Cytokine expression in severe pneumonia: a bronchoalveolar lavage study.

OBJECTIVE: To assess the cytokine expression (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta, and IL-6) in severe pneumonia, both locally (in the lungs) and systemically (in blood). DESIGN: Prospective sequential study with bronchoalveolar lavage (BAL) and blood sampling. SETTING: Six-bed respiratory intensive care unit of a 1,000-bed teaching hospital. PATIENTS: Thirty mechanically ventilated patients (>48 hrs) were allocated to either the pneumonia group (n = 20) or a control group (n = 10). INTERVENTIONS: Protected specimen brush and BAL samples for quantitative cultures, and serum and BAL fluid TNF-alpha, IL-1beta, and IL-6 levels were measured on days 1, 3, and 7. In the control group, the procedure was done on day 1 only. MEASUREMENTS AND MAIN RESULTS: Serum TNF-alpha levels were significantly higher in patients with pneumonia compared with controls (35 +/- 4 vs. 17 +/- 3 pg/mL, respectively, p = .001). IL-6 levels in serum and BAL fluid were higher in pneumonia than in control patients (serum, 837 +/- 260 vs. 94 +/- 35 pg/mL, respectively, p = .017; BAL fluid, 1176 +/- 468 vs. 234 +/- 83 pg/mL, respectively, p = .05). On days 1, 3, and 7 in patients with pneumonia, IL-1beta levels turned out to be higher in BAL fluid than in serum (71 +/- 17 vs. 2 +/-1 pg/mL on day 1; 49 +/- 8 vs. 6 +/- 2 pg/mL on day 3; and 47 +/- 16 vs. 3 +/- 2 pg/mL on day 7 for BAL fluid and serum, respectively, p < .05). No significant correlation between BAL fluid cytokine levels and lung bacterial burden was shown in presence of antibiotic treatment. Although no clear relationship was found between BAL fluid and serum cytokines and mortality, there was a trend toward higher serum IL-6 levels in nonsurvivors (1209 +/- 433 pg/mL) with pneumonia compared with survivors (464 +/- 260 pg/mL). In addition, serum TNF-alpha and IL-6 correlated with multiple organ failure score (r2 = .36, p = .004 for both) and with lung injury score (r2 = .30, p = .01, and r2 = .22, p = .03, for TNF-alpha and IL-6, respectively). CONCLUSIONS: The present study describes the lung and systemic inflammatory response in severe pneumonia. The lung cytokine expression seems to be independent from the lung bacterial burden in the presence of antibiotic treatment. Because of the limited sample size, we did not find a clear relationship between serum and BAL fluid cytokine levels and outcome.     

Inflammatory cytokine response in patients with septic shock secondary to generalized peritonitis

OBJECTIVES: The aims of this study were the following: a) to assess the proinflammatory cytokine (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1, and IL-6) response in patients with septic shock secondary to generalized peritonitis; and b) to evaluate the influence of bacteremic status, type of peritonitis (acute perforation or postoperative), and peritoneal microbial status (mono- or polymicrobial) on cytokine expression and mortality. DESIGN: Prospective study. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: Fifty-two consecutive patients with septic shock caused by generalized peritonitis. INTERVENTIONS: Routine blood tests, blood cultures, and cytokine assays were performed during the first 3 days after onset of shock. MEASUREMENTS AND MAIN RESULTS: Serum TNF-alpha and IL-6 concentrations were measured by using a radioimmunoassay, and IL-1 concentrations were measured by using ELISA. Median serum concentrations on day 1 were: TNF-alpha, 90 pg/mL; IL-1, 7 pg/mL; and IL-6, 5000 pg/mL. TNF-alpha and IL-6 concentrations decreased significantly between the first and third days of septic shock (p = .0001), whereas IL-1 concentrations remained low. The decrease in IL-6 tended to be more pronounced in the survivors group (p = .057). Median TNF-alpha serum concentrations were higher in bacteremic compared with nonbacteremic patients (151 vs. 73 pg/mL, p = .003). TNF-alpha, IL-1, and IL-6 serum concentrations and mortality were not different between acute perforation vs. postoperative peritonitis and mono- versus polymicrobial peritonitis. CONCLUSIONS: The systemic release of TNF-alpha and IL-6 during septic shock caused by generalized peritonitis was maximal on day 1 and decreased rapidly during the next days. No systemic release of IL-1 was observed. IL-6 serum concentrations remained higher in patients who subsequently died. Among the different features of peritonitis studied, only bacteremia influenced the systemic cytokine response (higher TNF-alpha).     

