Elevated plasma concentration of IP-10 in patients with type 2 diabetes mellitus

Recent studies have shown the important role of proinflammatory cytokines and chemokines in the pathogenesis of atherosclerosis and diabetes mellitus(DM). Interferon-inducible protein of 10 kD (IP-10/ CXCL10), a member of the C-X-C chemokine superfamily, is a potent chemoattractant for activated T lymphocytes and is reported to be involved in various disease states including atheroma plaque formation, inhibition of tumor angiogenesis and maintenance of podocyte function. However, the involvement of IP-10 in type 2 DM, especially in its vascular and renal complications, is largely unknown. To elucidate the etiopathological role of IP-10 in type 2 DM, we measured the concentrations of IP-10 together with IFN-gamma, TNF-alpha, IL-18, IL-6 and MCP-1 in plasma samples from 103 type 2 DM patients with various degrees of nephropathy. A significant difference in the plasma level of IP-10 was observed between the patients and the control subjects (183.3+/-12.5 pg/m/ vs 65.6+/-9.3 pg/ml, p<0.05). IP-10 correlated IL-18, IL-6, TNF-alpha and MCP-1. The IFN-gamma level was below the detectable range. IP-10 levels became higher with the progression of nephropathy : IP-10 levels were 148.9+/-14.5, 174.2+/-17.2 and 231.9+/-31.3 pg/m/ in patients with an urinary albumin creatinine ratio of <30, 30 to 300 and >300 microg/mg Cr, respectively. Similarly, IL-18, IL-6, MCP-1 and TNF-alpha levels in patients with overt albuminuria were significantly higher as compared with those without albuminuria (IL-18, 367.3 45.6 vs 203.5+/-17.6 pg/ml; IL-6, 1.61+/-0.26 vs 0.87+/-0.13 pg/ml; TNF-alpha, 1.83+/-0.48 vs 0.61+/-0.07 pg/ml; p<0.05, respectively) in consistent with previous reports. These results suggested that IP-10 may have an etiopathogenic role in type2 DM and diabetic nephropathy as one of the downstream effectors of proinflammatory cytokines.     

Tumor necrosis factor-alpha serum activity during treatment of acute decompensation of cachectic and non-cachectic patients with advanced congestive heart failure

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that produces left ventricular dysfunction and a negative inotropic effect in cardiac tissue when overexpressed in human subjects. Previous studies have shown that levels of circulating TNF-alpha are elevated in patients with advanced congestive heart failure (CHF) and especially in those with cardiac cachexia. To clarify the potential role of TNF-alpha in the unstable state of decompensated advanced CHF, we investigated the TNF-alpha serum activity in 25 cachectic and 22 non-cachectic CHF patients (New York Heart Association, NYHA functional classes III or IV), who were treated with intravenous diuretics and positive inotropic agents for acute decompensation of the disease, during a 5-day hospitalization period, as well as in 15 age-matched healthy control subjects. Cachectic CHF patients needed higher dosages of inotropic agents than non-cachectic patients and the determination of TNF-alpha serum concentrations in this patient group showed high levels of TNF-alpha at hospital admission (18.3 +/- 3.2 pg/ml) and a transient increase in circulating TNF-alpha during the treatment period with the highest levels on the 2nd day of hospitalization (32.5 +/- 7.1 pg/ml). The TNF-alpha serum levels were low in non-cachectic CHF patients and healthy controls on the 1st day (4.0 +/- 0.9 and 3.7 +/- 0.6 pg/ml, respectively) and did not change substantially during the course of the study. The present results show that TNF-alpha serum activity is transiently increased during the treatment of decompensated cachectic CHF patients only and may be related to the clinical instability and the consequent therapeutic interventions in this category of CHF patients.     

Interleukin-6 and B-type natriuretic peptide are independent predictors for worsening of heart failure in patients with progressive congestive heart failure.

BACKGROUND: Neurohormones and cytokines have been associated with poor prognosis in patients with congestive heart failure. However, direct comparisons between them are rare and the best predictor for worsening of heart failure remains to be elucidated. The aim of the study was to identify independent predictors for worsening of heart failure. METHODS: We studied 100 patients with congestive heart failure (LVEF 相似文献   

Prognostic value of serum cytokines in patients with congestive heart failure.

