Higher Levels Of IL-6 Research Articles

Role of Cytokines in Predicting Early Major Bleeding in Patients With Acute Pulmonary Embolism.

Anticoagulant therapy is critical for venous thromboembolism (VTE) management, though bleeding remains a major concern, ranging from mild to fatal events. This study aimed to assess the predictive value of cytokines for major bleeding in patients with acute pulmonary embolism (PE). In this prospective, observational study, patients aged ≥ 18 years with acute PE were enrolled from April 2021 to September 2022 and followed for 30 days. Exclusion criteria included asymptomatic PE, VTE without PE, and chronic anticoagulation. Major bleeding was defined as bleeding that required ≥ 2 transfused units of red blood cells, occurred in critical areas, or was fatal. Blood samples were collected at diagnosis to measure IL-6, IL-1beta, IL-8, IL-10, and TNF-alpha. Statistical analyses used bivariate and multivariate logistic regression (p < 0.05). Out of 191 patients (mean age 68.6 years, 52.9% male), 8.4% died, and 4.2% experienced major bleeding within 30 days. IL-8 > 40 pg/mL and TNF-alpha > 8.5 pg/mL were linked to major bleeding. IL-8 > 40 pg/mL independently predicted early major bleeding (adjusted OR 9.40; 95% CI 1.38-63.69). Cox regression showed HRs of 12.60 for IL-8 and 5.61 for TNF-alpha. High IL-8 levels at diagnosis were predictive of major bleeding in acute PE patients. Further studies are required to confirm these findings.

Physalis Calyx seu Fructus relieves chicken intestinal damage to heat via improving the antioxidant ability

Heat-stress-induced oxidative and inflammatory responses were important factors contributing to chicken intestinal damage. The purpose of this study was based on the antioxidant and anti-inflammatory activities of Physalis Calyx seu Fructus (Jin Deng Long, JDL) to investigate its efficacy and mechanism in relieving chicken heat stress damage. Primary chicken embryo duodenum cells and 90 30-day-old specific-pathogen-free chicken were randomly divided into control and JDL groups to establish heat stress models in vitro and in vivo. The mitigating effect was assessed through the oxidation-related enzymes and key genes, histopathology, and inflammatory factors. The results demonstrated that 100 µg/mL JDL extract could effectively alleviate heat stress damage to chicken embryo duodenum cells at 42°C. A strong antioxidant capacity of 100 µg/mL JDL extract was shown in the downregulation of LDH (at 5 h, P &amp;lt; 0.01) and MDA (at 5 h, P &amp;lt; 0.05), in the upregulation of SOD (at 5 and 10 h, P &amp;lt; 0.01), CAT (at 5 h, P &amp;lt; 0.01), and GSH-PX and T-AOC (at 0 h, P &amp;lt; 0.01) as well as in the high transcription level of NQO1 (at 5 and 10 h, P &amp;lt; 0.05) and HO-1 (at 5 and 10 h, P &amp;lt; 0.01). Supplements with 1 and 3 g/kg b.wt, respectively, in the drinking water both suppressed the rise of body temperature and had light pathological lesions of chicken duodenal tissues caused by heat stress at 40 ± 1°C. Accordingly, the chicken of JDL extract groups showed a lower inflammatory response as manifested by a lower level of IL-10 and higher levels of IL-6 and TNF-α and a strong antioxidant capacity characterized by lower level of MDA and higher levels of SOD and GSH-PX in the serum as well as also showed a higher transcription level of Nrf2, NQO1, and HO-1 in the duodenal tissues. In conclusion, JDL extract relieved chicken intestinal damage to heat via improving the antioxidant ability and reducing the inflammatory response.

The investigation of peripheral inflammatory and oxidative stress biomarkers in dementia with Lewy Bodies, compared with Alzheimer's Disease, and mild cognitive impairment.