Pre- and postoperative cytokine release after in vitro whole blood lipopolysaccharide stimulation and frequent toll-like receptor 4 polymorphisms

In a prospective cohort study, we examined 62 patients undergoing major surgical cancer therapy for Toll-like receptor 4 (TLR4) gene polymorphisms (Asp299Gly and Thr399Ile) and their influence on cytokine levels pre- and postoperatively, as well as cytokine levels after whole blood lipopolysaccharide (LPS) stimulation. Incidence of the TLR4 gene single nucleotide polymorphism (SNP) Asp299Gly/Thr399Ile was 14.5% (9/62). Overall, mortality was unaffected by the TLR4 SNP. Preoperative cytokine levels were low, with most of the values of cytokines being below the detection levels. After preoperative stimulation of whole blood with 50 pg/mL LPS, TNF-alpha and IL-6 values increased significantly in both groups. However, no significant influence was detectable between the TLR4 SNP group and the wild type group (WT group). Postoperative IL-6 levels, but not TNF-alpha levels, were significantly increased in both groups. Postoperative LPS stimulation resulted in significantly lower TNF-alpha levels compared with preoperative induction, with a more than 2.3-fold decrease in the TLR4 SNP group: 310.83 pg/mL (SD: 117.53) to 134.08 pg/mL (SD: 91.49; P < 0.001) and a 2.2-fold decrease in the WT group: 422.97 pg/mL (SD: 662.57) to 191.68 pg/mL (SD:147.26; P = 0.031). IL-6 levels after stimulation were comparably decreased with similarly no significant difference between the two groups. We conclude that the TLR4 polymorphism Asp299Gly/Thr399Ile has no influence on cytokine release after LPS stimulation in the early and late course after major surgery. The LPS adaptation effect of cytokine release after surgery is furthermore not affected by the presence of the TLR4 polymorphism Asp299Gly/Thr399Ile.     

超声对评估产后女性腹直肌的研究

目的:利用高频超声研究产后女性腹直肌的变化规律,为产后康复计划提供参考依据。方法:随机选择我院2014年1月-2018年12月期间280例产后女性及60例年龄相近的未孕未育女性,用高频超声测量并分析产后女性实验组I(产后1天)、实验组II(产后1月)、实验组III(产后2月)、实验组IV(产后3月)、实验组V(产后6月)、实验组VI(产后12月)六个阶段和对照组(未孕未育)女性的腹直肌厚度、腹直肌分离间距。结果:实验组的腹直肌厚度均低于对照组(P<0.05),实验组III、实验组IV、实验组V、实验组VI的腹直肌厚度呈递增关系(P<0.05),实验组VI的腹直肌厚度接近但低于对照组(P<0.05)。实验组的腹直肌间距均明显大于对照组(P<0.05),实验组II、实验组III、实验组IV、实验组V、实验组VI的腹直肌间距小于实验组I(P<0.05),且前者五组数据相近。结论:产后腹直肌厚度变薄,产后2个月后逐渐恢复变厚,但至产后12个月仍未恢复到对照组水平;产后腹直肌分离间距显著大于对照组,产后一个月明显恢复,之后平缓恢复至产后12个月均处于平台期,产后至12个月期间均未恢复到对照组水平。     

Proinflammatory cytokines in acute myocardial infarction with and without cardiogenic shock

BACKGROUND: Inflammatory response is an important feature of acute coronary syndromes and myocardial infarction (MI). The prognostic value of proinflammatory cytokines in patients with acute MI complicated by cardiogenic shock is unknown. METHODS AND RESULTS: In 41 patients admitted with acute MI (age 60 +/- 11 years, six females, 19 Killip class IV) serial plasma concentration of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and interleukin 1 receptor antagonist (IL-1Ra) were measured. Seven patients with cardiogenic shock (CS) developed a systemic inflammatory response syndrome (SIRS). Patients with CS-particularly those who developed SIRS-showed significantly higher cytokine levels than patients with uncomplicated MI. In patients with CS and SIRS peak levels of IL-1Ra were 223,973 pg/ml, IL-6 252.8 pg/ml and TNF-alpha 7.0 pg/ml. In CS without SIRS IL-1Ra levels were 19,988 pg/ml, IL-6 109.3 pg/ml and TNF-alpha 3.8 pg/ml. In uncomplicated MI peak IL-1Ra levels were 1,088 pg/ml, IL-6 34.1 pg/ml and TNF-alpha 2.6 pg/ml. CONCLUSIONS: The inflammation-associated cytokines TNF-alpha, IL-6 and IL-1Ra are significantly elevated in patients with MI complicated by CS when compared to patients with uncomplicated MI. Among shock-patients IL-1Ra levels are promising diagnostic markers for early identification of patients developing SIRS, heralding a poor outcome.     