BACKGROUND: Increased levels of circulating cytokines have been previously reported in patients with congestive heart failure; however, whether they have prognostic implications is still unknown. The aim of this study was to assess the prognostic implications of elevated serum cytokines in patients with heart failure and to identify the predictors of cytokine activation. METHODS AND RESULTS: We assessed neurohormonal determinations, circulating cytokines, ejection fraction (EF) and end-diastolic and end-systolic left ventricular lengths in 87 patients (aged 57 +/- 9 years) with left ventricular dysfunction (EF 24% +/- 6%). In 48 patients, we also assessed cytokine receptors. During follow-up (mean, 14 +/- 9 months), 8 patients died and 12 had new heart failure episodes that required hospital admission, 5 of whom underwent heart transplantation. The univariate predictors of these events were serum interleukin-6 (IL-6) (p = 0.00001), New York Heart Association (NYHA) functional class (p = 0.0004), tumor necrosis factor-soluble receptor I (p = 0. 001), atrial natriuretic peptide (p = 0.002), tumor necrosis factor-soluble receptor II (p = 0.004), angiotensin II (p = 0.006), serum interleukin-1 beta (p = 0.01), and plasma renin activity (p = 0.02). Increased serum interleukin-6 (>10 pg/ml) was a significant predictor of death or new heart failure episodes according to the Kaplan-Meier survival method by log-rank test (p = 0.004). By Cox regression analysis, serum IL-6 (p = 0.0005) and the NYHA functional class (p = 0.005) were identified as independent predictors of prognosis. CONCLUSIONS: In patients with congestive heart failure, increased serum IL-6 was identified as a powerful independent predictor of the combined end point: death, new heart failure episodes, and need for heart transplantation.     

Cardiac interleukin-6 release and myocardial recovery after aortic crossclamping. Crystalloid versus blood cardioplegia

BACKGROUND: Pro-inflammatory cytokines may play an important role in patient response to cardiopulmonary bypass (CPB). Since the myocardium is proposed to be a major source of cytokines, we studied the influence of the cardiolpegia type on interleukin-6 release and early myocardial recovery. METHODS: Experimental design: prospective, randomized study. Setting: university hospital, operative and intensive care. Patients: 20 consecutive patients (3 females) scheduled for elective coronary artery bypass grafting (CABG), mean age 62.8+/-5 years, history of myocardial infarction 11/20, left ventricular ejection fraction 62.9+/-15%. Interventions: patients were operated on using randomly either cold blood cardioplegia (B, n = 10) or cold crystalloid cardioplegia (C, n = 10). Measures: plasma levels of interleukin-6 (IL-6) were measured prior to CPB, after aortic declamping, after CPB, 1 hour, 6 hours and 12 hours postoperatively. RESULTS: Groups were comparable with respect to demographic data, left ventricular function, number of grafts, CPB and aortic crossclamp time. Group B patients demonstrated significant lower IL-6 levels after 1 hour (210+/-108 vs. 578+/-443 pg/ml), 6 hours (204+/-91 vs. 1210+/-671 pg/ml) and 12 hours (174+/-97 vs. 971+/-623 pg/ml). Post-CPB cardiac index was superior in group B (3.9+/-0.3 vs. 3.2+/-0.3 l/min/m2, p<0.05) with similar doses of inotropes. Group B patients could earlier be weaned off respirator (10+/-4 vs. 13+/-4 hours, p<0.05) and showed minor blood loss (635+/-211 vs. 918+/-347 ml, p<0.05). CONCLUSIONS: Inflammatory response to CPB is associated with delayed myocardial recovery. The use of blood cardioplegia may attenuate inflammatory reactions.     

An association between inflammatory state and left ventricular hypertrophy in hemodialysis patients

This study was performed to investigate the potential relationship between left ventricular hypertrophy (LVH) and proinflammatory cytokines in hemodialysis (HD) patients and the effect of HD on cytokine production. Serum interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) measurements and echocardiographic studies were performed in 35 stable HD patients. A variety of probable risk factors for LVH including age, HD duration, blood pressure (BP), body mass index, lipid profile, hemoglobin, albumin, parathormone and homocysteine levels were also investigated. Additionally, the effect of HD procedure on cytokine levels was evaluated. Predialysis serum levels of IL-1beta, IL-6, TNF-alpha, and homocysteine in HD patients were compared with 12 healthy subjects. Left ventricular hypertrophy was demonstrated in 20 (57%) of HD patients by echocardiography. Left ventricular mass index (LVMI) was correlated positively with systolic BP (r=0.556, p=0.001), diastolic BP (r=0.474, p=0.004), and serum levels of TNF-alpha (r=0.446, p=0.009). Multiple regression analysis showed that systolic BP and TNF-alpha levels were significant independent predictors of LVH. No relationship was observed between LVH and other parameters. The mean predialysis serum level of IL-6 was significantly higher in HD patients compared to healthy controls (15.7 +/- 8.7 vs. 7.3 +/- 0.7 pg/ mL, p=0.001). Predialysis serum levels of TNF-alpha in HD patients were higher when compared to healthy subjects, but the difference was not statistically significant (8.3 +/- 3 vs. 7 +/- 1.45 pg/mL, respectively, p>0.05). However, serum levels of IL-6 and TNF-alpha significantly elevated after HD, when compared to predialysis levels (from 15.7 +/- 8.7 to 17.8 +/- 9.5 pg/mL, p=0.001 and from 8.3 +/- 3.0 to 9.9 +/- 3.5 pg/mL p=0.004, respectively). As a conclusion, in addition to BP, proinflammatory cytokines, TNF-alpha in particular, seem to be associated with LVH in ESRD patients.     

