in pancreatic cancer (PC). Science Direct, PubMed, and Google Scholar were used for the literature review. The search was conducted until August 12, 2024, and particular keywords such as "Pancreatic Cancer," "Interleukins," "Pathophysiological Aspects," "Immunosuppression," "Invasiveness," and "Metastasis" were used. Focusing on interleukins related to pancreatic cancer, 61 original studies were included: 32 studies for human patients, 16 studies for animal models, and 13 studies for both animal models and human patients. All types of PC were considered. The timeframe of 1991 to 2024 was chosen for clinical studies. In epithelial pancreatic tumors, IL-1 is a major inflammation factor. Serum concentrations of soluble interleukin-2-receptor were considerably greater in patients with PC and chronic pancreatitis than in healthy individuals. In comparison to controls, pancreatic cancer patients had considerably greater levels of macrophage colony-stimulating factor and significantly lower levels of stem cell factor and IL-3. The tissues and cells of pancreatic cancer have higher concentrations of IL-4 receptors. IL-5 has a role in the accumulation of pancreatic fibrosis. For individuals with pancreatic ductal adenocarcinoma (PDAC), a high serum level of IL-6 may be a separate risk factor for the development of widespread liver metastases. PDAC patients' peripheral blood mononuclear cells exhibit a substantial upregulation of IL-7 receptor. The role of IL-8 in the growth and spread of PC in humans. The miR-200a/β-catenin axis may be the mechanism by which IL-9 stimulates the proliferation and metastasis of PC cells. Blocking IL-10 in the local microenvironment appears to result in a significant reversal of tumor-induced immunosuppression. The article concludes that interleukins 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 played significant roles in the pathogenesis of PC.

Dynamic Brain Lipid Profiles Modulate Microglial Lipid Droplet Accumulation and Inflammation Under Ischemic Conditions in Mice.

Microglia are critically involved in post-stroke inflammation affecting neurological outcomes. Lipid droplet (LD) accumulation in microglia results in a dysfunctional and pro-inflammatory state in the aged brain and worsens the outcome of neuroinflammatory and neurodegenerative diseases. However, the role of LD-rich microglia (LDRM) under stroke conditions is unknown. Using in vitro and in vivo stroke models, herein accumulation patterns of microglial LD and their corresponding microglial inflammatory signaling cascades are studied. Interactions between temporal and spatial dynamics of lipid profiles and microglial phenotypes in different post-stroke brain regions are found. Hence, microglia display enhanced levels of LD accumulation and elevated perilipin 2 (PLIN2) expression patterns when exposed to hypoxia or stroke. Such LDRM exhibit high levels of TNF-α, IL-6, and IL-1β as well as a pro-inflammatory phenotype and differentially expressed lipid metabolism-related genes. These post-ischemic alterations result in distinct lipid profiles with spatial and temporal dynamics, especially with regard to cholesteryl ester and triacylglycerol levels, further exacerbating post-ischemic inflammation. The present study sheds new light on the dynamic changes of brain lipid profiles and aggregation patterns of LD in microglia exposed to ischemia, demonstrating a mutual mechanism between microglial phenotype and function, which contributes to progression of brain injury.

Predictors of the presence of radiological abnormalities 6 months after severe COVID-19 pneumonia

BackgroundSARS-CoV-2 pneumonia can cause significant long-term radiological changes, even resembling pulmonary fibrosis. However, the risk factors for these long-term effects are unknown. This study aims to assess radiological abnormalities and their possible risk factors six months after hospital discharge due to COVID-19 pneumonia.Material and methodsThis cross-sectional study in a tertiary hospital included adults admitted for COVID-19 pneumonia from March 2020 to February 2021, who underwent high-resolution computed tomography (HRCT) scans of the chest six months after hospital discharge. The primary outcome was radiological abnormalities on HRCT, while the main explanatory variables were drawn from the patient’s medical history along with the disease course, analytical indicators, and the treatment received during admission.ResultsThe 189 included patients had a mean age of 61.5 years; 70.9% were male, and hypertension was the main comorbidity (45%). About two-thirds (67.2%) presented acute respiratory distress syndrome (ARDS). Most (97.9%) received systemic corticosteroid therapy, and 81% presented pathological findings on HRCT, most commonly ground glass (63.5%), followed by bronchial dilatation (36%) and subpleural bands (25.4%). The multivariable analysis showed that age was the main risk factor, associated with most radiological changes. Other factors were the duration of corticosteroid therapy for ground glass (adjusted odds ratio [aOR] 1.020) as well as a longer stay in the intensive care unit (ICU) (aOR 1.290) and high levels of IL-6 for bronchial dilation (aOR 1.002). ConclusionRadiological involvement of the lungs six months after COVID-19 pneumonia is frequent, especially ground glass. Elderly patients with prolonged ICU admission and a significant inflammatory response measured by IL-6 are more likely to present worse radiological evolution and are candidates for radiological follow-up after COVID-19 pneumonia.