Although inflammation and oxidative stress have been increasingly recognised as components of Alzheimer's disease (AD) and Parkinson's disease (PD) pathologies. Few studies have investigated peripheral inflammation, and none have examined oxidative stress in Dementia with Lewy bodies (DLB). The purpose of our study was to characterize and compare those biomarkers in DLB with those in AD and amnestic mild cognitive impairment (aMCI). Plasma samples were obtained from Chinese patients with DLB (n = 50), AD (n = 59), and aMCI (n = 30), and healthy controls (HCs) (n = 54). Peripheral inflammatory biomarkers, including interferon-gamma (IFN-γ), interleukins (IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Oxidative stress markers, such as superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px), were also assessed. The findings revealed that DLB patients had higher IL-6 levels than AD and HCs and elevated IL-10 and IL-17A levels compared to HCs. In terms of oxidative stress, the levels of SOD were significantly lower and MDA were significantly higher in the DLB and AD compared with HCs. Significant positive correlations were found between Unified Parkinson's Disease Rating Scale (UPDRS) scores and CRP levels. Our study identifies a unique peripheral immune and oxidative stress profile in DLB, characterized by elevated IL-6, MDA, and reduced SOD levels, distinguishing it from AD. These findings, linked to α-synuclein (α-Syn) pathology, provide novel insights into DLB mechanisms and highlight potential biomarkers for disease monitoring, targeted therapies, and future clinical trials.

Monocyte adhesion to and transmigration through endothelium following cardiopulmonary bypass shearing is mediated by IL-8 signaling.

The use of cardiopulmonary bypass (CPB) can induce sterile systemic inflammation that contributes to morbidity and mortality, especially in children. Patients have been found to have increased expression of cytokines and transmigration of leukocytes during and after CPB. Previous work has demonstrated that the supraphysiologic shear stresses existing during CPB are sufficient to induce proinflammatory behavior in non-adherent monocytes. The interactions between shear stimulated monocytes and vascular endothelial cells have not been well studied and have important translational implications. With these studies, we tested the hypothesis that non-physiological shear stress experienced by monocytes during CPB affects the integrity and function of the endothelial monolayer. We have used an in vitro CPB model to study the interaction between THP-1 monocyte-like cells and human neonatal dermal microvascular endothelial cells (HNDMVECs). THP-1 cells were sheared in polyvinyl chloride (PVC) tubing at 2.1 Pa, twice of the physiological shear stress, for 2 h. ELISA, adhesion and transmigration assays, qPCR, and RNA silencing were used to assess the interactions between THP-1 cells and HNDMVECs were characterized after co-culture. We found that sheared THP-1 cells adhered to and transmigrated through the HNDMVEC monolayer more readily than static THP-1 controls. Sheared THP-1 cells disrupted the VE-cadherin and led to the reorganization of cytoskeletal F-actin of HNDMVECs. A higher level of IL-8 was detected in the sheared THP-1 and HNDMVEC co-culture medium compared to the static THP-1 and HNDMVEC medium. Further, treating HNDMVECs with IL-8 resulted in increased adherence of non-sheared THP-1 cells, and upregulation in HNDMVECs of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). Finally, inhibition of HNDMVECs CXCR2/IL-8 receptor with Reparixin and of IL-8 expression with siRNA blocked sheared THP-1 cell adhesion to the endothelial monolayer. These results suggest that CPB-like sheared monocytes promote IL-8 production followed by increased endothelium permeability, and monocyte adhesion and transmigration. This study revealed a novel mechanism of post-CPB inflammation and will contribute to the development of targeted therapeutics to prevent and repair the damage to neonatal patients.

Akkermansia muciniphila- and Pathogenic Bacteria-Derived Endotoxins Differently Regulate Human Dendritic Cell Generation and γδ T Lymphocyte Activation.