TNF Alpha−308 Genotype and Renin–Angiotensin System in Hemodialysis Patients: An Effect on Inflammatory Cytokine Levels?

BACKGROUND: Renin-angiotensin system (RAS) was suggested to modulate inflammatory cytokine production. Angiotensin II was consistently shown to increase production of tumor necrosis factor alpha (TNF-alpha). However, inflammatory cytokines and RAS were modulated by genetic polymorphisms such as TNF-alpha-308 G > A and angiotensin-converting enzyme (ACE) I/D gene polymorphisms. The aim of this study was to investigate the effects of ACE and TNF-alpha genotypes on inflammatory cytokines in hemodialysis (HD) patients. METHODS: ACE I/D and TNF-alpha-308 G > A genotypes, pre- and postdialysis plasma renin activity (PRA), serum ACE, interleukin-1 beta (IL-1beta), and TNF-alpha levels were determined in 22 HD patients. RESULTS: Predialysis serum ACE activity is correlated with TNF-alpha (r = 0.63; P = 0.01), and PRA was correlated with IL-1beta levels (r = 0.49; P = 0.02). Pre/postdialysis IL-1beta and TNF-alpha were similar in DD and II/ID ACE genotypes. Predialysis TNF-alpha and IL-1beta (32.4 +/- 5; 35.1 +/- 4.2 vs. 28.1 +/- 3.7; 26.5 +/- 6.2 pg/mL; P < 0.05) and postdialysis TNF-alpha levels (30.4 +/- 1.4 vs. 28.4 +/- 0.82 pg/mL; P < 0.05) were significantly higher in TNF1/2 than TNF1/1 patients. CONCLUSION: ACE and TNF-alpha-308 G > A (1/2) gene polymorphisms may contribute to modulation of proinflammatory cytokine production and hence chronic inflammation in HD patients.     

Cytokines accumulated in acquired renal cysts in long-term hemodialysis patients

BACKGROUND: Cytokines play a pivotal role in growth, differentiation, and apoptosis. In this study, we measured cytokine content in the renal cyst fluid of patients with acquired cystic disease of the kidney (ACDK) in order to elucidate the possibility that cytokines are related to the development of ACDK. PATIENTS AND METHODS: All or some of 15 cytokines, IL-1a, -1b, -2, -4, -5, -6, -8, -10, IFN-alpha, -gamma, G-, M-, GM-CSF, TNF-alpha, and vascular endothelial growth factor (VEGF) were analyzed in cyst fluid and serum of 12 patients on hemodialysis (HD) including 8 with ACDK and 8 with normally functioning kidneys by sandwich enzyme-linked immunosorbent assay. RESULTS: Out of these cytokines, only IL-6, -8, M-CSF, and VEGF were detected in the cyst fluid of patients with ACDK. Moreover, IL-6, -8, and VEGF showed significantly higher concentrations in the cyst fluid than in the blood (194.9 +/- 90.9 vs. 0.0 +/- 0.0 pg/ml, 2,377. 5 +/- 602.9 vs. 0.0 +/- 0.0 pg/ml, 5,167.8 +/- 1,316.9 vs. 41.1 +/- 14.7 pg/ml, respectively), while M-CSF showed comparable concentrations in the cyst fluid with those in the blood (3,519.4 +/- 730.0 vs. 3,250.3 +/- 319.1 pg/ml, p = 0.69). Additionally, IL-6, -8, and VEGF accumulated more abundantly in the cyst fluid of patients with ACDK than in that of patients with other cystic nephropathies including ADPKD patients on HD (194.9 +/- 90.0 vs. 4.6 +/- 3.2 pg/ml, 2,377.5 +/- 602.9 vs. 76.8 +/- 46.5 pg/ml, 5,167.8 +/- 1,316.9 vs. 131.1 +/- 63.1 pg/ml, respectively). However, there was no significant correlation between the intracystic concentrations of these cytokines and the corresponding cyst diameters. CONCLUSION: These results showed that in ACDK patients a local environment exists in which production or accumulation of certain cytokines is selectively enhanced compared with patients with other cystic nephropathies. They imply that these cytokines are closely related to pathogenesis particular to ACDK.     