The FLARE Score and Circulating Neutrophils in Patients with Cancer and COVID-19 Disease.

Inflammation and neutrophils play a central role in both COVID-19 disease and cancer. We aimed to assess the impact of pre-existing tumor-related inflammation on COVID-19 outcomes in patients with cancer and to elucidate the role of circulating neutrophil subpopulations. We conducted a multicenter retrospective analysis of 524 patients with cancer and SARS-CoV-2 infection, assessing the relationship between clinical outcomes and circulating inflammatory biomarkers collected before and during COVID-19 infection. Additionally, a single-center prospective cohort study provided data for an exploratory analysis, assessing the immunophenotype of circulating neutrophils and inflammatory cytokines. The primary endpoints were 30-day mortality and the severity of COVID-19 disease. Prior to COVID-19, 25% of patients with cancer exhibited elevated dNLR, which increased to 55% at the time of COVID-19 diagnosis. We developed the FLARE score, incorporating both tumor- and infection-induced inflammation, which categorized patients into four prognostic groups. The poor prognostic group had a 30-day mortality rate of 68%, significantly higher than the 23% in the favorable group (p < 0.0001). This score proved to be an independent predictor of early mortality. This prospective analysis revealed a shift towards immature forms of neutrophils and higher IL-6 levels in patients with cancer and severe COVID-19 infection. A pre-existing tumor-induced pro-inflammatory state significantly impacts COVID-19 outcomes in patients with cancer. The FLARE score, derived from circulating inflammatory markers, emerges as an easy-to-use, globally accessible, effective tool for clinicians to identify patients with cancer at heightened risk of severe COVID-19 complications and early mortality who might benefit most from immediate and intensive treatment strategies. Furthermore, our findings underscore the significance of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease.

Dynamic cytokine profiles of bloodstream infection caused by Klebsiella pneumoniae in China

ObjectivesThe aim of this work was to assess dynamic cytokine profiles associated with bloodstream infection (BSI) caused by Klebsiella pneumoniae (Kpn) and investigate the clinical features associated with mortality.MethodsA total of 114 patients with positive BSI-Kpn and 12 sepsis individuals without blood positive bacteria culture were followed up. Cytokine profiles were analyzed by multiplex immunoassay on the first, third, seventh and fourteenth day after diagnosis. The test cytokines included arginase, interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-12 (p70), and IL-23. The minimum inhibitory concentration (MIC) of 24 antibiotics were tested for BSI-Kpn. Risk factors associated with the 30-day mortality and 120-day mortality were evaluated using logistic analyses and nomogram.ResultsThere were 55 out of 114 patients with BSI-Kpn were included. All isolates showed high susceptibility rate to novel avibactam combinations. The level of arginase was the highest in carbapenem-resistant Kpn (CRKP) patients. The AUCs of arginase, TNF-α and IL-4 reached 0.726, 0.495, and 0.549, respectively, whereas the AUC for the combination of these three cytokines was 0.805. Notably, 120-day mortality in patients with CRKP was higher than carbapenem-sensitive K. pneumoniae (CSKP). Furthermore, the long-term and high levels of IL-6 and IL-10 were associated with death.ConclusionsHigh expression of arginase is correlated with CRKP. In addition, BSI-CRKP could result in indolent clinic course but poor long-term prognosis. Continuous increase of IL-6 and IL-10 were associated with mortality.