Lipopolysaccharide (LPS) is a potent endotoxin released at high concentrations in acute infections, causing massive host inflammatory response. Accumulating evidence indicates that dysbiosis-associated chronic low levels of circulating LPS can sustain a prolonged sterile low-grade inflammation that increases the risk of several non-communicable diseases. Interventions aimed at increasing the abundance of beneficial/probiotic bacteria, including Akkermansia muciniphila, result in reduced inflammation, favoring metabolic and immune health. Immunosuppression is a common feature in conditions of chronic inflammation, and dendritic cells (DCs) represent key targets given their ability to shift the balance toward immunity or tolerance. In this study, the effects of low concentrations of LPS from pathogenic (Escherichia coli and Salmonella enterica) and probiotic (Akkermansia muciniphila) bacterial species on human DC generation and functions were compared. We report that monocyte precursor priming with Escherichia coli and Salmonella enterica LPS forces the differentiation of PD-L1-expressing DCs, releasing high levels of IL-6 and IL-10, and impairs their capacity to drive full TCR-Vδ2 T cell activation. Conversely, comparable concentrations of Akkermansia muciniphila promoted the generation of DCs with preserved activating potential and immunostimulatory properties. These results shed light on potential mechanisms underlying the impact of low endotoxemia on disease risk and pathogenesis, and increase our understanding of the immunomodulatory effects of Akkermansia muciniphila.

Tear inflammatory cytokine profiles in orbital inflammatory disease.

Tear inflammatory cytokines are a novel biomarker studied in a range of ocular surface diseases, periorbital and orbital conditions. This single-centre prospective study between 2022 and 2024 aims to characterise tear cytokine profiles (Interleukin-1β [IL-1β], IL-2, IL-6, Interferon-γ [IFN-γ] and Tumour Necrosis Factor-α [TNF- α]) in orbital inflammatory disease (OID). OID patients had pre-treatment tear collection via micropipette, and cytokine analysis via multiplex bead array analysis. Thirteen healthy controls with no prior ophthalmic history were enrolled for comparison. Eighteen tear specimens from seventeen OID patients (6 males; mean age: 52.1±17.1-years-old), with one repeat tear sample taken for recurrent contralateral orbital inflammation. Diagnoses included non-specific orbital inflammation (47.1%), IgG4-related orbital disease (17.6%), orbital granulomatosis with polyangiitis (5.9%), giant cell arteritis (5.9%), herpes zoster ophthalmicus with orbital apex inflammation (5.9%), viral dacryoadenitis (5.9%), bacterial dacryoadenitis (5.9%) and orbital inflammation of uncertain cause (5.9%). Overall, OID patients, and specifically those with dacryoadenitis, had greater IL-6 levels compared to controls (P=0.038 and 0.002, respectively). OID with dacryoadenitis had higher IL-1β levels compared to those without (P=0.029). Higher IL-6 levels were observed in idiopathic dacryoadenitis compared to healthy controls (P=0.008, respectively). There is significant variability in tear inflammatory cytokines profiles observed in OID. IL-1β and IL-6 levels may be non-specific markers of dacryoadenitis and may be particularly elevated in idiopathic dacryoadenitis. Tear cytokines may be affected by severity, localisation and pattern of inflammation. The utility of tear cytokines in the monitoring and prognostication of OID remains to be elucidated.

Monocyte transcriptome signatures of inflammation and enhanced neutrophil recruitment characterize immunopathology in the blood of TB patients

