组织因子、白介素-6和血管内皮生长因子对CHF患者预后的判断价值

目的:研究组织因子(tissuefactor,TF)、白细胞介素-6(interleukin-6,IL-6)和血管内皮生长因子(vascular endothelial growth factor,VEGF)在充血性心力衰竭(CHF)患者预后中的地位。方法:选择59例CHF患者和20例健康者,应用酶联免疫吸附法(ELASA)检测血浆中各细胞因子的含量。结果:与对照组相比,CHF患者血浆中TF、IL-6与VEGF含量明显升高(P<0.05);1年内发生心脏事件的TF、IL-6和VEGF含量分别为(267±32)pg/mL、(412±27)pg/mL和(148±12)pg/mL,与未发生心脏事件患者血浆中细胞因子含量相比,差异有显著性(P<0.05);线性相关分析IL-6、VEGF含量与TF含量成正相关(r=0.589、r=0.232,P<0.0001);Logistic多因素回归中年龄、糖尿病、甘油三酯、左心室射血分数(≤30%)、IL-6和TF与CHF患者预后成正相关,VEGF未进入回归模型,TF和IL-6与CHF患者的预后密切相关(r=5.12、r=6.34,P<0.012、P<0.011)。结论:血浆中I...     

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.     

Angiogenic factors in atrial fibrillation: a possible role in thrombogenesis?

BACKGROUND: The precise pathophysiological processes underlying the prothrombotic or hypercoagulable state in atrial fibrillation (AF) remain uncertain. We hypothesized a relationship between abnormal endothelial damage/dysfunction, coagulation, and angiogenic factors, thereby contributing to increased thrombogenicity. METHODS: Plasma levels of von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and tissue factor (TF, an index of coagulation), as well as the angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), were measured by enzyme-linked immunosorbant assay (ELISA) in 59 chronic AF patients. Data were compared to 40 age- and sex-matched healthy controls in sinus rhythm. RESULTS: Plasma vWF, VEGF and Ang-2 were significantly higher in AF patients compared to healthy controls (P=0.005, P=0.0055 and P<0.0001 respectively) but there were no significant differences in plasma Ang-1 or TF levels between the two groups (P=0.925 and P=0.121 respectively). Significant correlations were found between VEGF and vWF levels (Spearman, r=0.262, P=0.011) and between VEGF and Ang-2 (r=0.333, P=0.001). CONCLUSIONS: Raised VEGF in association with Ang-2 and vWF may reflect a link between abnormal endothelial damage/dysfunction and angiogenic factors. These may act together to alter TF expression and endothelial integrity, thereby contributing to the prothrombotic state in AF.     

Factors influencing heart rate variability power spectral analysis during controlled breathing in patients with chronic heart failure or hypertension and in healthy normotensive subjects

A decreased LFP (low-frequency power) spectral component of HRV [HR (heart rate) variability] is a risk factor for sudden death in patients with CHF (chronic heart failure). In the present study, we evaluated factors (age, arterial pressures and HR) influencing LFP and HFP (high-frequency power) components in short-term recordings during controlled breathing in patients with CHF or hypertension, and healthy normotensive subjects. In patients with CHF, we also compared LFP values with known markers of sudden death [NYHA (New York Heart Association) class, HR and ejection fraction]. All HRV measures were significantly lower in patients with CHF than in hypertensive and normotensive subjects (P<0.001), and in hypertensive than in normotensive subjects (P<0.05). Stepwise multiple regression analysis showed that, in patients with CHF, LFP was inversely associated with NYHA class (beta=-0.5, P<0.0001) and HR (beta=-0.2, P=0.001) and was positively associated with ejection fraction (beta=0.28, P<0.0001). In patients with CHF, LFP remained unchanged with age. In normotensive and hypertensive subjects, HFP decreased with age, but in patients with CHF it did not. In the >/=60<70 and >/=70 years of age subgroups, we found no difference between HFP in the three groups studied. Hence, in normotensives and hypertensives, LFP tended to diminish with age (beta=-0.4, P<0.0001 in normotensives; beta=-0.4, P<0.001 in hypertensives) and was inversely associated with HR (beta=-0.2, P=0.002 in normotensives; beta=-0.3, P=0.002 in hypertensives). Conversely, in patients with CHF, LFP is predominantly influenced by NYHA class, HR and ejection fraction, but not by age. LFP might therefore increase the sensitivity of factors already used in stratifying the risk of sudden death in patients with CHF.     