前列腺按摩液中IL-8和TNF-α测定在慢性前列腺炎诊断、分型中的临床意义

目的 :探讨检测前列腺按摩液 (EPS)中细胞因子白细胞介素 8(IL 8)和肿瘤坏死因子α(TNF α)在慢性前列腺炎诊断、分型中的意义。　方法 :ELISA法检测 78例临床诊断的慢性前列腺炎患者 [其中慢性前列腺炎(CBP)组 12例 ,慢性非细菌性前列腺炎 /慢性骨盆疼痛综合征 (CPPS)ⅢA组 38例 ,CPPSⅢB组 2 8例 ]和 12例正常对照者EPS中IL 8和TNF α浓度。分析各组EPS中IL 8和TNF α浓度差异。　结果 :CBP组和CPPSⅢA组EPS中IL 8水平 [(10 96 7.5± 3477.7) pg/ml;(92 6 8.4± 2 0 34.6 ) pg/ml]和TNF α水平 [(84 .1± 5 4 .7) pg/ml;(32 .6± 18.6 ) pg/ml]显著高于CPPSⅢB组和正常对照组EPS中的IL 8水平 [(2 72 6 .1± 2 77.5 ) pg/ml;(2 80 0 .0± 32 0 .2 )pg/ml]和TNF α水平 [(12 .6± 7.1)pg/ml;(12 .9± 10 .1)pg/ml](P均 <0 .0 1)。　结论 :检测EPS中IL 8、TNF α水平可能有助于CBP、慢性非细菌性前列腺炎 /慢性骨盆疼痛综合征的分型诊断。     

Alterations in immunocyte tumor necrosis factor receptor and apoptosis in patients with congestive heart failure

OBJECTIVE: To examine systemic immune cell proinflammatory receptor expression and apoptosis in patients with congestive heart failure (CHF). SUMMARY BACKGROUND DATA: Prior studies have demonstrated that CHF is associated with a chronic myocardial inflammatory state, including increased plasma proinflammatory cytokine and soluble receptor expression. By contrast, it has also been shown that tumor necrosis factor (TNF) receptor protein expression is decreased in the failing myocardium. However, no studies to date have examined systemic immune cell proinflammatory receptor expression or function as disease markers in patients with heart failure. METHODS: Twenty-nine patients were studied prospectively over an 8-month period at a single institution. One group (n = 16) had a history of clinical symptoms of CHF and moderate to severe left ventricular dysfunction. The second group (n = 13) consisted of patients who had coronary artery disease without symptoms of CHF and documented preservation of left ventricular function. Blood samples were analyzed for polymorphonuclear cell (PMN) and monocyte TNF and CD95 membrane-associated receptor expression, spontaneous and CD95 (Fas)-mediated PMN apoptosis, and plasma cytokine and soluble TNF receptor levels. Isolated PMNs were incubated for 6 hours with or without CH 11, a CD95 agonist. Propidium iodide/RNAase staining and flow cytometry was used to assess apoptosis, defined as PMNs expressing hypodiploid DNA (<2 n DNA). Membrane-associated TNF receptor and CD95 were also measured by flow cytometry. Plasma levels of TNF, interleukin (IL)-6, IL-10, and soluble TNF receptors 1 and 2 were quantified using enzyme-linked immunosorbent assay. RESULTS: Compared to patients without CHF, circulating PMN and monocyte TNF receptor levels were significantly decreased in patients with CHF. By contrast, PMN and monocyte CD95 expression was not significantly changed in patients with CHF versus those without CHF. Patients with CHF had a 60% decrease in spontaneous PMN apoptosis compared to patients without CHF, whereas no significant difference in CD95-mediated apoptosis was observed between the two groups. Pearson-product movement correlation of monocyte TNF receptor expression and spontaneous PMN apoptosis rates versus patients' ejection fraction was performed and was statistically significant. Plasma levels of soluble TNF receptor 2 (p75) were elevated in CHF patients versus patients without CHF, while there was no significant difference in soluble TNF receptor 1 (p55), TNF, IL-6, and IL-10 between the two groups. CONCLUSIONS: These data demonstrate a systemic alteration in immune cell phenotype and apoptosis in patients with CHF. These findings provide support for the concept that inflammatory mediators either contribute to myocardial dysfunction or are elaborated systemically by left ventricular compromise. This present study suggests that immune cell TNF receptor expression and diminished PMN apoptosis may serve as biologic markers of myocardial failure.     