Influence of methylprednisolone on cytokine balance during cardiac surgery

OBJECTIVE: To determine the influence of methylprednisolone on the cytokine balance during cardiac surgery. DESIGN: Prospective, randomized, nonblinded study. SETTING: University hospital. PATIENTS: Twenty-one patients on cardiopulmonary bypass undergoing aortocoronary bypass surgery. INTERVENTIONS: According to a randomized sequence, the patients either received methylprednisolone (30 mg/kg) [corrected] before cardiopulmonary bypass and before declamping of the aorta (MPS group, n = 11) or received nothing (control group, n = 10). MEASUREMENTS AND MAIN RESULTS: Serum proinflammatory cytokines (interleukin [IL]-8, IL-6) and anti-inflammatory cytokines (IL-10, IL-1ra) were measured by enzyme-linked immunosorbent assays. Serum IL-6 and IL-8 concentrations in the control group (15.2 +/- 4.1 and 14.1 +/- 1.9 pg/mL, preoperatively) increased to 242 +/- 70.1 and 97.3 +/- 18.3 pg/mL at 60 mins after declamping of the aorta (p < .01, p < .01, respectively). The increases were greater than those from 2.5 +/- 0.6 and 2.5 +/- 0.5 pg/mL to 109.5 +/- 29.0 and 33 +/- 4.1 pg/mL in the MPS group for IL-6 and IL-8, respectively. Serum IL-10 concentrations increased significantly 60 mins after declamping of the aorta compared with its preoperative value in the two groups (the control group, from 1.0 +/- 0 to 537.9 +/- 61.7 pg/mL; the MPS group, from 0.3 +/- 0.2 to 654.9 +/- 24 pg/mL [p < .01, p < .01, respectively]). No difference was found between the two groups. Similarly, serum IL-1ra concentrations in the two groups increased the preoperative value in the control group from 304 +/- 120 to 44,374 +/- 14,631 pg/mL and in the MPS group from 616.5 +/- 109.6 to 35,598 +/- 9,074 pg/mL at 60 mins after declamping of the aorta (p < .01, p < .01, respectively). There was no difference between the two groups. CONCLUSIONS: Methylprednisolone reduces the production of IL-6 and IL-8 but not that of IL-10 and IL-1ra. These results suggest that one of the mechanisms of the cytoprotective effect of methylprednisolone may be to make changes in the proinflammatory and anti-inflammatory cytokine balance.     

Sequential changes in plasma cytokine and endotoxin levels in cirrhotic patients with bacterial infection

To delineate the clinical roles of plasma cytokine or endotoxin levels in the natural course of infection in patients with decompensated cirrhosis, 66 cirrhotic patients were studied within a 1.5-year period. Plasma levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-8 and endotoxin were determined on days 1, 4 and 7 after admission when hospital infection was suspected and 4 months later. A total of 24 patients (36.4%) were proven to be infected during hospitalization (group A), while 42 others were not infected (group B). Fever occurred in a very high proportion (22/24) of group A patients. Baseline levels of TNF-alpha (37.7+/-15.2 compared with 8.7+/-1.2 pg/ml; P<0.01) and IL-6 (180.5+/-20.5 compared with 24.6+/-7.5 pg/ml; P<0.0001) were higher in group A patients, while IL-1beta, IL-8 and endotoxin levels were not significantly different between the two groups. For patients with hospital infection, IL-6 levels determined during the episode were significantly higher than baseline levels. Using IL-6 >80 pg/ml as a baseline cut-off level to diagnose bacterial infection, the sensitivity, specificity and accuracy were 87.5, 100 and 95.5% respectively. The one-year cumulative probability of mortality (61.1% compared with 23.7%; P<0.001) and of bacterial re-infection (72.2% compared with 18.4%; P<0.0001) was higher in group A than in group B. Plasma TNF-alpha and IL-6 levels determined at 4 months were not different between the two groups. In conclusion, fever or elevated plasma IL-6 levels in patients with decompensated cirrhosis calls for early antibiotic treatment to prevent life-threatening bacterial infection. Bacterial infection is likely to recur in those patients with increased IL-6 levels, while severe episodes of infection occur in patients with increased TNF-alpha levels.     

Serum levels of leptin and proinflammatory cytokines in patients with gastrointestinal cancer

The aim was to investigate the serum levels of leptin, TNF-alpha, IL-1 beta, IL-6, insulin, and growth hormone in patients with upper gastrointestinal cancer and cachexia. A total of 39 patients with various advanced stage (stage IV) gastrointestinal malignancies were enrolled. These cancer patients were divided into two groups according to the presence or absence of cachexia. Fifteen healthy adults were recruited as the control group. Body mass index (BMI; kg/m2) was calculated. Serum leptin, tumour necrosis factor (TNF)-alpha interleukin (IL)-1 beta, interleukin (IL)-6, growth hormone, insulin, glucose, triglyceride, total protein, albumin, erythrocyte sedimentation rate, and CRP were measured. In both cancer groups (cachectic and non-cachectic) body mass index and serum leptin levels were lower than controls (p < 0.001). Serum IL-1 beta, IL-6, and growth hormone levels were higher in both cachectic and non-cachectic groups than those of controls (p < 0.05). Serum TNF-alpha level in non-cachectic group was also significantly higher than in control group (p < 0.01). There is no significant difference between three groups in terms of insulin resistance as assessed by HOMA index. Our results showed that some proinflammatory cytokine levels were increased and leptin level was decreased due to upper gastrointestinal cancers. Increased cytokine levels may lead to decreased food intake and caused a weight loss.     