Tuberculosis (TB) is characterized by immunopathology in the blood and monocytes have been shown to be highly sensitive to plasma environment changes in TB patients. Here, we investigated TB plasma effects on ‘reference monocytes’ using RNA sequencing to characterize a potential immunomodulatory role of monocytes in TB. Candidate pathways induced by plasma samples from TB patients (n=99) compared to healthy controls (n=62) were analyzed for changes in signal transduction, phenotype and secreted cytokines by flow cytometry. Finally, potential implications were characterized in blood samples from corresponding patients and controls.Reference monocytes treated with TB plasma showed an enrichment of pathways involved in inflammation and chemotaxis. Inflammatory cytokines were accompanied by enhanced phosphorylation of STAT molecules (i.e., STAT1/3/5) and strong positive correlations were detected for Interleukin (IL)-6 only in TB plasma-treated monocytes. Moreover, monocyte chemokine receptors (i.e., CCR-1, CCR-5) and pro-inflammatory chemokines (i.e., CXCL-1, CXCL-2, CXCL-8, G-CSF, CCL-2) that attract granulocytes and monocytes were significantly higher in TB plasma-treated monocytes. Notably, corresponding clinical samples also showed higher plasma levels for a subset of inflammatory cytokines/chemokines and, in particular, high IL-6 levels correlated positively with accumulation of neutrophil granulocytes in the blood of TB patients. Finally, monocytes from TB patients were characterized by increased chemokine receptor expression, higher proportions of a CCR-2+ subpopulation and aberrant high SOCS3 expression.These results suggest that monocytes may play a significant role in amplifying plasma immunopathology, leading to sustained mobilization and accumulation of neutrophil granulocytes and chronic inflammation in the blood of TB patients.

Increase in Blood Eosinophil Count Over Time and Sputum IL8 are Associated with FEV1 Decline in Asthma

BackgroundAsthma is associated with accelerated rate of FEV1 decline.ObjectiveTo determine predictive factors associated with accelerated FEV1 decline in adult asthma and evaluate sputum cytokines as potential biomarkers for airflow decline.MethodsWe recruited 125 asthmatics evaluated at the asthma clinic of Liège and reevaluated them at least 5 years later. Clinical, functional and inflammatory characteristics were compared between patients with accelerated decline (FEV1 decline > 0.85% pred.y−1) and others. Predictive factors were highlighted with linear regression analysis. Sputum EGF, VEGF, FGF, IL5, IL8, TGF-β, and IgE levels were measured in 58 of these patients at both visits by Human XL cytokine Luminex Performance assay and Elisa.ResultsPost-BD FEV1 decline was 0.06 ± 2.44% pred.y−1 in the overall population. Median (IQR) time between visits was 66 (62 – 86) months. The multivariable analysis showed that an increase in blood eosinophils over time (Δ BEC) (Reg. Coef. (95%CI): 0.002 (0.001 to 0.004), p = 0.005)) and onset of asthma (0.04 (0.003 to 0.07), p = 0.036) were independently associated with FEV1 decline. IL8 levels measured at baseline were higher (499 (408—603) pg/ml, p = 0.0040) in patients with accelerated decline compared to others (143 (88—308) pg/ml).ConclusionIn this study, we have confirmed that an increase in blood eosinophil counts over a follow-up of at least 5 years and later onset of asthma are associated with accelerated annual FEV1 decline. Moreover, high sputum IL8 levels could be a risk factor for accelerated decline in asthma patients.

Higher levels of IL-6 and IL-10 cytokines in visceral leishmaniasis-HIV co-infected patients from Brazilian high endemic area

Visceral Leishmaniasis (VL) is an endemic disease in Latin America, and the clinical outcome worsens when a patient has HIV co-infection. In these patients, the immune response is complex and cytokines profile variable. We evaluate Th1/Th2/Th17 cytokine profile in VL/HIV patients from Brazilian high endemic area. In this cross-sectional study, the serological cytokines production was compared with clinical and epidemiological traits of the VL/HIV, VL and HIV patients. VL/HIV patients are predominantly male (89.2 %) with relapses in 35.5 % of the cases. There is higher serum levels of IL-6 (p = 0.006) and IL-10 (p < 0.001) in VL/HIV patients. Furthermore, there is a moderate or strong positive correlation in the serum levels of IL-6 and TNF-α (Rho = 0.635, p < 0.001), IL-10 and IFN-γ (Rho = 0.523, p < 0.001), IL-6 and IL-10 (Rho = 0.506, p < 0.001), IL-2 and IL-4 (Rho = 0.506, p < 0.001). Then, VL/HIV patients who died during VL treatment (p = 0.033), patients with oedema (p = 0.011), and patients with jaundice (p = 0.019) had statistically high levels of IL-6. In conclusion, VL/HIV patients have production or reduction of specific cytokines, highlights IL-6 and IL-10.