Microparticle‐associated tissue factor activity,venous thromboembolism and mortality in pancreatic,gastric, colorectal and brain cancer patients

Summary. Background: Tissue factor (TF) expression by tumors contributes to tumor growth. Release of TF‐positive microparticles (MPs) may contribute to venous thromboembolism (VTE). Objectives: To conduct a prospective cohort study to determine whether elevated MP‐associated TF (MP‐TF) activity is predictive of VTE and mortality in four cancer types. Patients/Methods: We determined MP‐TF activity in pancreatic, gastric, colorectal and brain cancer patients. We used a chromogenic endpoint assay for all patients and also a chromogenic kinetic assay for patients with pancreatic and brain cancer. Results: During follow‐up, 12/60 (20%) pancreatic, 6/43 (14%) gastric, 12/126 (10%) colorectal and 19/119 (16%) brain cancer patients developed VTE; 46/60 (77%), 30/43 (70%), 47/126 (37%) and 67/119 (56%), respectively, died. MP‐TF activity levels were highest in pancreatic cancer. We did not find a statistically significant association of MP‐TF activity with the risk of VTE in any of the four cancer types by using two statistical methods. An association of MP‐TF activity with the risk of mortality was detected in pancreatic cancer with the endpoint assay (hazard ratio [HR] 1.8 and 95% confidence interval [CI] 1.4–2.3 per doubling of activity, P < 0.001) and the kinetic assay (HR 1.2, 95% CI 1.1–1.4, P < 0.001); adjustment for type of treatment was not performed. In pancreatic cancer, MP‐TF activity correlated with D‐dimer level (endpoint assay, r = 0.51; chromogenic assay, r = 0.48), and a correlation between assays (r = 0.61) was found. Conclusion: MP‐TF activity was not associated with future VTE in pancreatic, gastric, colorectal and brain cancer. However, we found a strong association of MP‐TF activity with mortality in pancreatic cancer. MP‐TF activity might be reflective of an aggressive pancreatic cancer phenotype.     

Selected growth factors in peritoneal dialysis: their relationship to markers of inflammation, dialysis adequacy, residual renal function, and peritoneal membrane transport.

OBJECTIVES: Markers of chronic inflammation, acute-phase reactants, and growth factors may be concomitantly involved in a number of pathologic processes in the general population and uremic patients. In addition, growth factors may influence peritoneal membrane transport characteristics. However, the association between plasma growth factors, markers of chronic inflammation, and peritoneal membrane transport remains largely unknown.The aim of this study was to evaluate the relationship between plasma levels of selected growth factors [basic fibroblast growth factor (bFGF), transforming growth factor beta1 (TGFbeta1), vascular endothelial growth factor (VEGF)] and markers of chronic inflammation [interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen] in continuous ambulatory peritoneal dialysis (CAPD) patients.The potential link between the above substances and dialysis adequacy was also explored. DESIGN: Single-center, cross-sectional study. SETTING: Peritoneal Dialysis Unit, Medical Faculty, Jagiellonian University Hospital, Kraków, Poland. PATIENTS: 32 stable end-stage renal disease patients (13 M, 19 F; mean age 53.6 +/- 13.7 years) on CAPD for a median period of 19.5 months. Patients free from signs and symptoms of any inflammatory disease (including peritonitis) for at least 3 months were included into the study. All patients underwent measurements of dialysis dose [Kt/V, weekly creatinine clearance (wCCr)] and peritoneal solute transport using a standard peritoneal equilibration test (PET). METHODS: TGFbeta1, bFGF, VEGF, and IL-6 were measured with ELISA, CRP was assayed with immunonephelometry, and fibrinogen with Multifibren U reagent (Dade Behring Marburg GmbH, Marburg, Germany). Nephron 97 for Windows software was used to assess dialysis adequacy. RESULTS: Significant positive correlations between plasma bFGF and IL-6, as well as fibrinogen concentrations (R = 0.36, p < 0.05 and R = 0.39, p < 0.05, respectively), were found. VEGF correlated significantly with IL-6 and CRP (R = 0.65, p < 0.0001 and R = 0.51, p < 0.005, respectively). An association between VEGF and bFGF was also found (R = 0.59, p < 0.0005). Serum level of TGFbeta1 revealed no relationship with any marker of acute-phase activation, remaining growth factors, or dialysis adequacy. Positive correlation between TGFbeta1 concentration and dialysate-to-plasma ratio for creatinine in PET (R = 0.35, p < 0.05) was found. In addition, patients with lower solute transport (low/low-average transporters) had lower serum levels of both bFGF and TGFbeta1 compared to patients with higher solute transport. Patients with total wCCr > 60 L/ week/m2 were characterized by lower levels of bFGF and IL-6. Serum level of IL-6 and plasma levels of bFGF and VEGF were significantly lower among subjects with residual renal function (RRF) > 2.0 mL/minute. CONCLUSIONS: Our results indicate that systemic inflammation in peritoneal dialysis patients is associated with increased plasma VEGF and bFGF but not TGFbeta1. The negative correlation with RRF suggests that either the renal clearance of these cytokines and growth factors may contribute to their elimination, or cytokines and growth factors have a negative impact on RRF. We also suggest an association between serum levels of growth factors tested and peritoneal membrane function.     