The relationship between visceral ischemia, proinflammatory cytokines, and organ injury in patients undergoing thoracoabdominal aortic aneurysm repair

OBJECTIVES: Plasma proinflammatory, anti-inflammatory cytokine, and soluble tumor necrosis factor (TNF) receptor concentrations were examined in hospitalized patients after abdominal and thoracoabdominal aortic aneurysm (TAAA) repair, with and without left atrial femoral bypass. Changes in plasma cytokine concentrations were related to the duration of visceral ischemia and the frequency rate of postoperative, single, or multiple system organ dysfunction (MSOD). DESIGN: Prospective, observational study. SETTING: Two academic referral centers in the United States and The Netherlands. PATIENTS: We included 16 patients undergoing TAAA repair without left atrial femoral bypass, 12 patients undergoing TAAA repair with left atrial femoral bypass, and nine patients undergoing infrarenal aortic aneurysm repair. MEASUREMENTS AND MAIN RESULTS: Timed, arterial blood sampling for proinflammatory and anti-inflammatory cytokine and soluble TNF receptor concentrations (p55 and p75), and prospective assessment of postoperative single and MSOD. Plasma appearance of TNF-alpha, interleukin (IL)-6, IL-8, and IL-10 peaked 1 to 4 hrs after TAAA repair, and concentrations were significantly elevated compared with infrarenal abdominal aortic aneurysm repair (p < .05). Left atrial femoral bypass significantly reduced the duration of visceral ischemia (p < .05) and the systemic TNF-alpha, p75, and IL-10 responses (p < .05). Plasma TNF-alpha concentrations >150 pg/mL were more common in patients with extended visceral ischemia times (>40 mins). Additionally, patients with early peak TNF-alpha concentrations >150 pg/mL and IL-6 levels >1,000 pg/mL developed MSOD more frequently than patients without these elevated plasma cytokine levels (both p < .05). CONCLUSIONS: Thoracoabdominal aortic aneurysm repair results in the increased plasma appearance of TNF-alpha, IL-6, IL-8, IL-10, and shed TNF receptors. The frequency and magnitude of postoperative organ dysfunction after TAAA repair is associated with an increased concentration of the cytokines, TNF-alpha, and IL-6 and the increased plasma levels of these cytokines appear to require extended visceral ischemia times.     

Effects of mild hypothermia on survival and serum cytokines in uncontrolled hemorrhagic shock in rats

Previous studies have suggested benefit of mild hypothermia during hemorrhagic shock (HS). This finding needs additional confirmation and investigation into possible mechanisms. Proinflammatory cytokines are mediators of multiple organ failure following traumatic hemorrhagic shock and resuscitation. We hypothesized that mild hypothermia would improve survival from HS and may affect the pro- and anti-inflammatory cytokine response in a rat model of uncontrolled HS. Under light halothane anesthesia, uncontrolled HS was induced by blood withdrawal of 3 mL/100 g over 15 min followed by tail amputation. Hypotensive (limited) fluid resuscitation (to prevent mean arterial pressure [MAP] from decreasing below 40 mmHg) with blood was started at 30 min and continued to 90 min. After hemostasis and resuscitation with initially shed blood and Ringer's solution, the rats were observed for 72 h. The animals were randomized into two HS groups (n = 10 each): normothermia (38 degrees C +/- 0.5 degrees C) and mild hypothermia (34 degrees C +/- 0.5 degrees C) from HS 30 min until resuscitation time (RT) 60 min; and a sham group (n = 3). Venous blood samples were taken at baseline, RT 60 min, and days 1, 2, and 3. Serum interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations were quantified by ELISA. Values are expressed as median and interquartile range. Survival time by life table analysis was greater in the hypothermia group (P = 0.04). Survival rates to 72 h were 1 of 10 vs. 6 of 10 in the normothermia vs. hypothermia groups, respectively (P = 0.057). All cytokine concentrations were significantly increased from baseline at RT 60 min in both HS groups, but not in the shams. At RT 60 min, in the normothermia vs. hypothermia groups, respectively, IL-1beta levels were 185 (119-252) vs. 96 (57-135) pg/mL (P = 0.15); IL-6 levels were 2242 (1903-3777) vs. 1746 (585-2480) pg/mL (P = 0.20); TNF-alpha levels were 97 (81-156) vs. 394 (280-406) pg/mL (P= 0.02); and IL-10 levels were 1.7 (0-13.3) vs. 15.8 (1.9-23.0) pg/mL (P = 0.09). IL-10 remained increased until day 3 in the hypothermia group. High IL-1beta levels (>100 pg/mL) at RT 60 min were associated with death before 72 h (odds ratio 66, C.I. 3.5-1255). We conclude that mild hypothermia improves survival time after uncontrolled HS. Uncontrolled HS induces a robust proinflammatory cytokine response. The unexpected increase in TNF-alpha with hypothermia deserves further investigation.     

