IL-33/IL-33R in various types of carotid artery atherosclerotic lesions.

OBJECTIVE: Inflammation plays a crucial role in the progression of atherosclerotic plaques. The aim of the study was to investigate serum levels and expression of Interleukin-33 (IL-33) and ST2 receptor in atherosclerotic plaques and to analyze correlation with the type of the carotid plaques in patients with carotid disease. METHODS: This study included 191 consecutive patients submitted for carotid endarterectomy (CEA). Preoperative serum levels of IL-33 and soluble ST2 (sST2) were measured. Atherosclerotic plaques obtained during surgery were initially histologically classified and immunohistochemical analyzes of IL-33, IL-33R, CD68 and alpha-SMA expression was performed. Ultrasound assessment of the level of carotid stenosis in each patient was performed prior to carotid surgery. Demographic and clinical data such as gender, age, smoking status, blood pressure, glycaemia, hemoglobin and creatinine levels, and comorbidities were collected and the comparisons between variables were statistically evaluated. RESULTS: Serum levels of IL-33 (35.86 ±â€¯7.93 pg/ml vs.12.29 ±â€¯1.8 pg/ml, p < 0.05) and sST2 (183 ±â€¯8.03 pg/ml vs. 122.31 ±â€¯15.89 pg/ml, p < 0.05) were significantly higher in the group of CEA patients vs. healthy subjects. We demonstrated abundant tissue expression of IL-33 and ST2 in atherosclerotic carotid artery lesions. The levels of IL-33 and IL-33R expression were significantly higher in vulnerable plaques and significantly correlated with the degree of inflammatory cells infiltration in these plaques (R = 0.579, p = 0.049). Immunohistochemical analysis also revealed that cells responsible for IL-33 expression are not only mononuclear cells confined to inflammatory atherosclerotic lesions, but also smooth muscle cells which gained phenotypic characteristics of foam cells and were loaded with lipid droplets. CONCLUSION: The obtained results confirm the importance of IL-33/ST2 axis in the process of atherosclerosis, and indicate its ambiguous function in immune response, whether as proinflammatory cytokine in advanced atherosclerotic lesions, or as profibrotic, in early lesions.

Preoperative Midregional Pro-Adrenomedullin and High-Sensitivity Troponin T Predict Perioperative Cardiovascular Events in Noncardiac Surgery.

OBJECTIVE: We evaluated the utility of preoperative midregional (MR) pro-adrenomedullin (proADM) and cardiac troponin T (TnT) for improved detection of patients at high risk for perioperative cardiac events and mortality after major noncardiac surgery. SUBJECTS AND METHODS: This prospective, single-center, observational study enrolled 79 patients undergoing major noncardiac surgery. After initial clinical assessment (clinical history, physical examination, echocardiogram, blood tests, and chest X-ray), MR-proADM and high-sensitivity TnT (hsTnT) were measured within 48 h prior to surgery by immunoluminometric and electrochemiluminescence immunoassay. Patients were followed by the consulting physician until discharge or up to 14 days in the hospital after surgery. Perioperative cardiac events included myocardial infarction and development or aggravation of congestive heart failure. Data were compared between patients who developed target events and event-free patients. RESULTS: Within 14 days of monitoring, 14 patients (17.72%) developed target events: 9 (11.39%) died and 5 (6.33%) developed cardiovascular events. The average age of the patients was 71.29 ± 6.62 years (range: 55-87). Sex, age, and hsTnT did not significantly differ between groups. MR- proADM concentration was higher in deceased patients (p = 0.01). The upper quartile of MR-proADM was associated with a fatal outcome (66.7 vs. 20.0%, p < 0.01) and with cardiovascular events (64.3 vs. 16.9%, p < 0.01). MR-proADM above the cutoff value (≥0.85) was associated with a fatal outcome (88.9 vs. 20.0%, p < 0.01) and cardiovascular events (71.4 vs. 28.6%, p < 0.01); this association was not observed for hsTnT. CONCLUSION: Preoperative measurement of MR-proADM provides useful information for perioperative cardiac events in high-risk patients scheduled for noncardiac surgery.

Scoring system to predict early carotid restenosis after eversion endarterectomy by analysis of inflammatory markers.