Enalapril prevents clinical proteinuria in diabetic patients with low ejection fraction

OBJECTIVE: Clinical proteinuria is a risk factor for both end-stage renal disease and cardiovascular disease. The prevalence of clinical proteinuria, its correlates and predictive value, and the effect of ACE inhibitors in preventing clinical proteinuria in diabetic and nondiabetic patients with left ventricular (LV) dysfunction are unknown. RESEARCH DESIGN AND METHODS: The Studies of Left Ventricular Dysfunction (SOLVD) trials were analyzed to determine the baseline distribution of clinical proteinuria and related cardiovascular risk factors, the effect of baseline proteinuria on the risk of hospitalization for congestive heart failure (CHF) and mortality, and the effect of enalapril in preventing new clinical proteinuria. RESULTS: A total of 5,487 out of 6,797 SOLVD participants (81%) were assessed for proteinuria at baseline. A total of 177 patients (3.2%) had baseline proteinuria. These patients had significantly higher systolic (137 vs. 125 mmHg, P < or = 0.001) and diastolic (83 vs. 77 mmHg, P < or = 0.001) blood pressure levels, a higher prevalence of diabetes (41 vs. 18%, P < or = 0.001), a lower ejection fraction (26.2 vs. 27.3%, P < or = 0.05), and greater degree of CHF (New York Heart Association [NYHA] class III/IV in 22 vs. 10%, P < or = 0.001) than patients without baseline proteinuria. Patients with baseline proteinuria also had higher rates of hospitalization for CHF (relative risk 1.81 [95% CI 1.37-2.41], P = 0.0001) and mortality (1.73 [1.34-2.24], P = 0.0001). Enalapril prevented clinical proteinuria in diabetic patients (0.38 [0.17-0.81], P = 0.0123) but not in nondiabetic patients (1.43 [0.77-2.63], P = 0.2622) without baseline proteinuria. CONCLUSIONS: Clinical proteinuria is an independent predictor of hospitalization for CHF and mortality in diabetic and nondiabetic patients with LV dysfunction. Enalapril significantly reduces the risk of clinical proteinuria in diabetic patients with LV dysfunction.     

The changing face of sympathetic overactivity in hypertension

Background. The precise pathophysiological processes underlying the prothrombotic or hypercoagulable state in atrial fibrillation (AF) remain uncertain. We hypothesized a relationship between abnormal endothelial damage/dysfunction, coagulation, and angiogenic factors, thereby contributing to increased thrombogenicity.

Methods. Plasma levels of von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and tissue factor (TF, an index of coagulation), as well as the angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin‐1 (Ang‐1) and angiopoietin‐2 (Ang‐2), were measured by enzyme‐linked immunosorbant assay (ELISA) in 59 chronic AF patients. Data were compared to 40 age‐ and sex‐matched healthy controls in sinus rhythm.

Results. Plasma vWF, VEGF and Ang‐2 were significantly higher in AF patients compared to healthy controls (P = 0.005, P = 0.0055 and P<0.0001 respectively) but there were no significant differences in plasma Ang‐1 or TF levels between the two groups (P = 0.925 and P = 0.121 respectively). Significant correlations were found between VEGF and vWF levels (Spearman, r = 0.262, P = 0.011) and between VEGF and Ang‐2 (r = 0.333, P = 0.001).