Cytokine responses and myocardial injury in coronary artery bypass grafting

OBJECTIVE: Cardiopulmonary bypass is acknowledged to be one of the major causes of a complex systemic inflammatory response after cardiac surgery, and it may contribute to postoperative complications and even multiple organ dysfunction. We here compared the cytokine responses and the degree of myocardial injury after coronary artery bypass grafting with or without cardiopulmonary bypass. METHODS: Nine patients underwent off-pump revascularization and 13 with cardiopulmonary bypass. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8 and IL-10 were measured before anesthesia induction, and 5 min, 1, 4, and 20 h after reperfusion to the myocardium. Levels of the MB isoenzyme of creatine kinase (CK-MB) were also measured after the operation. RESULTS: Levels of TNF-alpha were low in both groups. A delayed elevation of IL-6 was noted in the off-pump group. IL-8 and IL-10 levels were significantly higher in the CPB than in the off-pump patients after reperfusion (p=0.006 and 0.001 respectively). Postoperative CK-MB levels were significantly higher in the CPB than in the off-pump group (p=0.001). Cytokine levels correlated with CK-MB values. CONCLUSION: The results indicated that off-pump revascularization was associated with reduced cytokine responses and less severe myocardial injury. The degree of myocardial injury, as defined by CK-MB release, correlated with cytokine release. Intervention designed to reduce cytokine responses in cardiac surgery may be advantageous for patients with severe comorbidity.     

Proinflammatory cytokine levels in hyperthyroidism

BACKGROUND: Among suspected causes of the osteoporosis frequently seen in untreated thyrotoxicosis are the osteotrophic cytokines. We studied serum levels of osteotrophic cytokines including interlukin (IL)-1, IL-6, IL-8 and tumour necrosis factor alpha (TNF-alpha) in patients with various hyperthyroid states. METHODS: Serum cytokines were detected in 4 groups of SUBJECTS: 14 patients with Graves' disease, 9 patients with toxic nodular goitre, 27 patients with toxic multinodular goitre and 30 euthyroid control subjects. The levels of IL-1-beta, IL-6, IL-8 and TNF-alpha in the serum were determined by the IMMULITE autoanalyzer, using a chemoilluminesence method. RESULTS: Compared with euthyroid control subjects, patients with hyperthyroidism had significantly elevated serum levels of IL-8 (506.8 pg/mL v. 7.0 pg/mL, p < 0.001) and TNR-alpha (18.6 pg/mL v. 8.7 pg/mL, p < 0.05). Levels of IL-1-beta (12.2 pg/mL v. 5.0 pg/mL) and IL-6 (30.3 pg/mL v. 5.3 pg/mL) were also higher in controls, but the differences were not statistically significant. Levels of the cytokines were similar in 14 patients with diffuse goitre compared with 36 patients having nodular goitre. Cytokine levels in 20 premenopausal and 20 postmenopausal women with hyperthyroidism were also similar. INTERPRETATION: We conclude that increased circulating cytokine concentrations observed in patients with hyperthyroidism may derive from the activation of humoral reactions in sites other than the thyroid.     

Biochemical changes after trauma and skeletal surgery of the lower extremity: quantification of the operative burden