Profiles of inflammatory cytokines following colorectal surgery: Relationship with wound healing and outcome

Inflammation is an essential component of normal wound healing. This study has correlated systemic (plasma) and local (wound fluid) concentrations of inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-alpha [TNF-alpha], and IL-1beta) with wound healing and surgical outcome following elective colorectal surgery. Paired plasma and wound fluid samples were collected (n = 44) postoperatively (days 1, 3, 5, 7) and analyzed by enzyme-linked immunosorbent assay (pg/mL). Cytokine levels were significantly greater in drain fluid than plasma on each postoperative day (POD); e.g., POD 1 : IL-6; drain fluid, median, 77,050 pg/mL (range 9,928-456,408); plasma, 241 pg/mL (22-1,333). Daily profiles of IL-6 and TNF-alpha were similar in drain fluid and plasma; IL-6 levels peaked on POD 1 decreasing to POD 7, and TNF-alpha levels increased from PODs 1 to 7. However, IL-1beta in plasma peaked on POD 1 and plateaued, whereas drain fluid showed two peaks (PODs 1 and 7). Only plasma levels of cytokines correlated to clinical parameters; IL-6 levels significantly correlated with postoperative complications; e.g., POD 5, complications 92(1-597) and no complications, 14(2-217). IL-6 also correlated with tumor pathology (Dukes stage, tumor depth, vascular invasion), and TNF-alpha levels correlated with the estimated blood loss during surgery. We conclude that local wound levels of cytokines correlated with the stage of wound healing, whereas systemic levels correlated with postoperative complications and tumor pathology.     

Aminoterminal pro type B natriuretic peptide as a predictive and prognostic marker in patients with chronic heart failure.

BACKGROUND: B-type natriuretic peptide (BNP) is released from the cardiac ventricles in response to increased wall tension. We studied the relation of NT-proBNP to Heart Failure Survival Score (HFSS) and New York Heart Association (NYHA) class in patients with chronic heart failure (CHF). We also studied the impact for recipient selection for cardiac transplant and assessed it as a predictive and prognostic marker of CHF. METHODS: A total of 550 patients with dilative cardiomyopathy (n = 323), and coronary artery disease (n = 227) were prospectively examined. All patients underwent spiroergometry, echocardiography, right heart catheterization, and electrocardiogram. Routine blood levels and NT-proBNP were measured. The clinical selection for cardiac transplant candidates was adjudicated by 2 independent cardiologists who were blinded to the results of NT-proBNP assays. Clinical outcome and predictive power of NT-proBNP were analyzed. RESULTS: NT-proBNP levels in patients clinically considered for cardiac transplantation were significantly higher (2293 ng/ml vs 493 ng/ml; p < 0.001). The receiver operating characteristic (ROC) analysis regarding transplant candidacy showed an area under the ROC curve (AUC) of 0.84 +/- 0.01 for HFSS, 0.86 +/- 0.001 for NYHA, and 0.96 +/- 0.01 for NT-proBNP. Patients with increasing NT-proBNP levels or remaining elevated levels despite adequate heart insufficiency treatment were maintained with left ventricular assist device implantation (n = 10) or urgent heart transplantation (n = 2). Patients with NT-proBNP levels above 5000 pg/ml had a mortality rate of 28.4% per year. Twenty-eight patients died during the observation period; all these patients were within NYHA Classes 3 and 4 (NT-proBNP 5423 +/- 423 ng/ml). CONCLUSIONS: NT-proBNP discriminates patients at high likelihood of being a candidate for transplantation and provides prognostic informations in patients with CHF. NT-proBNP levels above 5000 pg/ml at admission were associated with death, and these levels markedly discriminated candidates for left ventricular assist devices or urgent transplantation.     

Higher plasma interleukin-18 levels associated with poor quality of sleep in peritoneal dialysis patients.

BACKGROUND: Sleep disorders are prevalent in patients with end-stage renal disease. Increasing evidence suggests that cytokines are involved in the regulation of sleep and wakefulness. The purpose of this study was to examine the relationship between quality of sleep and plasma interleukin-18 levels in peritoneal dialysis patients. METHODS: Plasma interleukin-18 levels were determined by the enzyme-linked immunosorbent assay (ELISA) methodology in 57 peritoneal dialysis patients. Quality of sleep was measured using the Pittsburgh Sleep Quality Index. Demographic and routine laboratory data were recorded. RESULTS: In our cohort, the poor sleepers had higher plasma interleukin-18 levels (559.16 +/- 261.22 pg/ml vs 397.49 +/- 191.81 pg/ml, P = 0.01). The plasma interleukin-18 level was positively correlated with the Pittsburgh Sleep Quality Index score (r = 0.286, P = 0.031), that is, there was a positive association between higher plasma interleukin-18 levels and poorer quality of sleep. CONCLUSION: This study demonstrates that interleukin-18 may be involved in sleep disorders in end-stage renal disease patients. Higher plasma interleukin-18 levels are associated with poorer quality of sleep in peritoneal dialysis patients. Whether a cause-and-effect relationship exists between interleukin-18 and quality of sleep deserves further study.     