Conclusions. Raised VEGF in association with Ang‐2 and vWF may reflect a link between abnormal endothelial damage/dysfunction and angiogenic factors. These may act together to alter TF expression and endothelial integrity, thereby contributing to the prothrombotic state in AF.     

Nicotinamide inhibits endotoxin-induced monocyte tissue factor expression

Summary.  Background : Tissue factor (TF) is the main initiator of blood coagulation in vivo . Its increased expression on activated monocytes is associated with thrombotic complications and mortality in conditions such as sepsis, disseminated intravascular coagulation and coronary artery disease. Objective : The effect of the vitamin B derivative nicotinamide on endotoxin-induced monocyte TF and CD11b expression, soluble interleukin(IL)-6, and clotting onset time (COT) was studied. Methods : Experiments were conducted in human peripheral blood leukocyte suspensions and in whole blood from eight healthy volunteers. Free oscillating rheometry (measuring COT) and flow cytometry were applied to evaluate the effect of endotoxin on TF, CD11b, IL-6 and the overall coagulation response of plasma supplemented with activated autologous leukocytes. Results : In response to endotoxin, there was an increase in IL-6, TF and CD11b expression and a procoagulant shift of COT. At 4 mmol L⁻¹ nicotinamide, inhibition of TF expression and IL-6 and a normalization of COT were seen. At 16 mmol L⁻¹ nicotinamide, CD11b decreased also. The level of monocyte TF expression correlated with the COT readings, and the endotoxin-induced procoagulant shift of COT could be totally inhibited by blocking TF with an inhibitory antibody. Conclusions : These results demonstrate the ability of nicotinamide to inhibit the activation of coagulation associated with endotoxemia. We have previously shown that nicotinamide exerts strong anti-inflammatory effects. Evidence is accumulating for nicotinamide to have a therapeutic potential in modulating disease states in which there is a profound activation of coagulation and inflammation, such as in sepsis and disseminated intravascular coagulation.     

慢性心力衰竭中细胞因子的变化及其临床意义

目的观察肿瘤坏死因子α（TNF-α）、白介素6（IL-6）、C-反应蛋白（CRP）、转化生长因子-β1（TGF-β1）在慢性心力衰竭（CHF）患者中的变化及其临床意义。方法抽取49例基础疾病为缺血性心脏病、扩张型心肌病及高血压性心脏病的CHF患者和30例健康体查者的血清,用酶联免疫检测法（ELISA）测定血清TNF－α、IL－6及TGF-β1浓度,用速率散射比浊法测定CRP浓度,超声心动图测定左室射血分数（LVEF）,并进行比较分析。结果CHF患者血清TNF-α、IL－6和CRP水平明显高于健康对照组（P〈0．01）,并与LVEF呈显著负相关（r＝－0．72,P〈0．01;r＝－0．78,P〈0．01;r＝－0．81,P〈0．01）。CHF患者血清TGF-β1水平明显低于健康对照组（P〈0．01）,并与LVEF呈显著正相关（r＝0．74,P〈0．01）。且心衰越重,上述变化越明显。结论CHF患者细胞因子网络失衡,炎性反应因子升高,抗炎因子降低,失衡的细胞因子网络参与了CHF的发生和发展。细胞因子的浓度可以作为CHF患者评估的参考指标。     

Plasma vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in diabetes: implications for cardiovascular risk and effects of multifactorial intervention

OBJECTIVE: Vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-1 and Ang-2 are mediators of angiogenesis. More recent data suggest that the balance between these growth factors may affect vascular endothelial integrity. Because diabetes is closely associated with endothelial perturbation, we studied plasma levels of these angiogenic growth factors in patients with diabetes; their relationship with glycemia, inflammation, and endothelial damage/dysfunction; and the effect of intensified cardiovascular risk management. RESEARCH DESIGN AND METHODS: We measured plasma VEGF, Ang-1, and Ang-2 alongside plasma von Willebrand factor (vWf) and urine albumin-to-creatinine ratio (marking endothelial damage/dysfunction) and interleukin (IL)-6 in 94 patients (38 with overt cardiovascular disease [CVD]) with diabetes and 34 normal control subjects. RESULTS: Plasma vWf (P=0.009), IL-6 (P <0.001), VEGF (P=0.001), and Ang-2 (P=0.001), but not Ang-1 (P=0.635), were higher in diabetic patients with and without CVD than in control subjects. On multivariate analysis, HbA1c was an independent predictor of plasma VEGF (P=0.032) and Ang-2 (P=0.015). Of the 94 patients, a subgroup of 33 patients with and 31 patients without CVD participated in a year of intensified cardiovascular risk management. HbA1c and LDL cholesterol reduced significantly with treatment, along with associated reductions in plasma vWf and VEGF in both groups (P <0.001). Ang-2 decreased (P <0.001) only in patients without CVD. There were no significant changes in plasma IL-6 levels in both groups. CONCLUSIONS: Plasma Ang-2 (but not Ang-1), like VEGF levels, are selectively elevated in patients with diabetes and are associated with indexes of endothelial damage/dysfunction, regardless of vascular disease. Intensive multifactorial intervention is associated with reductions in plasma VEGF, vWf, and (in patients without CVD) Ang-2 levels, possibly reflecting an improved vascular profile with treatment.     