OBJECTIVE: To quantify changes in variables of inflammation, coagulation, and fibrinolysis in blunt trauma patients with lower extremity fractures who underwent different types of surgical procedures. DESIGN: Prospective, cohort study. SETTING: Level I university trauma center. PATIENTS: We allocated 83 blunt trauma patients in stable condition and 22 patients eligible for elective hip replacement to four treatment groups. INTERVENTIONS: In 34 multiply traumatized patients with femoral fracture (group PTFF) and in 28 patients with an isolated femoral fracture (group IFF), primary unreamed intramedullary nailing for stabilization of the femoral shaft fracture was performed. In 22 patients, an elective uncemented total hip arthroplasty (group THA) was inserted for osteoarthritis, and in 21 control patients, an isolated ankle fracture (group AF) was acutely stabilized. MEASUREMENTS AND MAIN RESULTS: From serially sampled central venous blood, the perioperative concentrations of interleukin (IL)-6, of tumor necrosis factor-alpha, of prothrombin fragments 1 + 2, and of D-dimer cross-linked fibrin degradation products were evaluated. Intramedullary instrumentation for an isolated femur fracture caused a significant perioperative increase in the concentrations of IL-6 (preoperative IL-6, 52 +/- 12 pg/mL; IL-6 30 mins postinsertion, 78 +/- 14 pg/mL; p = .02). This increase was comparable with group THA (preoperative IL-6, 46 +/- 16 pg/mL; IL-6 30 mins postinsertion, 67 +/- 11 pg/mL; p = .03). A positive correlation occurred between both groups (r = .83, p < .0004). Multiple trauma patients demonstrated significantly (p = .0002) higher IL-6 concentrations than all other groups throughout the study period and showed a significant increase after femoral nailing (preoperative IL-6, 570 +/- 21 pg/mL; IL-6 30 mins postinsertion, 690 +/- 24 pg/mL; p = .003), whereas no perioperative change was seen in group AF. The highest IL-6 increases were associated with a longer ventilation time (group PTFF) and a longer period of positive fluid balances (groups PTFF, IFF, THA). The coagulatory variables demonstrated similar perioperative increases in groups IFF and THA, but not in groups PTFF and AF. The IL-6 concentrations and the prothrombin fragments 1 + 2 concentrations correlated between groups THA and IFF at 30 mins and at 1 hr after surgery (r2 = .64, p < .02). In all patients the clinical variables were stable perioperatively. CONCLUSIONS: Major surgery of the lower extremity causes changes to the inflammatory, fibrinolytic, and coagulatory cascades in patients with stable cardiopulmonary function. The inflammatory response induced by femoral nailing is biochemically comparable to that induced by uncemented total hip arthroplasty. In multiple trauma patients, increases, which occurred in addition to those induced by the initial trauma, were measured. Definitive primary femoral stabilization by intramedullary nailing imposes an additional burden to the patient with blunt trauma. A careful preoperative investigation is required to evaluate whether primary definitive stabilization can be performed safely.     

Decrease of serum levels of the anti-inflammatory cytokine interleukin-10 in patients with advanced chronic heart failure

Inflammation plays a significant contributory role in the pathogenesis of chronic heart failure (CHF). Many studies have shown enhanced plasma levels of proinflammatory cytokines [i.e. tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6] in patients with CHF. However, there are only few reports on the regulation of anti-inflammatory cytokines such as IL-10. IL-10 has potent deactivating properties in macrophages and T-cells and thus acts as a down-regulator of cell-mediated immune responses. The aim of the present study was to assess whether serum concentrations of IL-10 significantly differ between patients with CHF and healthy control subjects. Patients with CHF [ n =50; 66.9+/-12.6 years; mean ejection fraction, 22.1+/-9.2%; New York Heart Association (NYHA) class II-IV] and 25 healthy controls (63.6+/-10.2 years) were examined. Of the 50 patients with CHF, 32 patients were taking aspirin (100 mg/day) and 33 patients had lipid-lowering therapy with a statin. Serum IL-10 as well as TNF-alpha concentrations were measured using commercially available immunoassays. Patients with CHF showed significantly lower IL-10 concentrations (2.3+/-1.9 compared with 5.2+/-2.3 pg/ml; P <0.001). Patients with advanced CHF (NYHA class III and IV) had the lowest IL-10 plasma levels. Aspirin and statin therapy did not significantly influence serum levels of IL-10. The ratio of TNF-alpha to IL-10 was significantly higher in patients with advanced CHF (NYHA class III and IV, ratio 3.2+/-1.2 and 3.1+/-1.1 respectively, compared with control 0.4+/-0.2; P <0.01). Our present study demonstrates significantly decreased serum levels of IL-10 in patients with advanced CHF. Since IL-10 is known as a potent anti-inflammatory cytokine, its decrease in advanced CHF may favour the inflammatory milieu in CHF.     

The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data

BACKGROUND: Clarithromycin is an antimicrobial agent that can be used for treatment of chronic obstructive pulmonary disease (COPD) exacerbations with bronchodilator therapy. However, it has also been shown that clarithromycin has antiinflammatory effects by the inhibition of cytokine production. OBJECTIVE: To evaluate the antiinflammatory effect of clarithromycin on serum and sputum interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and leukotriene B4 levels in patients with COPD. METHODS: Thirty men with mild to moderate COPD were enrolled in this prospective, single-center, double-blind, placebo-controlled study. None of the patients was receiving systemic or inhaled corticosteroids during the study. Subjects received either clarithromycin or placebo for 14 days. Before and after this treatment period, spirometric tests and arterial blood gas analysis were performed, blood was drawn for measurement of serum inflammatory markers, and sputum was induced. RESULTS: There were no statistically significant differences in baseline clinical or laboratory parameters between the groups. After the treatment, the induced sputum total cell counts, and IL-8 and TNF-alpha levels decreased significantly in the clarithromycin group compared with pretreatment levels (mean +/- SD IL-8 1606 +/- 367.3 vs 882 +/- 143.6 pg/mL, p = 0.001; TNF-alpha 638.2 +/- 287.5 vs 390 +/- 235 pg/mL, p = 0.001). Similarly, decreases in serum inflammatory markers were found in the clarithromycin group while there was no significant change in the placebo group. CONCLUSIONS: This study demonstrated that the decrease in IL-8 and TNF-alpha levels might be related to the antiinflammatory effect of clarithromycin. Thus, we suggest that the use of clarithromycin in COPD exacerbations may either treat the infection or help control the inflammation. Future studies are needed to determine the clinical significance of these findings.     