BACKGROUND: Inflammation is one of the mechanisms that leads to carotid restenosis (CR). The aim of this study was to examine the influence of increased values of inflammation markers (high-sensitivity C-reactive protein [hs-CRP], C3 complement, and fibrinogen) on CR development after eversion carotid endarterectomy (CEA). METHODS: A consecutive 300 patients were included in the study, in which eversion CEA was performed between March 1 and August 1, 2010. Demographic data, atherosclerosis risk factors, comorbidities, and ultrasound plaque characteristics were listed in relation to potential risk factors for CR. Serum concentrations of hs-CRP, fibrinogen, and C3 complement were taken just before surgery (6 hours); 48 hours after CEA; and during regular checkups at 1 month, 6 months, 1 year, and 2 years. An "inflammatory score" was also created, which consisted of six predictive values of inflammatory markers (hs-CRP just before and just after CEA, fibrinogen just before and just after CEA, and C3 complement just before and just after CEA) with a maximum score of 6 and a minimum score of 0. At every follow-up visit to the outpatient clinic, ultrasound assessment of the carotid artery for restenosis was done. RESULTS: Our results showed an increased risk of early CR within 1 year in patients with increased hs-CRP before CEA (6 hours) and increased fibrinogen 48 hours after surgery and in patients not taking aspirin after CEA. Sex was determined to be an independent predictor of CR, with female patients having a higher risk (P = .002). Male patients taking aspirin with an inflammatory score >2 had an increased risk for restenosis compared with male patients with inflammatory score <2. Not taking aspirin after CEA and fibrinogen (48 hours) were the strongest predictors, and the Fisher equation incorporating these predictors was used to predict CR. A computer program was created to calculate whether the patient was at high or low risk for CR by selecting whether the patient was taking aspirin (yes or no) and whether fibrinogen was increased 48 hours after CEA (yes or no) and to display the recommended therapeutic algorithm consisting of aspirin, clopidogrel, cilostazol, and statins. CONCLUSIONS: Increased hs-CRP before CEA, increased fibrinogen 48 hours after CEA, and not taking aspirin were the main predictors of early CR. With the clinical implementation of the Fisher equation, it is possible to identify patients at high risk for early CR and to apply an aggressive therapeutic algorithm, finally leading to a decreased CR rate.

Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis.

BACKGROUND: In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings. METHODS: Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects. FINDINGS: We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 [9%] deaths in 3336 procalcitonin-guided patients vs 336 [10%] in 3372 controls; adjusted odds ratio [OR] 0·83 [95% CI 0·70 to 0·99], p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (pinteractions>0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days [95% CI -2·71 to -2·15], p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 [95% CI 0·57 to 0·82], p<0·0001). INTERPRETATION: Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance. FUNDING: National Institute for Health Research.

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections.

BACKGROUND: Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT-guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta-analysis first published in 2012 designed to look at the safety of PCT-guided antibiotic stewardship. OBJECTIVES: The aim of this systematic review based on individual participant data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017. SELECTION CRITERIA: We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT-guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment. DATA COLLECTION AND ANALYSIS: Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic-related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed-effect model. The different trials were added as random-effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta-analysis. MAIN RESULTS: From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects.Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results. AUTHORS' CONCLUSIONS: This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.

Copeptin Levels Do Not Correlate With Cross-Clamping Time in Patients Undergoing Carotid Endarterectomy Under General Anesthesia.

Copeptin is a sensitive and more stable surrogate marker for arginine vasopressin. In this study, we evaluated copeptin levels in carotid endarterectomy (CEA) patients, perioperatively, to determine whether copeptin levels can be related to carotid artery cross clamping (CC) time and to postoperative neurological outcomes. Copeptin, interleukin 6, C-reactive protein, cortisol, and brain natriuretic peptide were measured preoperatively (T1) and 3 hours postoperatively (T3) as well as intraoperatively (T2). We recruited 77 patients. Values of copeptin rose gradually over the observed times: T1 = 7.9 (6.4-9.6), T2 = 12.6 (9.3-16.8), and T3 = 72.3 (49.1-111.2) pmol/L. There was a significant difference for repeated measurement ( P = .000, P = .000, and P = .000). Duration of carotid artery CC during CEA does not affect postoperative copeptin level (CC ≤ 13 minutes: 106.8 ± 93.6 pmol/L, CC > 13 minutes: 96.7 ± 89.1 pmol/L; P = .634). Preoperative copeptin level was significantly higher in patients with ulcerated plaque morphology. Activation of the stress axis in patients undergoing CEA results in copeptin elevation. Duration of CC during CEA does not affect postoperative copeptin levels.