Relation of inflammatory cytokines to atrial fibrillation after off-pump coronary artery bypass grafting.

OBJECTIVE: It has been observed that a systemic inflammatory response after on-pump coronary artery bypass grafting (CABG) participates in the pathogenesis of postoperative atrial fibrillation (AF). In patients undergoing off-pump CABG, it is plausible that inflammation is associated with the development of postoperative AF. The present study examined relation of proinflammatory cytokines, which play an important role in the upstream of inflammatory cascade, to the development of AF after off-pump CABG. METHODS: The present study included 39 patients undergoing off-pump CABG. Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8, were measured by enzyme-linked immunosorbent assay, on anesthetic induction, after sternotomy before anastomoses, at the completion of anastomoses, 3 and 6h thereafter, and on postoperative days (POD) 1-4. C-reactive protein (CRP) was also measured by turbidimetric immunoassay, preoperatively, and on POD 1, 2, 3, 6, 9, and 13. RESULTS: Eleven patients (28%) developed postoperative AF. Patients with postoperative AF were older (70+/-6.4 years vs 60+/-8.8 years, P=0.001); however, there was no difference in other pre- and perioperative variables. TNF-alpha level did not change during the study period. However, IL-8 and CRP levels significantly increased after the surgery, although there was no significant difference between the two groups. IL-6 level also increased after the surgery with its peak at 6h after the completion of anastomoses. IL-6 levels of 3 and 6h after anastomoses were significantly higher in patients with postoperative AF (360+/-143 pg/ml vs 230+/-94 pg/ml, P=0.0047, 435+/-175 pg/ml vs 247+/-102 pg/ml, P=0.0005, respectively). Logistic regression analysis indicated that the highest quartile of IL-6 level immediately after the surgery (odds ratio 7.63; 95% CI, 1.06-54.9; P=0.04) and age (odds ratio 1.18; 95% CI, 1.01-1.39; P=0.04) independently predict postoperative AF. Furthermore, the maximum level of IL-6 immediately after the surgery significantly correlated to age and intraoperative blood loss (r=0.04, P=0.01, and r=0.47, P=0.04, respectively). CONCLUSIONS: Advanced age was a major risk factor for postoperative AF. Furthermore, inflammatory response induced by surgical trauma was also associated with the development of AF after off-pump CABG.     

Comparison of systemic cytokine levels in patients with acute respiratory distress syndrome, severe pneumonia, and controls

BACKGROUND: The inflammatory response has been widely investigated in patients with acute respiratory distress syndrome (ARDS) and pneumonia. Studies investigating the diagnostic values of serum cytokine levels have yielded conflicting results and only little information is available for the differential diagnosis between ARDS and pneumonia. METHODS: Clinical and physiological data, serum concentrations of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, and quantitative cultures of lower respiratory tract specimens were obtained from 46 patients with ARDS and 20 with severe pneumonia within 24 hours of the onset of the disease and from 10 control subjects with no inflammatory lung disease. Cytokine concentrations were compared between groups and determinants in addition to the diagnosis were tested. RESULTS: Serum TNF-alpha levels were significantly higher in ARDS patients (67 (57) pg/ml) than in patients with severe pneumonia (35 (20) pg/ml; p = 0.031) or controls (17 (8) pg/ml; p = 0.007). For IL-1beta and IL-6 the observed differences were not statistically significant between patients with ARDS (IL-1beta: 34 (65) pg/ml; IL-6: 712 (1058) pg/ml), those with severe pneumonia (IL-1beta: 3 (4) pg/ml, p = 0.071; IL-6: 834 (1165) pg/ml, p = 1.0), and controls (IL-1beta: 6 (11) pg/ml, p = 0.359; IL-6: 94 (110) pg/ml, p = 0.262). TNF-alpha (standardised coefficient beta = 0.410, p<0.001) and IL-1beta (standardised coefficient beta = 0.311, p = 0.006) were most strongly associated with the degree of lung injury, even when the diagnostic group was included in the statistical model. CONCLUSIONS: Serum TNF-alpha levels were higher in patients with ARDS than in those with severe pneumonia or in control subjects. Multivariate results suggest that the levels of systemic TNF-alpha and IL-1beta reflect the severity of the lung injury rather than the diagnosis.     