Application of the Sponge Model Implants in the Study of Vaccine Memory in Mice Previously Immunized with LBSap.

Considering the large number of candidates in vaccine-testing studies against different pathogens and the amount of time spent in the preclinical and clinical trials, there is a pressing need to develop an improved in vivo system to quickly screen vaccine candidates. The model of a polyester-polyurethane sponge implant provides a rapid analysis of the specific stimulus-response, allowing the study of a compartmentalized microenvironment. The sponge implant's defined measurements were standardized as a compartment to assess the immune response triggered by the vaccinal antigen. The LBSap vaccine (composed of Leishmania braziliensis antigens associated with saponin adjuvant) was used in the sponge model to assess the antigen-specific immunological biomarker, including memory generation after initial contact with the antigen. Mice strains (Swiss, BALB/c, and C57BL/6) were previously immunized using LBSap vaccine, followed by an antigenic booster performed inside the sponge implant. The sponge implants were assessed after 72 h, and the immune response pattern was analyzed according to leukocyte immunophenotyping and cytokine production. After LBSap vaccination, the innate immune response of the antigenic booster in the sponge implants demonstrated higher levels in the Ly+ neutrophils and CD11c+ dendritic cells with reduced numbers of F4/80+ macrophages. Moreover, the adaptive immune response in Swiss mice demonstrated a high CD3+CD4+ T-cell frequency, consisting of an effector memory component, in addition to a cytoxicity response (CD3+CD8+ T cells), displaying the central memory biomarker. The major cell surface biomarker in the BALB/c mice strain was related to CD3+CD4+ effector memory, while the increased CD3+CD8+ effector memory was highlighted in C57/BL6. The cytokine profile was more inflammatory in Swiss mice, with the highest levels of IL-6, TNF, IFN-g, and IL-17, while the same cytokine was observed in in C57BL/6 yet modulated by enhanced IL-10 levels. Similar to Swiss mice, BALB/c mice triggered an inflammatory environment after the antigenic booster in the sponge implant with the increased levels in the ILL-6, TNF, and IFN-g. The findings emphasized the impact of genetic background on the populations engaged in immune responses, suggesting that this model can be utilized to enhance and track both innate and adaptive immune responses in vaccine candidates. Consequently, these results may inform the selection of the most suitable experimental model for biomolecule testing, taking into account how the unique characteristics of each mouse strain affect the immune response dynamics.

From geriatric assessment to inflammation. A pilot, observational, study about frailty components in older patients with persistent atrial fibrillation

BackgroundAtrial fibrillation (AF) is the most common arrhythmia diagnosed at an older age. AF is associated with frailty, a condition possibly justifying the higher rate of complications and mortality in aged individuals. This study was aimed at describing the characteristics correlated to frailty in older AF subjects. MethodsAfter having excluded a < 3 months major surgery procedure, cancer or other conditions associated with activation of inflammation, and a life expectancy < 12 months, we consecutively enrolled patients ≥ 65 years with persistent AF. They underwent a Comprehensive Geriatric Assessment evaluation. In particular, Mini-Mental State Examination, 15-item Geriatric Depression Scale and Short-Physical Performance Battery (SPPB) described, respectively, cognitive profile, depressive symptoms and physical performance. A venous blood sample was collected to measure interleukin-6 (IL-6; marker of low-grade inflammation) and acylcarnitines, expression of mitochondrial dysfunction and abnormal energy production. ResultsOverall, 49 patients (mean age: 76 ± 6 years; women 30.6 %) were studied. Cluster analysis described two different patterns; the second (N = 18, 36.7 %), when compared to the first one (N = 31, 63.3 %), was characterized by a worse phenotype, identified by the simultaneous presence of lower body mass index, higher CHA2DS2-VASc score (index of clinical complexity), worse SPPB functional performance, and high IL-6 levels. Second cluster patients had a higher concentration of 13 of the 35 acylcarnitines evaluated and increased 5-year mortality. All these features can outline a frail condition. ConclusionsBody size, clinical complexity, physical performance and low-grade inflammation seem to rapidly and adequately describe frailty.