DUMB CANE (DIEFFENBACHIA SEGUINE (JACQ.) SCHOTT) EXTRACT NANOEMULSION: PREPARATION, CHARACTERIZATION AND ITS ACTIVITY AS AN INFLAMMATION-INDUCING AGENT IN RATS

Objective: This study aimed to characterize Dumb cane extract nanoemulsion for injection preparation and test its activity as an inflammation-inducing agent in rat intraplantar with IL-6 and TNF-alpha parameters in blood serum as well as the swelling response in paw. Methods: Nanoemulsion was made from an emulsion base of olive oil, coconut oil, tween 80 propylene glycol, and water for injection, as well as varying concentrations of Dumb cane extract (1%, 2%, and 4%) using vortex mixing and sonication methods. The characterization included particle size, zeta potential, and polydispersity index using the Zetasizer tool. Induction was carried out intraplantar in male rats. The parameters observed were the volume of swelling in paw and IL-6 and TNF-alpha in blood serum. Results: Dumb cane extract nanoemulsion concentrations of 1%, 2%, and 4% have particle size characteristics in the range of 20.3±0.17–30.1±0.68 nm, and zeta potential -31.4±1.59–33.1±1.33 mV. Dumb cane nanoemulsion can induce intraplantar inflammation with high IL-6 and TNF-alpha levels, significantly different from normal controls. Volume swelling occurred 4 h after intraplantar induction at a nanoemulsion concentration of 4%. Conclusion: Dumb cane extract nanoemulsion can be an alternative agent for inducing intraplantar inflammation in rat models.

Analysis of the expression of cytokines and chemokines, platelet-leukocyte aggregates, sCD40L and sCD62P in cutaneous melanoma.

Cutaneous melanoma (CM) is a malignancy with a variable incidence worldwide and a poor advanced-stage prognosis. Melanoma growth is closely associated with the immune system. A cross-sectional study was performed on CM patients admitted at the Hospital de Cancer de Pernambuco (HCP) between 2015 and 2018. Fifty-one CM patients were included, and 30 healthy individuals. The study aimed to evaluate the association of platelet activation mechanisms and inflammatory response in patients with cutaneous melanoma. Elevated serum IL10 and low serum TNF levels in CM patients compared to controls (p < 0.05). High IL6 levels in patients with negative lymph nodes LN (-) compared to positive lymph nodes group (LN +, p = 0.0005). Low RANTES levels in patients compared to controls (p < 0.05). Elevated levels of platelet-lymphocyte (PLA), platelet-monocytes (PMA), and platelet-neutrophils (PNA) aggregates were observed in patients compared to controls (p < 0.05). CM patients with stage II had lower PMA levels than stages I and III (p < 0.05). High PMA levels were observed in patients with LN (+) compared to the LN (-) group (p < 0.0001). Patients with SSM had high levels of sCD40L and sCD62P compared to controls (p < 0.05)). High sCD40L levels in stage II compared to the stage III group, and sCD62P in stages I and II compared to the stage III group (p < 0.05). High sCD62P levels in patients with LN (-) compared to the group LN (+) (p < 0.05). It was observed the immunosuppressive profile in CM may favor tumor progression. High levels of platelet-leukocyte aggregates, sCD40L, and sCD62P may be associated with the worst prognosis.

Multiparametric identification of putative senescent cells in skeletal muscle via mass cytometry.

Senescence is an irreversible arrest of the cell cycle that can be characterized by markers of senescence such as p16, p21, and KI-67. The characterization of different senescence-associated phenotypes requires selection of the most relevant senescence markers to define reliable cytometric methodologies. Mass cytometry (a.k.a. Cytometry by time of flight, CyTOF) can monitor up to 40 different cell markers at the single-cell level and has the potential to integrate multiple senescence and other phenotypic markers to identify senescent cells within a complex tissue such as skeletal muscle, with greater accuracy and scalability than traditional bulk measurements and flow cytometry-based measurements. This article introduces an analysis framework for detecting putative senescent cells based on clustering, outlier detection, and Boolean logic for outliers. Results show that the pipeline can identify putative senescent cells in skeletal muscle with well-established markers such as p21 and potential markers such as GAPDH. It was also found that heterogeneity of putative senescent cells in skeletal muscle can partly be explained by their cell type. Additionally, autophagy-related proteins ATG4A, LRRK2, and GLB1 were identified as important proteins in predicting the putative senescent population, providing insights into the association between autophagy and senescence. It was observed that sex did not affect the proportion of putative senescent cells among total cells. However, age did have an effect, with a higher proportion observed in fibro/adipogenic progenitors (FAPs), satellite cells, M1 and M2 macrophages from old mice. Moreover, putative senescent cells from muscle of old and young mice show different expression levels of senescence-related proteins, with putative senescent cells of old mice having higher levels of p21 and GAPDH, whereas putative senescent cells of young mice had higher levels of IL-6. Overall, the analysis framework prioritizes multiple senescence-associated proteins to characterize putative senescent cells sourced from tissue made of different cell types.