Plasma cytokine levels predict mortality in patients with acute renal failure

BACKGROUND: Critically ill patients with acute renal failure (ARF) experience a high mortality rate. Animal and human studies suggest that proinflammatory cytokines lead to the development of a systemic inflammatory response syndrome (SIRS), which is temporally followed by a counter anti-inflammatory response syndrome (CARS). This process has not been specifically described in critically ill patients with ARF. METHODS: The Program to Improve Care in Acute Renal Disease (PICARD) is a prospective, multicenter cohort study designed to examine the natural history, practice patterns, and outcomes of treatment in critically ill patients with ARF. In a subset of 98 patients with ARF, we measured plasma proinflammatory cytokines [interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha)], the acute-phase reactant C-reactive protein (CRP), and the anti-inflammatory cytokine IL-10 at study enrollment and over the course of illness. RESULTS: When compared with healthy subjects and end-stage renal disease patients on maintenance hemodialysis, patients with ARF had significantly higher plasma levels of all measured cytokines. Additionally, the proinflammatory cytokines IL-6 and IL-8 were significantly higher in nonsurvivors versus survivors [median 234.7 (interdecile range 64.8 to 1775.9) pg/mL vs. 113.5 (46.1 to 419.3) pg/mL, P= 0.02 for IL-6; 35.5 (14.1 to 237.9) pg/mL vs. 21.2 (8.5 to 87.1) pg/mL, P= 0.03 for IL-8]. The anti-inflammatory cytokine IL-10 was also significantly higher in nonsurvivors [3.1 (0.5 to 41.9) pg/mL vs. 2.4 (0.5 to 16.9) pg/mL, P= 0.04]. For each natural log unit increase in the levels of IL-6, IL-8, and IL-10, the odds of death increased by 65%, 54%, and 34%, respectively, corresponding to increases in relative risk of approximately 30%, 25%, and 15%. The presence or absence of SIRS or sepsis was not a major determinant of plasma cytokine concentration in this group of patients. CONCLUSION: There is evidence of ongoing SIRS with concomitant CARS in critically ill patients with ARF, with higher levels of plasma IL-6, IL-8, and IL-10 in patients with ARF who die during hospitalization. Strategies to modulate inflammation must take into account the complex cytokine biology in patients with established ARF.     

Intracellular monocyte cytokine production and CD 14 expression are up-regulated in severe vs mild chronic heart failure.

BACKGROUND: The role of circulating monocytes in the process of low-grade inflammation, characteristic of chronic heart failure (CHF), has recently been questioned. Lipopolysaccharide (LPS) desensitization has been proposed to mediate reduced monocyte cytokine elaboration in patients with severe CHF. METHODS: Intracellular monocyte production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha, and monocyte CD 14 expression were measured flow-cytometrically without and after 8-hour LPS stimulation in 46 patients with CHF and in a healthy control group. RESULTS: Basal cytokine concentrations were similar for the control and the mild CHF groups (New York Heart Association [NYHA] Class I or II). After LPS stimulation, IL-6 (p=0.002) and TNF-alpha levels (p=0.001) were lower in the latter group, whereas IL-1 beta production was comparable. For the moderate-severe CHF patients, unstimulated IL-1 beta (p=0.04) was higher, whereas IL-6 (p=0.2) and TNF-alpha (p=0.1) levels were not different from the controls. Measurement of LPS-stimulated cytokine production showed no differences between the control group and patients with moderate-severe CHF (all p= 0.5). Upon comparing mild vs moderate-severe CHF patients, higher levels of unstimulated cytokine production (IL-1 beta, p=0.002; IL-6, p=0.01; TNF-alpha, p=0.003), stimulated IL-1 beta (p=0.002) and IL-6 (p=0.008) were found in the latter patients. CD 14 expression in the moderate-severe CHF group was higher than in the mild-CHF group (p = 0.03) and was strongly related to stimulated IL-1 beta (r=0.62, p<0.0001), IL-6 (r=0.56, p=0.0002) and TNF-alpha (r=0.41, p=0.006) production. CONCLUSIONS: CD 14 expression and monocyte cytokine production, both unstimulated and after LPS stimulation, are increased in moderate-severe CHF when compared with mild CHF. These data suggest that circulating monocytes, possibly via increased CD 14 expression, may play a significant role in the immunologic dysbalance observed in advanced CHF.     