Cytokine Storm among Bangladeshi adults with COVID-19: A prospective cohort study

ObjectiveIn COVID-19, cytokine storms (CS) result in higher mortality and morbidity. Our study evaluated the rate of cytokine storms among COVID-positive Bangladeshi adults. MethodsFrom October 2020 to March 2022, this cohort study enrolled both COVID-positive and COVID-negative healthy adults. COVID-positive cases were treated in a makeshift COVID unit of icdr,b Dhaka Hospital. CS was defined as having IL-6 >80 pg/mL or any three of the following: high CRP, ferritin, LDH, D-dimer, or low lymphocyte. Stored plasma samples were tested for the cytokines IL-6, IL-1β, and TNF-α. ResultsThis study involved 77 participants, 32 were in the severe-critical group, 30 were in the mild-moderate group, and 14 were COVID-negative. Twelve participants in the severe-critical group had CS. Thus, the rate of CS was 37.5 % (12/32). Compared to COVID-19-negative patients, COVID-19-positive patients had higher IL-6 levels, which decreased at discharge except for those dying. Among the COVID-19-positive patients, nine died. For both the mild-moderate and severe-critical patients, IL-6 increased with increasing CRP (p < 0.001). ConclusionDuring the COVID-19 pandemic, Bangladeshi adults experienced a surge in cytokine storms. The rate of cytokine storm in Bangladeshi COVID-19-positive adults was 37.5 %.

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

Biomarker analyses are an integral part of cancer research. Despite the intense efforts to identify and characterize biomarkers in patients with cancer, 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 eight 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, fasting status, and sampling factors. ICC was calculated to determine the reliability of each biomarker. Hepatocyte growth factor was the most stable marker (ICC = 0.973), while platelet-derived growth factor (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, TGFβ1, PDGF-AA) had ICC values <0.4. Greater age was associated with higher IL6 (P = 0.0114). Higher body mass index was associated with higher levels of IL6 (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. These data further support the validation of the angiome biomarker assay and its application as an integrated biomarker in clinical trial testing.

Hyperresponsiveness of Corticoid-Resistant Th17/Tc-17 Cells to TLR-2 and TLR-4 Ligands is a Feature of Multiple Sclerosis Patients at Higher Risk of Therapy Failure.

The presence of T cells expressing TLR-2 and TLR-4 has been associated with relapsing-remitting multiple sclerosis (RRMS) pathogenesis. Here, we evaluated whether the effectiveness of DMT in controlling clinical activity of the disease would be associated with modulation of proportion of TLRs+ T cells. Whole peripheral blood mononuclear cells, purified CD4+ and CD8+ T cells from RRMS patients were cultured with different stimuli. The frequency of IL-17-secreting CD4+ and CD8+ T cells positive for TLR-2 and TLR-4 was determined by flow cytometry. The cytokine profile of these T cells following TLR-2 and TLR-4 stimulation was determined by Multiplex. Some of these T cell cultures were treated with hydrocortisone. The levels of LPS-binding protein (LBP) were dosed by ELISA. Clinical (occurrence of relapses) and radiological (number of active brain lesions) activity were evaluated during the 1-year follow-up. Despite DMT, high intensity of TLR-2 and TLR-4 expression on (CD4+ and CD8+) T-cells, as well as the frequency of IL-17-secreting (CD4+ and CD8+) T-cells, are predictive of future RRMS relapses. Moreover, higher cytokine production related to Th17/Tc-17 phenotypes in response to TLR-2 and TLR-4 agonists was observed in DMT-treated patients and displayed an elevated number of brain lesions. The hyperresponsiveness of MS-derived T-cells to TLR-2 and TLR-4 ligands, with high levels of IL-1β, IL-6, IL-17, IFN-γ and GM-CSF in response to both TLR agonists, positively correlated with plasma LBP levels. Interestingly, corticoid was less efficient in reducing Th17 and Tc-17 cytokine production induced by TLR-2 and TLR-4 ligands in DMT-treated patients who relapsed during follow-up. Collectively, the data suggested that persistence of circulating Th17 and Tc17 cells expressing elevated levels of functional TLR-2 and TLR-4 could indicate high disease activity and lower therapeutic efficacy in RRMS patients.