A bio-behavioral model of systemic inflammation at breast cancer diagnosis and fatigue of clinical importance 2 years later

We aimed to generate a model of cancer-related fatigue (CRF) of clinical importance 2 years after diagnosis of breast cancer building on clinical and behavioral factors and integrating pre-treatment markers of systemic inflammation. Women with stage I-III hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer were included from the multimodal, prospective CANTO cohort (NCT01993498). The primary outcome was global CRF of clinical importance [European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 ≥40/100] 2 years after diagnosis (year 2). Secondary outcomes included physical, emotional, and cognitive CRF (EORTC QLQ-FA12). All pre-treatment candidate variables were assessed at diagnosis, including inflammatory markers [interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, interferon γ, IL-1 receptor antagonist, tumor necrosis factor-α, and C-reactive protein], and were tested in multivariable logistic regression models implementing multiple imputation and validation by 100-fold bootstrap resampling. Among 1208 patients, 415 (34.4%) reported global CRF of clinical importance at year 2. High pre-treatment levels of IL-6 (quartile 4 versus 1) were associated with global CRF at year 2 [adjusted odds ratio (aOR): 2.06 (95% confidence interval [CI] 1.40-3.03); P= 0.0002; area under the receiver operating characteristic curve= 0.74]. Patients with high pre-treatment IL-6 had unhealthier behaviors, including being frequently either overweight or obese [62.4%; mean body mass index 28.0 (standard deviation 6.3 kg/m2)] and physically inactive (53.5% did not meet World Health Organization recommendations). Clinical and behavioral associations with CRF at year 2 included pre-treatment CRF [aOR versus no pre-treatment CRF: 3.99 (95% CI 2.81-5.66)], younger age [aOR per 1-year decrement: 1.02 (95% CI 1.01-1.03)], current tobacco smoking [aOR versus never: 1.81 (95% CI 1.26-2.58)], and worse insomnia or pain [aOR per 10-unit increment: 1.08 (95% CI 1.04-1.13), and 1.12 (95% CI 1.04-1.21), respectively]. Secondary analyses indicated additional associations of IL-2 [aOR per log-unit increment: 1.32 (95% CI 1.03-1.70)] and IL-10 [0.73 (95% CI 0.57-0.93)] with global CRF and of C-reactive protein [1.42 (95% CI 1.13-1.78)] with cognitive CRF at year 2. Emotional distress was consistently associated with physical, emotional, and cognitive CRF. This study proposes a bio-behavioral framework linking pre-treatment systemic inflammation with CRF of clinical importance 2 years later among a large prospective sample of survivors of breast cancer.

Early Cerebral Microvasculature Impairment and Increased Body Mass Index in Patients with Psoriasis.

Psoriasis induces systemic atherosclerosis, but its impact on cerebrovascular function remains unclear. However, stroke prevention must be considered in psoriasis, as it is commonly comorbid with classic cardiovascular risk factors. Thus, the aim of the study is to assess cerebral microvasculature function and its confounders in patients with psoriasis. The study protocol included cerebral autoregulation assessment with measurements of vasomotor reactivity reserve (VMRr) on the middle cerebral arteries with the use of a Transcranial Doppler (TCD) in 50 patients with psoriasis without cerebrovascular events (46; 21-74 years) and 26 healthy controls (41; 29-58 years). Analyses of VMRr relationships with the psoriasis course, comorbidities, inflammatory markers and intima-media thickness (IMT) were performed. The study showed that VMRr was lower (64% vs. 76%, p = 0.001), and the IMT was higher (0.65 vs. 0.52 mm, p = 0.001) in patients compared to controls. The patients were also characterized by a higher body mass index (BMI) and a higher level of Il-6 than the controls (29.14 vs. 25.76 kg/m2, p = 0.004 and 585 vs. 204 pg/mL, p < 0.001, respectively), but only BMI was independently impacting VMRr reduction (p = 0.02). In conclusion, early cerebral microvasculature dysfunction may occur in patients with psoriasis, and its extent is associated with an increase in BMI. Thus, body mass reduction should be strongly recommended for stroke prophylaxis in patients with psoriasis.