Clinical features and treatment outcome of idiopathic membranous nephropathy in Chinese patients

We retrospectively studied the clinical course and treatment outcome of idiopathic membranous nephropathy (IMN) amongst 38 Chinese patients (25 male, 13 female, age 51.6 +/- 14.6 years, follow-up duration 58.2 +/- 51.1 months) who presented over a 10-year review period. Eight never received any form of specific treatment (group I), seven received oral corticosteroid alone for 6-9 months (group II), 17 were given corticosteroid plus cyclophosphamide for 6-12 months (group III), and six were treated with methylprednisolone alternating with chlorambucil every other month for 6 months (group IV). No untoward effect from drugs sufficient to alter the dosage used was recorded. After 6 months of treatment, over 50% of patients went into remission: a significant reduction in proteinuria (p = 0.01, 0.01, 0.02) with a corresponding rise in serum albumin levels (p = 0.01, 0.01, 0.04) was observed in groups II, III, and IV, respectively, but not in group I. During follow-up, one patient in each of groups I, III, IV, and two of group II developed renal function deterioration, which correlated with an abnormal presenting serum creatinine. In six group I and eight group III patients who have been followed for at least 5 years, there was progressive reduction in proteinuria in group III (p < 0.05), but not in group I: serum creatinine has remained unchanged in both groups. IMN runs a benign course in Chinese patients in Hong Kong, with 2.6% of patients going into end-stage renal failure during the study period. Contrary to reports in Caucasians, there is similar treatment response to steroid alone or a combination of steroid and cytotoxic agents.     

Cerebrospinal fluid of patients administered moxifloxacin modulates the secretion of cytokines from human monocytes

To evaluate the ex vivo immunomodulatory properties of moxifloxacin, we applied serum and cerebrospinal fluid (CSF) samples from 50 patients who received a single oral dose of 400 mg. Patients were divided into 5 groups according to time lapsing between sampling and drug intake: group I, 0.5 to 1 h; group II, 1 to 2 h; group III, 2 to 4 h; group IV, 4 to 6 h; and group V, 6 to 8 h. Samples were added to cultures of U937 monocytes stimulated by 10 ng/mL of lipopolysaccharide (LPS) and 1 x 10(5) colony-forming unit (CFU) of 1 heat-killed penicillin-resistant isolate of Streptococcus pneumoniae. Concentrations of cytokines were estimated in supernatants. Concentrations of interleukin (IL)-1beta, IL-10, and IL-12 released after stimulation by LPS were significantly decreased by CSF of groups I, IV, and V. After stimulation by the heat-killed isolate, concentrations of tumor necrosis factor alpha (TNF-alpha), IL-1beta, IL-6, and IL-10 were increased in the presence of CSF of group III; those of IL-12p70 were decreased by CSF of groups I and II. Concentrations of IL-1beta, IL-6, and IL-8 drawn after stimulation by LPS were significantly decreased upon addition of serum from all groups. After stimulation by the heat-killed isolate, concentrations of TNF-alpha were decreased by serum drawn from all patients; IL-1beta was increased after addition of serum of groups I, II, and V. It is concluded that CSF and serum of patients administered moxifloxacin may effectively modulate the production of pro- and anti-inflammatory cytokines by human monocytes. These results render new perspectives for the therapy for meningitis.     

Perfluorocarbon blocks tumor necrosis factor-alpha-induced interleukin-8 release from alveolar epithelial cells in vitro