Extracellular vesicles containing SARS-CoV-2 proteins are associated with multi-organ dysfunction and worse outcomes in patients with severe COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and has been related to more than 7 million deaths globally since 2019. The association of high levels of IL-6 with severe cases led to the early evaluation of the anti-IL6 inhibitor tocilizumab as a potential treatment, which unfortunately failed to improve survival in many trials. Moreover, little is known about the development of COVID-19 sequelae, and biomarkers are needed to understand and anticipate these processes. Because extracellular vesicles (EVs) play an important role in viral infection and immune response, they could potentially serve as predictive and prognostic biomarkers. We isolated EVs from 39 patients with severe COVID-19, from which 29 received tocilizumab and 10 were considered controls. Blood samples, which were collected at hospitalisation before treatment, at Day 7, and Day 15 during follow-up, were assessed by immunoblot for longitudinal expression of spike (S) and nucleocapsid (N) proteins. Dynamic expression was calculated and compared with clinicopathological and experimental variables. Expression of EV S was validated by immunogold and imaging flow-cytometry, revealing an enrichment in CD9+ EVs. As a result, decreasing expression of EV viral proteins was observed in patients treated with tocilizumab. Moreover, higher increase in EV S was observed in patients with lower antibody response, hyperfibrinogenemia, lower respiratory function, higher blood pressure and shorter outcomes. These findings lay the foundation for future studies characterizing the role of EVs in multiorgan assessment and identifying biomarkers in patients with severe COVID-19 and possible long COVID.

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&amp;lt;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.

Variants rs3804099 and rs3804100 in the TLR2 Gene Induce Different Profiles of TLR-2 Expression and Cytokines in Response to Spike of SARS-CoV-2.

The present study aimed to identify in patients with severe COVID-19 and acute respiratory distress syndrome (ARDS) the association between rs3804099 and rs3804100 (TLR2) and evaluate the expression of TLR-2 on the cell surface of innate and adaptive cells of patients' carriers of C allele in at least one genetic variant. We genotyped 1018 patients with COVID-19 and ARDS. According to genotype, a subgroup of 12 patients was selected to stimulate peripheral blood mononuclear cells (PBMCs) with spike and LPS + spike. We evaluated soluble molecules in cell culture supernatants. The C allele in TLR2 (rs3804099, rs3804100) is not associated with a risk of severe COVID-19; however, the presence of the C allele (rs3804099 or rs3804100) affects the TLR-2 ability to respond to a spike of SARS-CoV-2 correctly. The reference group (genotype TT) downregulated the frequency of non-switched TLR-2+ B cells in response to spike stimulus; however, the allele's C carriers group is unable to induce this regulation, but they produce high levels of IL-10, IL-6, and TNF-α by an independent pathway of TLR-2. Findings showed that TT genotypes (rs3804099 and rs3804100) affect the non-switched TLR-2+ B cell distribution. Genotype TT (rs3804099 and rs3804100) affects the TLR-2's ability to respond to a spike of SARS-CoV-2. However, the C allele had increased IL-10, IL-6, and TNF-α by stimulation with spike and LPS.

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.