Effect of the hemodialysis membrane on the inflammatory reaction in vivo

BACKGROUND: Increased levels of C-reactive protein (CRP), a marker of systemic inflammation, are associated with myocardial infarction, stroke and the development of peripheral arterial disease. Hemodialysis patients show signs of an inflammatory reaction indicated by elevated plasma levels of CRP and by increased plasma levels of interleukins. PATIENTS AND METHODS: To investigate the effect of the dialysis membrane on the inflammatory reaction, we conducted a randomized study in 18 hemodialysis patients. Patients were subsequently treated with dialyzers containing polyamide, polycarbonate or cuprophan for 8 weeks on each dialyzer in a crossover design. During each treatment period, CRP plasma levels were measured 6 times at weekly intervals. The total content and the spontaneous and lipopolysaccharide- (LPS) stimulated production of interleukin-1beta (IL-1beta), IL-6 and IL-1 receptor antagonist (IL-1Ra) were determined in whole blood samples. RESULTS: CRP plasma levels were significantly higher in hemodialysis patients (all patients, 1.63 +/- 0.23 mg/dl) compared to normals (0.14 +/- 0.02 mg/dl, p < 0.0001). CRP levels were lower when patients were dialyzed with polyamide (1.19 +/- 0.18 mg/dl) compared to the levels when the same patients were dialyzed with cuprophan (1.77 +/- 0.37 mg/dl, p = 0.02) or with polycarbonate (1.34 +/- 0.2 mg/dl, n.s). The whole blood content of IL-1Ra in non-incubated samples was significantly lower in normal subjects (512 +/- 60 pg/ml) compared to hemodialysis patients (980 +/- 80 pg/ml, p < 0.01). The whole blood content of IL-1Ra was higher when patients were dialyzed with cuprophan (1,062 +/- 119 pg/ml) compared to the same patients on polyamide (906 +/- 78 pg/ml, p < 0.05) or on polycarbonate (973 +/- 80 pg/ml, n.s.). Spontaneous and LPS-induced production of IL-1beta and IL-6 was similar for all dialyzers. CONCLUSION: We conclude that the inflammatory reaction in hemodialysis patients is affected by the choice of the dialyzer.     

Sequential big endothelin plasma levels in heart transplant recipients during bridging therapy and after successful heart transplantation.

BACKGROUND: The purpose of this study was to investigate the impact of successful heart transplantation in patients with refractory heart failure receiving bridging therapy on sequential plasma levels of big endothelin, norepinephrine, atrial natriuretic peptide and aldosterone. METHODS: Fourteen patients (2 women, 12 men) accepted for heart transplantation were studied. All had severe chronic heart failure refractory to optimized oral therapy with angiotensin-converting enzyme inhibitors and furosemide, were in New York Heart Association functional Class IV, and had a left ventricular ejection fraction of <15%, Right heart catheterization was performed in all patients (cardiac index 1.9 +/- 0.1 liters/min. m(2), pulmonary capillary wedge pressure 30 +/- 2 mmHg, systemic vascular resistance index 2,827 +/- 253 dyn. s/cm(5). m(2)). As bridging therapy, patients received either prostaglandin E(1), prostaglandin E(1) and dobutamine or dobutamine alone as a continuous infusion. Neurohumoral variables were measured prior to bridging therapy and 3.5 months before and 7 and 10 months after successful heart transplantation. RESULTS: Big endothelin, norepinephrine and atrial natriuretic peptide plasma levels decreased from 7.4 +/- 2.9 fmol/ml, 1112 +/- 686 pg/ml and 366 +/- 312 pg/ml to 6.0 +/- 4.5 fmol/ml, 720 +/- 503 pg/ml and 198 +/- 160 pg/ml, respectively, after bridging therapy, and further to 2.1 +/- 0.9 fmol/ml (p < 0.00001 vs baseline), 527 +/- 31 pg/ml (p < 0.02 vs baseline) and 115 +/- 70 pg/ml (p < 0.03 vs baseline), respectively, after cardiac transplantation. Aldosterone plasma levels decreased from 242 +/- 220 pg/ml to 183 +/- 142 pg/ml during bridging therapy and increased after heart transplantation to 252 +/- 189 pg/ml. Plasma creatinine levels increased from 1.2 +/- 0.4 mg/dl at baseline to 1.4 +/- 0.2 mg/dl after transplantation (NS). CONCLUSIONS: The study suggests that excessive overproduction of big endothelin, atrial natriuretic peptide and norepinephrine is predominantly related to pump failure and, after cardiac transplantation, a moderate spillover of big endothelin persists. Its specific origin, however, remains to be elucidated. Furthermore, our data suggest a protective effect of prostaglandin E(1) on kidney function after heart transplantation.