In vivo effects of 17ß-estradiol on cardiac Na(+)/K(+)-ATPase expression and activity in rat heart.

In this study the in vivo effects of estradiol in regulating Na(+)/K(+)-ATPase function in rat heart was studied. Adult male Wistar rats were treated with estradiol (40µg/kg, i.p.) and after 24h the animals were sacrificed and the heart excised. Following estradiol administration, cardiac Na(+)/K(+)-ATPase activity, expression of the α1 subunit, and phosphorylation of the α1 subunit were significantly increased. These animals also had significantly decreased levels of digoxin-like immunoreactive factor(s). Na(+) levels were also significantly reduced but to a level that was still within the normal physiological range, highlighting the ability of the Na(+)/K(+)-ATPase to balance the ionic composition following treatment with estradiol. Estradiol treated rats also showed increased phosphorylation of protein kinase B (Akt), and extracellular-signal-regulated kinase 1/2 (ERK1/2). We therefore suggest a role for Akt and/or ERK1/2 in estradiol-mediated regulation of cardiac Na(+)/K(+)-ATPase expression and activity in rat heart.

Copeptin level after carotid endarterectomy and perioperative stroke.

We evaluated the prognostic value of copeptin levels in a cohort of surgical patients after elective carotid endarterectomy (CEA). Twenty-one patients with perioperative stroke were prospectively recruited. The diagnosis of cerebrovascular event (CVE) was confirmed by computed tomography. Additionally, 21 patients with CEA without any complications (control patients) were enrolled. Blood samples were taken within 3 hours of the symptom onset. Circulating copeptin level was significantly higher in patients with CVE when compared to controls (P = .025), and significantly higher in nonsurvivors than in survivors (P = .030) after CVE. Plasma concentrations of interleukin 6 (IL-6) and C-reactive protein (CRP) were also elevated in patients with CVE (IL-6: P = .043; CRP: P = .002). We conclude that the activation of the stress axis in patients with CEA results with copeptin elevation, but more so in patients with perioperative stroke. Copeptin may be a helpful biomarker for stroke risk assessment in patients after CEA.

Inverse production of IL-6 and IL-10 by abdominal aortic aneurysm explant tissues in culture.

BACKGROUND: Abdominal aortic aneurysm is considered an atherosclerosis-related disease, but the mechanisms underlying abdominal aortic aneurysm remain poorly defined. Despite the large number of cytokines identified in an aneurysm sample, the relative importance of particular cytokines in aneurysm formation is unknown. We have studied the production of interleukin-6 and interleukin-10 cytokines in plasma and cultures of abdominal aortic aneurysm explant samples obtained from patients subjected to elective surgery and their correlation with cellular composition. MATERIALS AND METHODS: Inflammatory cells from the abdominal aortic aneurysm samples were phenotypically characterized using specific monoclonal antibodies (anti-CD3, -CD4, -CD8, -CD19, -CD38, -CD68, -HLA-DR) by means of immunocytochemistry staining. Production of interleukin-6 and interleukin-10 in culture supernatants of abdominal aortic aneurysm explant samples expanded in vitro for 24 h was measured by enzyme-linked immunosorbent assay. RESULTS: We showed that the levels of interleukin-6 and interleukin-10 in supernatants of abdominal aortic aneurysm sample cultures were higher by 73 and 86 times compared to their levels in plasma, respectively. In individual abdominal aortic aneurysm explant cultures, a negative correlation between interleukin-6 and interleukin-10 production was observed. Such inverse correlation was not detected in plasma. Based on these results, we divided abdominal aortic aneurysm into two cytokine-producing groups and showed that the interleukin-6(hi)/interleukin-10(lo) group contained higher percentages of granulocytes, HLA-DR(+), and CD68(+) cells but lower percentages of lymphocytes and plasma cells compared to the interleukin-6(lo)/interleukin-10(hi) group. Exogenously added interleukin-10 suppresses the production of interleukin-6 by abdominal aortic aneurysm explants. CONCLUSION: These results suggest that interleukin-6 and interleukin-10 may have a different role in the pathogenesis of abdominal aortic aneurysm.

