P5565S100A8/A9 serum levels as a diagnostic biomarker and its potential connection to NOD2-NLRP3 in patients with a recent onset of myocarditis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
I Mueller ◽  
U Uwe Kuehl ◽  
T Thomas Vogl ◽  
A Alexander Krannich ◽  
S Sophie Van Linthout ◽  
...  

Abstract Background The alarmin S100A8/A9 has been shown to be of importance in several inflammatory cardiovascular disorders. We recently demonstrated the pivotal role of cardiac S100A8/A9 in human and experimental Coxsackievirus B3 (CVB3)-induced myocarditis (MC). Purpose We aimed to evaluate whether serum S100A8/A9 levels are a marker in patients with a recent onset of MC Methods Serum S100A8/A9, hsCRP, and NT pro-BNP levels were analyzed in patients with a recent onset of MC (≤30 days (d), n=29; ejection fraction (EF): 44.3%±13%), dilated cardiomyopathy patients with inflammation (DCMi: n=112; EF: 28.8%±12%) or without inflammation (DCM: n=58; EF: 26.7%±9%), and controls (co: n=25; EF: 68.5%±5%). Blood samples and endomyocardial biopsies (EMB) were collected at time point (T1). In a subgroup, S100A8/A9 serum levels and EMB were available at T1 (n=10) and follow-up (T2, n=10, mean follow-up 8 months). Results MC ≤30 d patients showed a 4.5-fold (p<0.0001), 19.3-fold (p<0.0001), and 4.0-fold (p<0.0001) increase in S100A8/A9, hsCRP, NT pro-BNP levels vs co, respectively. S100A8/A9 levels correlated with the disease activity, displayed by EMB counts of inflammatory cells (CD3: r=0.464, p=0.0128, XY pairs=28, LFA-1: r=0.551, p=0.002, XY pairs=28, Mac-1: r=0.418, p=0.026, XY pairs=28), and the EF (r=0.545, p=0.0027, XY pairs=28). MC ≤30 d patients showed an association between serum S100A8/A9 levels and EMB S100A8 (r=0.482, p=0.060, XY pairs=16), S100A9 (r=0.441, p=0.088, XY pairs=16), nucleotide-binding oligomerization domain containing-protein 2 (NOD2, r=0.55, p=0.035, XY=15), and Nod-like receptor family, pyrin domain-containing 3 protein (NLRP3, r=0.52, p=0.048, XY=15) mRNA levels. Also EMB S100A8 and S100A9 mRNA levels showed a significant correlation with EMB NOD2 and NLRP3 mRNA expression. Serum S100A8/A9 levels were increased by 3.0-fold (p<0.0001) and 1.8-fold (p=0.0005) in DCMi (n=112), and DCM (n=58) patients vs co, respectively. However, the S100A8/A9 levels of DCMi and DCM patients were 1.5-fold (p=0.07) and 2.5-fold (p<0.0001) lower vs MC ≤30 d patients. ROC analyses of S100A8/A9 in MC ≤30 d provided a cut-off of 583 ng/ml with a specificity=92%, sensitivity=86.2%, a PPV=92.6%, a NPV=85.2%, and an AUC=0.934 vs co, which was superior to hsCRP (cut-off=5 mg/l): specificity=95.8%, sensitivity=58.6%, a PPV=94.4%, a NPV=65.7%, AUC=0.885. In the subgroup, S100A8/A9 levels decreased after heart failure medication (T1: 2454±1931 ng/ml vs T2: 934.4±552 ng/ml; p=0.002), reflected by a decrease of EMB inflammatory cells. Baseline serum S100A8/A9 levels predicted the change in EMB CD3 and Mac-1. Conclusions These results support an additional value for S100A8/A9 serum levels as a potential diagnostic biomarker and as a tool to monitor the course of the disease. We provide first evidence that S100A8/A9 is connected to the NOD2-NLRP3 pathway in these patients. Acknowledgement/Funding Novartis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Chaloupka ◽  
J Krejci ◽  
H Poloczkova ◽  
P Hude ◽  
E Ozabalova ◽  
...  