Interleukin-6 and Cardiovascular Events in Healthy Adults: MESA

BackgroundElevated interleukin (IL)-6 levels have been linked to adverse outcomes in patients with and without baseline cardiovascular disease (CVD). ObjectivesThe purpose of this study was to examine the association between circulating IL-6 levels and CVD events without baseline CVD across racial and ethnic groups. MethodsWe conducted an observational analysis utilizing the MESA (Multi-Ethnic Study of Atherosclerosis), a multicenter, prospective community-based study of CVD at baseline from 4 racial and ethnic groups. IL-6 levels were measured at the time of enrollment (visit 1) and were divided into 3 terciles. Patient baseline characteristics and outcomes, including all-cause mortality, CV mortality, heart failure, and non-CV mortality, were included. Cox proportional hazard regression models were used to assess associations between IL-6 levels and study outcomes with IL-6 tercile 1 as reference. ResultsOf 6,622 individuals, over half were women (53%) with a median age of 62 (IQR: 53-70) years. Racial and ethnic composition was non-Hispanic White (39%) followed by African American (27%), Hispanic (22%), and Chinese American (12%). Compared to tercile 1, participants with IL-6 tercile 3 had a higher adjusted risk of and all-cause mortality (HR: 1.98 [95% CI: 1.67-2.36]), CV mortality (HR: 1.55 [95% CI: 1.05-2.30]), non-CV mortality (HR: 2.05 [95% CI: 1.65-2.56]), and heart failure (HR: 1.48 [95% CI: 0.99-2.19]). When tested as a continuous variable, higher levels of IL-6 were associated with an increased risk of all individual outcomes. Compared to non-Hispanic White participants, the unadjusted and adjusted risk of all outcomes across all races and ethnicities was similar across all IL-6 terciles. ConclusionsHigh levels of circulating IL-6 are associated with worse CV outcomes and increased all-cause mortality consistently across all racial and ethnic groups.

Assessment of COVID-19 risk factors of early and long-term mortality with prediction models of clinical and laboratory variables

BackgroundCoronavirus disease (COVID-19) may lead to serious complications and increased mortality. The outcomes of patients who survive the early disease period are burdened with persistent long-term symptoms and increased long-term morbidity and mortality. The aim of our study was to determine which baseline parameters may provide the best prediction of early and long-term outcomes.MethodsThe study group comprised 141 patients hospitalized for COVID-19. Demographic data, clinical data and laboratory parameters were collected. The main study endpoints were defined as in-hospital mortality and 1-year mortality. The associations between the baseline data and the study endpoints were evaluated. Prediction models were created.ResultsThe in-hospital mortality rate was 20.5% (n = 29). Compared with survivors, nonsurvivors were significantly older (p = 0.001) and presented comorbidities, including diabetes (0.027) and atrial fibrillation (p = 0.006). Assessment of baseline laboratory markers and time to early death revealed negative correlations between time to early death and higher IL-6 levels (p = 0.032; Spearman rho − 0.398) and lower lymphocyte counts (p = 0.018; Pearson r -0.438). The one-year mortality rate was 35.5% (n = 50). The 1-year nonsurvivor subgroup was older (p < 0.001) and had more patients with arterial hypertension (p = 0.009), diabetes (p = 0.023), atrial fibrillation (p = 0.046) and active malignancy (p = 0.024) than did the survivor subgroup. The model composed of diabetes and atrial fibrillation and IL-6 with lymphocyte count revealed the highest value for 1-year mortality risk prediction.ConclusionsDiabetes and atrial fibrillation, as clinical factors, and LDH, IL-6 and lymphocyte count, as laboratory determinants, are the best predictors of COVID-19 mortality risk.