Steroids and statins: an old and a new anti-inflammatory strategy compared.

OBJECTIVES: This study compared the anti-inflammatory effects of methylprednisolone (MP) and atorvastatin and analysed their influences on clinical variables in patients undergoing coronary revascularization. METHODS: Ninety patients with compromised left ventricular ejection fraction (≤30%) undergoing elective coronary surgery were equally randomized to one of three groups: statin group, treatment with atorvastatin (20 mg/day) 3 weeks before surgery; methylprednisolone group, a single shot of methylpredniosolone (10mg/kg); and control group. RESULTS: Postoperative IL-6 was higher in the control group when compared to the methylprednisolone and statin groups (p<0.01). IL-6 was higher in the statin-treated patients (p<0.05 versus methylprednisolone). Administration of methylprednisolone as well as statin treatment increased postoperative cardiac index, left ventricular stroke work index, decreased postoperative atrial fibrilation rate and reduced ICU stay (p<0.05 versus control). The number of patients requiring inotropic support was lower in the methylprednisolone group when compared with the other two groups (p<0.01). Tracheal intubation time was reduced in patients who received methylprednisolone (p<0.01 versus control). CONCLUSIONS: Preoperative administration of either methylprednisolone or atorvastatin reduced pro-inflammatory cytokine release, improved haemodynamics, decreased postoperative atrial fibrilation rate and reduced ICU stay in patients with significantly impaired cardiac function undergoing coronary revascularization. Treatment with methylprednisolone was associated with less inotropic support requirements and reduced mechanical ventilation time.

Procalcitonin-based therapeutic strategy to reduce antibiotic use in patients after cardiac surgery: a randomized controlled trial.

INTRODUCTION: Procalcitonin (PCT) is a thyroid gland prohormone, and its serum concentration is elevated in systemic bacterial infections. The diagnostic cut-off value of PCT in patients early after cardiac surgery remains unclear. OBJECTIVE: We investigated whether procalcitonin-guidance could reduce antibiotic usage safely. METHODS: The prospective study included 205 patients who underwent open heart surgery. The patients were randomly assigned for procalcitonin-guided antibiotic treatment (PCT-group; n = 102) or standard care (standard group; n = 103). On the basis of serum procalcitonin concentrations, usage of antibiotics was encouraged (PCT > or = 0.5 ng/mL) or discouraged. RESULTS: A relative risk of antibiotic exposure in the standard group compared with the PCT-group was 3.81 (95% CI = 2.03-7.17; p < 0.0001). The mean cost of antibiotics per patient in procalcitonin group was Euro 193.3 +/- 636.6 vs. Euro 372.1 +/- 841.1 (p = 0.206) in the standard group, while the mean cost per hospital day was Euro 8.0 +/- 18.4 vs. Euro 17.8 +/- 36.3 (p = 0.028). We found that non-infectious complications occurred in 40/102 vs. 41/103 (p = 0.592) while infections appeared in 5/102 vs. 22/103 (p = 0.001) cases. A statistically significant difference was observed in the treatment of urinary infections between PCT-group and standard group; 1/102 vs. 9/103 (p = 0.016). In the PCT-group, the ICU stay was 5.74 +/- 11.49 days and in the standard group 6.97 +/- 11.61 (p = 0.812). The hospital stay was 12.08 +/- 11.28 vs. 12.93 +/- 10.73 (p > 0.05) days, respectively. Mortality rates were equal in both groups of patients (p = 0.537). CONCLUSION: Procalcitonin-guided antibiotic treatment is safe and can significantly reduce the cost of postoperative care. Additionally, the antibiotic use during immediate postoperative course should be timely controlled and limited to documented bacterial infections.