Abstract Background The aetiology of recent-onset dilated cardiomyopathy (RODCM) includes inflammatory, genetic, toxic and metabolic causes. Delineating the role of inflammation on the genetic background could improve risk stratification. Purpose We aimed to ascertain the role of inflammation evaluated by serum CRP immunohistochemical and PCR analysis of endomyocardial biopsy (EMB) in conjunction with genetic testing in left ventricular reverse remodelling (LVRR) in 12-month follow-up. Methods 83 RODCM patients enrolled in this prospective observational study underwent 12-month echocardiographic follow up whole-exome sequencing, and EMB. Presence of cardiotropic viruses was determined by PCR analysis of the EMB samples. Inflammation was defined according to TIMIC immunohistochemical criteria as the presence of &gt;7 CD3+ lymphocytes/mm2 and/or &gt;14 infiltrating leukocytes (LCA+ cells/mm2). LVRR was defined as an absolute increase in LV ejection fraction &gt; +10% and a relative decrease of LV end-diastolic diameter &gt;−10% at 12 months. Results LVRR occurred in 28 (34%) of all cases. PCR analysis uncovered cardiotropic viruses in 55 (66%) patients, with highest prevalence of parvovirus B19 (47%). (Figure 1) EMB analysis detected inflammation in 28 (34%) cases and inflammation significantly positively predicted LVRR (P=0.019). Sequencing identified disease-related gene variants (ACMG class 3–5) in 45 (54%) patients. Carriers of non-titin gene variants showed a lowest probability of 12-month LVRR (19%) P=0.041. Combination of genetic findings and inflammation did not improve the prediction of LVRR in 12 months. (Table 1) Conclusion Both myocardial inflammation and disease-causing variants can be identified in a large proportion of RODCM cases. Prognostic value of CRP and virus detection is low. Non-titin disease-related variants carriers of are less likely to reach LVRR. In contrast, myocardial inflammation detected by EMB predicts favourable remodelling in 12 months. Figure 1 Funding Acknowledgement Type of funding source: None


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Francesco Santoro ◽  
Tecla Zimotti ◽  
Adriana Mallardi ◽  
Alessandra Leopizzi ◽  
Enrica Vitale ◽  
...  

AbstractTakotsubo syndrome (TTS) is an acute heart failure syndrome with significant rates of in and out-of-hospital mayor cardiac adverse events (MACE). To evaluate the possible role of neoplastic biomarkers [CA-15.3, CA-19.9 and Carcinoembryonic Antigen (CEA)] as prognostic marker at short- and long-term follow-up in subjects with TTS. Ninety consecutive subjects with TTS were enrolled and followed for a median of 3 years. Circulating levels of CA-15.3, CA-19.9 and CEA were evaluated at admission, after 72 h and at discharge. Incidence of MACE during hospitalization and follow-up were recorded. Forty-three (46%) patients experienced MACE during hospitalization. These patients had increased admission levels of CEA (4.3 ± 6.2 vs. 2.2 ± 1.5 ng/mL, p = 0.03). CEA levels were higher in subjects with in-hospital MACE. At long term follow-up, CEA and CA-19.9 levels were associated with increased risk of death (log rank p < 0.01, HR = 5.3, 95% CI 1.9–14.8, HR = 7.8 95% CI 2.4–25.1, respectively, p < 0.01). At multivariable analysis levels higher than median of CEA, CA-19.9 or both were independent predictors of death at long term (Log-Rank p < 0.01). Having both CEA and CA-19.9 levels above median (> 2 ng/mL, > 8 UI/mL respectively) was associated with an increased risk of mortality of 11.8 (95% CI 2.6–52.5, p = 0.001) at follow up. Increased CEA and CA-19.9 serum levels are associated with higher risk of death at long-term follow up in patients with TTS. CEA serum levels are correlated with in-hospital MACE.


2020 ◽  
Vol 6 (3) ◽  
pp. 89-91
Author(s):  
Christina Hari Nawangsih Prihharsanti ◽  
Muhamad Rizqi Setyarto ◽  
Dion Firli Bramantyo