OBJECTIVE: To determine whether tumor necrosis factor (TNF)-alpha-induced interleukin (IL)-8 production by pulmonary alveolar epithelial cells is blocked by perfluorocarbon (PFC). DESIGN: Controlled, laboratory investigation of IL-8 production by pulmonary alveolar epithelial cells after exposure to PFC in vitro. SETTING: University research laboratory. SUBJECT: The human alveolar epithelial cell line with pulmonary type II (A549) cell properties. INTERVENTIONS: The A549 cells on a polycarbonate porous filter were stimulated either on the apical or the basolateral side with TNF-alpha. To determine TNF-alpha-induced IL-8 production, IL-8 was measured by using a human IL-8 kit in both control and experimental groups. MEASUREMENTS AND MAIN RESULTS: TNF-alpha stimulation induced a large increase in IL-8. When PFC was added to the medium immediately after TNF-alpha stimulation, PFC separated the medium from the cells and IL-8 production was markedly reduced (TNF-alpha alone, 8342+/-470 pg vs. TNF-alpha followed by PFC, 417+/-88 pg, p < .05). Preincubation of A549 cells with PFC for 24 hrs before stimulation with TNF-alpha followed by removal of PFC did not affect IL-8 production (8834+/-204 vs. 8342+/-470 pg; p = NS). When added to the lower chamber, TNF-alpha also induced IL-8 production unaffected by the addition of PFC to the upper chamber. The decrease in TNF-alpha-induced IL-8 production depended on the time of PFC administration after the initiation of TNF-alpha stimulation. The earlier PFC was added, the more pronounced the diminution was in IL-8. CONCLUSIONS: PFC appears to function as a physical barrier, thus reducing cytokines produced by alveolar epithelial cells in vitro. This mechanism may partially explain the decreased inflammatory response observed during liquid ventilation in models of acute lung injury.     

Methylprednisolone prevents inflammatory reaction occurring during cardiopulmonary bypass: effects on TNF-alpha, IL-6, IL-8, IL-10

OBJECTIVE: This study examined the correlation between tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-8, IL-10 and methylprednisolone pretreatment. METHODS: This is a prospective, randomized and double-blinded study. Sixty patients undergoing coronary artery bypass grafting (CABG) were randomized to receive either intravenous methylprednisolone (n = 30, Group M) or intravenous placebo (n = 30, Group S). The patients received intravenously either 30 mg/kg methylprednisolone (Group M) or placebo (Group S) 10 min before and after cardiopulmonary bypass (CPB). In an intensive care unit (ICU), four additional doses were given at 6-hourly intervals. Blood samples for the measurements of TNF-alpha, IL-6, IL-8 and IL-10 were obtained before induction of anaesthesia (T0 = control value), after induction (T1), before starting CPB (T2), after aortic declamping (T3), at the end of CPB (T4) and 6 hours (T5), 12 hours (T6) and 24 hours (T7) after skin closure. Creatine kinase (CK) and creatine kinase isoenzyme MB (CK-MB) were evaluated at the following intervals: T0, T5, T6 and T7. RESULTS: When compared with the control value, TNF-alpha, IL-6 and IL-8 significantly increased in Group S and Group M (p < 0.05), but these values were significantly greater in Group S than in Group M (p < 0.05). In comparison with the control value, IL-10 increased in both groups (p < 0.05), but was significantly greater in Group M than in Group S (p < 0.05). CK and CK-MB were increased in both groups in postoperative values compared to control values. In Group S, CK and CK-MB levels were significantly lower than in Group M (p < 0.05). CONCLUSION: In this study, we have found that preoperative administration of methylprednisolone has decreased TNF-alpha, IL-6 and IL-8 release, and increased the perfusing IL-10 levels after CPB. Thus, methylprednisolone may decrease the inflammatory response during the CPB procedure.     

Pathogenic role of interleukin-6 in the development of sepsis. Part I: Study in a standardized contact burn murine model

OBJECTIVE: To establish a representative model for the evaluation of interleukin (IL)-6 and IL-6 receptor for pathogenicity and lethality in the postburn period. DESIGN: Ten-week-old C 57 BL/6J mice received a 20% body surface area contact burn and/or lipopolysaccharide (LPS) 48 hrs later. Standardized burns were created with a metal stamp of 150 degrees C of defined pressure and surface area (2.4525 Newton/0.00166 m2) over a period of 11 secs. The depth of dermal injury was verified histologically. The following groups were formed: I: no burn, no LPS (n = 35); II: burn, no LPS (n = 140); III, no burn, LPS (n = 56); and IV, burn, LPS (n = 80), to study the effect of burn alone, sepsis alone, or the combination. Lethal LPS dose (LD100) was determined by application of LPS in increasing doses (200, 300, 400, and 500 microg, n = 32) after burns. MEASUREMENTS: Concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), and leukocytes, platelets and organ pathology were evaluated. SETTING: Research laboratory. RESULTS: Burn and LPS showed an additive effect on the release of IL-6 but not of TNF-alpha and IFN-gamma. Leukocyte and platelet numbers decreased significantly (group IV) compared with the other groups (I-III). The maximal levels of IL-6 in group IV were reached earlier than those of TNF-alpha. The contact burn model has a mortality rate of 30%, which is close to clinical outcome. We found the model of contact burn superior to scald or flame burn models. A dose of 400-microg LPS was found to be the lethal LPS dose (LD100). CONCLUSIONS: Our data suggest that preexisting burn injury increases the response to endotoxin. TNF-alpha is not involved in priming. IL-6 on the other hand is a very representative parameter for priming. Because TNF-alpha was obviously not the causative factor, it was concluded that the application of anti-IL-6-mAb should be of great value. Therefore, a therapeutic application was designed, see part II.