Background: Keloid is a benign growth of connective tissue. There are several risk factors that play a role in keloid growth. Excision surgery is one of the modalities in the treatment of keloids. However, excision surgery alone has a recurrence rate of 45-100%.Case: Male, 37 years old, with complaints arising from a keloid lesions in the left earlobe since three years ago with a history of previous injuries. The lesions is then operated on but always grows back postoperatively. The number of surgeries that have been carried out three times with further treatment in the form of corticosteroid injection. However, keloid still recurrence. Finally it was decided to undergo treatment with surgery followed by radiotherapy within a period of no more than 24 hours postoperatively. Follow-up after six months gave good results without recurrence.Discussion: Keloid has a high recurrence rate after excision surgery. Surgery followed by radiotherapy has a low recurrence rate compared to surgery or surgery followed by administration of corticosteroid injections. Radiotherapy as adjuvant therapy for postoperative keloid excision has the role of sterilizing the connective tissue stem cell active fibroblasts and acute inflammatory cells that grow in the early postoperative period. A study states that administration of postoperative radiation with electrons in keloids in the earlobe at a dose of 15 Gy in three fractions gives a low recurrence rate and a low risk of side effects in the surrounding soft tissue. 


2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Francesco Drago ◽  
Giulia Ciccarese ◽  
Francesco Broccolo ◽  
Massimo Ghio ◽  
Paola Contini ◽  
...  

Introduction. Pityriasis rosea (PR) is an exanthematous disease related to human herpesvirus- (HHV-) 6/7 reactivation. The network of mediators involved in recruiting the infiltrating inflammatory cells has never been studied.Object. To investigate the levels of serum cytokines, growth factors, and chemokines in PR and healthy controls in order to elucidate the PR pathogenesis.Materials and Methods. Interleukin- (IL-) 1, IL-6, IL-17, interferon- (IFN-)γ, tumor necrosis factor- (TNF-)α, vascular endothelial growth factor (VEGF), granulocyte colony stimulating factor (G-CSF), and chemokines, CXCL8 (IL-8) and CXCL10 (IP-10), were measured simultaneously by a multiplex assay in early acute PR patients’ sera and healthy controls. Subsequently, sera from PR patients were analysed at 3 different times (0, 15, and 30 days).Results and discussion. Serum levels of IL-17, IFN-γ, VEGF, and IP-10 resulted to be upregulated in PR patients compared to controls. IL-17 has a key role in host defense against pathogens stimulating the release of proinflammatory cytokines/chemokines. IFN-γhas a direct antiviral activity promoting NK cells and virus specific T cells cytotoxicity. VEGF stimulates vasculogenesis and angiogenesis. IP-10 can induce chemotaxis, apoptosis, cell growth, and angiogenesis.Conclusions. Our findings suggest that these inflammatory mediators may modulate PR pathogenesis in synergistic manner.


1992 ◽  
Vol 7 (3) ◽  
pp. 167-170 ◽  
Author(s):  
E. Seregni ◽  
E. Bombardieri ◽  
A. Bogni ◽  
F. Crippa ◽  
E. de Jager ◽  
...  

CEA determination has attained an important role in the clinical management of patients with tumors of the colorectal tract. In this paper the experience of the Istituto Tumori of Milan is reviewed and the results are discussed. Three hundred and thirty-six patients were followed after curative resection of colorectal carcinoma. The follow-up period was 15 years, from January 1975 to December 1990 (global follow-up 1358 years). In the course of follow-up 136 patients developed recurrent disease. The number of CEA determinations for each patient ranged from 1 to 37 (mean 8, total 3330). CEA levels of presurgical patients were related to the clinical stage. Among patients who developed recurrences 61% showed an increase in CEA serum levels. In 200 patients with a negative follow-up we observed only 15 cases of false-positive results.


Blood ◽  
1992 ◽  
Vol 80 (1) ◽  
pp. 194-202 ◽  
Author(s):  
E Shacter ◽  
GK Arzadon ◽  
J Williams

Abstract Intraperitoneal (i.p.) injection of a mineral oil such as pristane induces a chronic inflammatory response in mice. This is characterized by a large influx of macrophages and other inflammatory cells into the peritoneal cavity for months after injection of the oil. By using the B9 cell bioassay, it was found that injection of pristane caused a marked and prolonged elevation of interleukin-6 (IL-6) levels in the peritoneal cavities of the mice. IL-6 was undetectable (less than 15 U/mL) in the peritoneal fluids of unprimed mice and during the first week after injecting pristane. From 4 to 20 weeks, the concentration of IL-6 increased to an apparent plateau with concentrations ranging from 200 to 2,000 U/mL. Increasing the dose of pristane did not substantially increase the peritoneal levels of IL-6 established at 20 weeks after pristane treatment. At later times (by day 250), the level decreased to 263 +/- 217 U/mL. However, mice that developed plasma cell tumors around day 300 showed high levels of IL-6 in the ascites fluid (650 to 2,400 U/mL). Serum levels of IL-6 were also elevated in pristane-primed mice but were substantially lower than those found in the peritoneal cavity. Chronic administration of the nonsteroidal anti- inflammatory drug indomethacin decreased the levels of IL-6 by 75% to 80%. Experiments performed in vitro showed that pristane-elicited macrophages secreted low levels of IL-6 constitutively and high levels of IL-6 in the presence of lipopolysaccharide. Both IL-6 and prostaglandin E2 production were inhibited by addition of indomethacin to macrophage cultures in vitro. Treatment of mice with pristane may provide a model system for studying the inflammatory pathways that control IL-6 levels in vivo. The relevance of these results to elucidation of the role of IL-6 in plasma cell tumorigenesis is discussed.


Cardiology ◽  
2019 ◽  
Vol 142 (1) ◽  
pp. 7-13
Author(s):  
Gabriele Di Gesaro ◽  
Giuseppa Caccamo ◽  
Diego Bellavia ◽  
Calogero Falletta ◽  
Chiara Minà ◽  
...  

Heart failure (HF) with reduced ejection fraction (HFrEF) has a well-known epidemic relevance in western countries. It affects up to 1–2% of patients > 60 years and reaches a prevalence of 12% in octogenarian patients. The role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitive troponin I (hsTnI) in risk stratifying HFrEF patients has been established; at present, evidence is exclusively based on one-time assessments, and the prognostic usefulness of serial biochemical assessments in this population still remains to be determined. We prospectively recruited 226 patients with chronic HFrEF, who were all referred to the Outpatient Clinic of our institution from November 2011 through September 2014. Recruited patients underwent full clinical evaluation with complete history taking and physical examination as well as ECG, biochemical assessment, and standard 2D and Doppler flow echocardiography at the first visit, and then again at each visit during the follow-up, repeated every 6 months. During the follow-up period, cardiovascular (CV) death, which occurred in 16 patients, was not statistically correlated with gender (p = 0.088) or age (p = 0.1636); however, baseline serum levels of NT-proBNP, which were 3 times higher in deceased patients, were significantly related to this clinical event (p = 0.001). We found that NT-proBNP represents a strong and independent predictor of CV outcome; serum levels of hsTnI, which are significantly related to an increased risk of hospitalization, cannot properly predict the relative risk of CV mortality. Our study validates, eventually, the multimarker strategy, which reflects the complexity of the HF pathophysiology.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Foteinos-Ioannis D. Dimitrakopoulos ◽  
Anna G. Antonacopoulou ◽  
Anastasia E. Kottorou ◽  
Nikolaos Panagopoulos ◽  
Fotini Kalofonou ◽  
...  

Abstract A growing number of studies has shed light on the role of the NF-κΒ in non-small-cell lung cancer (NSCLC). To address the significance of major effectors of the NF-κΒ alternative pathway, we investigated the relationship between NF-κΒ2, RelB, NIK and Bcl3 expression (mRNA and protein) and the clinical outcome of NSCLC patients. NF-κΒ2, RelB, NIK and Bcl3 protein expression levels were assessed by immunohistochemistry in tissue samples from 151 NSCLC patients who had curative resection. mRNA levels were also evaluated in 69 patients using quantitative real-time PCR. Although all studied proteins were overexpressed in NSCLC (P < 0.001 for all), only RelB mRNA levels were strongly increased in cancerous specimens compared to tumor-adjacent non-neoplastic tissues (P = 0.009). Moreover, NF-κB2, RelB and Bcl3 expression was associated with overall survival (OS). In particular, cytoplasmic and mRNA expression of RelB was related to 5-year OS (P = 0.014 and P = 0.006, respectively). Multivariate analysis also showed that Bcl3 expression (nuclear and cytoplasmic) was associated with increased 5-year OS (P = 0.002 and P = 0.036, respectively). In addition, higher Bcl3 mRNA levels were associated with inferior OS in stages I & II and improved OS in stages III and IV after 5-year follow-up (P = 0.004 and P = 0.001, respectively). Furthermore, stage I patients with lower NF-κB2 mRNA levels had better 5-year survival in univariate and multivariate analysis (P = 0.031 and P = 0.028, respectively). Interestingly, RelB expression (cytoplasmic and mRNA) was inversely associated with relapse rates (P = 0.027 and P = 0.015, respectively), while low NIK cytoplasmic expression was associated with lower relapse rates (P = 0.019). Cytoplasmic NIK expression as well as NF-κB2/ Bcl3 detection was associated with lymph node infiltration (P = 0.039 and P = 0.014, respectively). The present study confirms the deregulation of the NF-κB alternative pathway in NSCLC and also demonstrates the importance of this pathway in prognosis, recurrence and infiltration of regional lymph nodes.


2019 ◽  
Vol 47 (7) ◽  
pp. 3332-3343
Author(s):  
Tana Gegen ◽  
Yanxia Zhu ◽  
Qinnuan Sun ◽  
Benxiang Hou

Objective This study investigated interleukin (IL)-33 expression in chronic apical periodontitis (CAP) lesions and possible relationships with receptor activator of nuclear factor κ-Β ligand (RANKL) and osteoprotegerin (OPG). Methods Inflammatory cell infiltration in CAP lesions and samples of healthy periapical tissue (n = 30 each) was evaluated by hematoxylin and eosin staining. IL-33, RANKL, and OPG expression levels were assessed by immunohistochemistry and real-time PCR. In CAP lesions alone, relationships between mRNA level of IL-33 and mRNA levels of both RANKL and OPG were analyzed by Spearman rank correlation. Results Histological analysis revealed a large number of inflammatory cells in CAP lesions, and immunohistochemistry revealed IL-33-positive cells. There were more IL-33- and RANKL-positive cells in CAP lesions than in healthy periapical tissue, whereas there were fewer OPG-positive cells in CAP lesions than in healthy periapical tissue. In CAP lesions alone, IL-33 mRNA level was negatively correlated with mRNA level of RANKL and positively correlated with mRNA level of OPG. Conclusions IL-33 is highly expressed in CAP lesions, where it is negatively correlated with RANKL and positively correlated with OPG expression. IL-33 may protect against bone resorption via RANKL suppression and OPG induction, and constitutes a potential target for CAP treatment.


2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Maria Maldonado ◽  
Juan Santacruz ◽  
Sara Afonso ◽  
Teresa Olea ◽  
Lina León ◽  
...  

Abstract Background and Aims The evolution of renal disease and its global impairment in patients diagnosed with ANCA-associated vasculitis (AAV) has been related to baseline C3 serum levels in several studies. The objective of this study is to evaluate in patients diagnosed with AAV and renal impairment the association between baseline serum C3 levels and the clinical outcomes. Method Our cohort included 56 patients diagnosed with AAV diagnosed from January 1986 to January 2018 in Hospital La Paz. According to C3 serum level measurements, patients were divided into low and normal concentration groups at onset. Histological, clinical and laboratory data were compared between groups. Results Among the 56 AAV cases, 58.9% were women and 96.5% Caucasian with an age mean and SD of 61.08 ± 15.11 years. Mean follow-up was 10.03 ± 7.02 years. MPO ANCAs were found in 69.8% of the patients and PR3 ANCAs in 22.64%. AAV diagnosis was earlier in PR3 AVV (47.59 ± 13.62 years) compared to MPO AVV (65.66 ± 11.53 years) (p=0.001). At diagnosis, baseline serum C3 was measured in 53 patients (94.6%) being lower in MPO AAV (112.79 ± 33.98) vs PR3 AAV (132.41 ± 20.69) (p=0.023). Low C3 was way more frequent in patients with higher percentage of glomeruli showing &gt;50% of sclerosis (100% vs 32.5%) (p=0.007). Staphylococcus aureus nasal carriers were more frequent in patients with low C3 (27.2% vs 3.1%, p=0.045). 15 patients (27.77%) died during follow-up and patient survival median was 21.75 years (IC 95%: 15.41-28.08). 17 patients (31.48%) reached end-stage renal disease (ESRD) during follow-up and renal survival median was 20.1 years (IC 95%: 19.27-21.05). There were no statistical differences in the levels of baseline serum C3 according to sex, relapses, extrarenal manifestations, treatment, malignancy, cardiovascular events and time to ESRD or death. Conclusion Baseline serum C3 was lower in MPO AV, in Staphylococcus aureus nasal carriers and higher severity histological damage (glomerular sclerosis &gt;50%). Despite previous evidence, in our cohort, time to ESRD and time to death seemed not to be affected.


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