多发性骨髓瘤骨髓基质细胞分泌IGF-1、VEGF和IL-6的动态变化

目的研究骨髓基质细胞（BMSCs）分泌的IL-6、血管内皮生长因子（VEGF）、胰岛素样生长因子（IGF-1）在多发性骨髓瘤（MM）进展中的变化和意义以及这三种细胞因子之间的相互作用。方法取28例MM患者（分为活动组和稳定组）、10例缺铁性贫血患者（对照组）及2例意义未明的单克隆免疫球蛋白血症（MGUS）患者的骨髓，建立BMSCs的体外培养体系。用ELISA法检测单独培养的BMSCs，以及BMSCs与U266细胞混合培养后IL-6、VEGF、IGF-1在培养上清中的浓度；应用外源性IL-6、VEGF、IGF-1作用于BMSCs后三种细胞因子的分泌量。结果①单独培养BMSCs所分泌的IL-6和VEGF浓度，对照组〈稳定组〈活动组（P〈0．05），IGF-1的浓度在三组之间差异无统计学意义（P〉0．05）；②U266细胞和BMSCs均分泌IL-6、VEGF和IGF-1；U266与BMSCs黏附后IL-6、VEGF、IGF-1的分泌明显升高（P〈0．05）；混合培养上清中IL-6、VEGF、IGF-1浓度，对照组〈稳定组〈活动组（P〈0．05）；③BMSCs分别加入外源性IL＆／VEGF／IGF-1后，诱导VEGF、IGF-1／IL-6、IGF一1／VEGF、IL-6分泌增加（P〈0．05）；④MGUS患者BMSCs分泌IL-6、VEGF、IGF-1的水平与对照组相似。结论BMSCs分泌的细胞因子IL-6、VEGF、IGF-1与MM的进展有关；IL-6、VEGF、IGF-1三种细胞因子影响BMSCs的分泌，三者之间有相互促进分泌的作用。     

再生障碍性贫血患者血清sVCAM-1、IL-18和VEGF水平及其临床意义

本研究探讨再生障碍性贫血（AA）患者血清可溶性血管细胞黏附分子-1（sVCAM-1）、白介素18（IL-18）和血管内皮生长因子（VEGF）水平及其临床意义。采用双抗体夹心酶联免疫吸附法（ELISA）检测30例AA患者和25例正常人血清sVCAM—1、IL-18和VEGF水平。结果表明：AA患者血清sVCAM-1和IL-18水平分别为（839．08±173．97）ng／ml和（380．354-47．76）pg／ml,较正常对照组的（538．164-91．21）rig／ml和（256．39±59．52）pg／ml明显升高（p均〈0．01）;且重型AA的sVCAM-1和IL-18水平[（969．94±182．54）ng／m]、（388．96±46．06）pg／ml]较慢性AA的sVCAM和IL-18水平[（709．26±165．32）ng／ml、（352．21±47．08）pg／ml]升高更为明显（P〈0．01;P〈0．05）;而AA患者血清VEGF水平[（69．634-27．42）pg／ml]较正常对照组[（125．62±32．15）pg／ml]明显降低（P〈0．01）,且重型AA[（51．30±29．86）pg／ml]较慢性AA[（80．02±25．14）pg／ml]降低更显著（P〈0．01）。AA患者治疗后血清sVCAM-1和IL—18水平[（623．84±176．57）ng／ml、（295．25±89．31）pg／ml]较治疗前[（847．33±186．41）ng／ml,（368．50±62．02）pg／ml]明显降低（p〈0．01;P〈0．05）,而VEGF治疗后水平[（90．61±28．76）pg／ml]较治疗前[（63．93±26．04）pg／ml]则明显升高（p〈0．05）。结论：高水平的sVCAM-1、IL-18及低水平的VEGF细胞因子,可能与AA的发生、发展及病情进展相关。     

Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and correlates with vascular permeability

Meningococcal septic shock is an important cause of morbidity and mortality in children and young adults worldwide and is the prototypical gram-negative septic shock. One of the key factors in the development of shock is increased microvascular permeability. Vascular endothelial growth factor (VEGF) is a central factor in angiogenesis and is an important mediator of vascular permeability. Thirteen patients with meningococcal infection (eight presenting with shock) were investigated in the early phase of invasive meningococcal disease. Cytokines, complement activation, and VEGF plasma concentrations were measured during the first 48 h on the pediatric intensive care unit. Increased cytokine concentrations and activation of the complement system were observed. VEGF plasma concentrations were increased (median 193 pg/mL, range 71-1082) and were highest in the presence of shock (208 pg/mL, 169-1082) compared with patients presenting without shock (92 pg/mL range 71-299). VEGF concentration at admission correlated with the severity of disease (pediatric risk of mortality score, R=0.90 [Spearman], P=0.0001) and the amount of fluids administered within the first 24 h (R=0.90, P<0.0001). In all patients, a decrease in VEGF was associated with a decrease in fluid intake during t=24 to 48 h. The results suggest that apart from correlation with IL-1 beta, -10, -12, and complement activation, microvascular permeability in sepsis is also closely linked to the plasma concentration of VEGF. The role of VEGF in sepsis-associated increased microvascular permeability needs further exploration and may represent a new therapeutic target.     

Myocardial gene expression of leukaemia inhibitory factor, interleukin-6 and glycoprotein 130 in end-stage human heart failure

BACKGROUND: Studies in different animal models and plasma analyses in humans suggest that members of the interleukin-6 (IL-6) cytokine family may be involved in the pathogenesis of congestive heart failure (CHF). Accordingly, we have examined IL-6-related cytokines in chronic CHF in humans by analysing gene and protein expression in myocardium derived from patients with end-stage heart failure and donor hearts. METHODS: Gene expression of cytokines/receptors of the IL-6 family was documented in myocardial samples using cDNA array hybridization and RNase protection assays. Immunohistochemistry was used to detect leukaemia inhibitory factor (LIF), IL-6 and glycoprotein 130 (gp130) in myocardial tissues. RESULTS: Myocardial gene activity was documented for the majority of IL-6 family cytokines and their receptors. Immunohistochemical analysis localized IL-6, LIF and their common receptor subunit gp130 to myocytes and vascular smooth muscle cells. LIF mRNA levels were enhanced in the left ventricles of CHF patients relative to the left ventricles of donor hearts (patients 4.6 +/- 4.7 vs. donors 0.3 +/- 0.3, P < 0.005). Myocardial IL-6 and gp130 mRNA levels were not statistically different between patients and donors, but in contrast to LIF mRNA expression in heart explants, gp130 mRNA levels were significantly higher in left atrium compared with left ventricle in both patients and donors. CONCLUSIONS: Both mRNA and proteins of gp130 and its ligands IL-6 and LIF are expressed in both nonfailing and failing human myocardium. The elevated LIF mRNA levels in left ventricles from patients with end-stage heart failure suggest a role for LIF in the pathogenesis of CHF.     

Vitreous levels of vascular cell adhesion molecule and vascular endothelial growth factor in patients with proliferative diabetic retinopathy: a case-control study

OBJECTIVE: To evaluate the intravitreous concentration of vascular cell adhesion molecule (VCAM)-1 in diabetic patients with proliferative diabetic retinopathy (PDR) and the relationship of VCAM-1 with vascular endothelial growth factor (VEGF). RESEARCH DESIGN AND METHODS: Serum and vitreous fluid samples were obtained simultaneously at the onset of vitrectomy from 20 diabetic patients with PDR and 20 nondiabetic control subjects with nonproliferative ocular disease. Both groups were matched by serum levels of VCGM-1 and VEGF. VCAM-1 and VEGF were determined by enzyme-linked immunosorbent assay. Statistics were determined using the Mann-Whitney U test and Spearman's rank correlation test. RESULTS: The intravitreous concentration of VCAM-1 was signifcantly elevated in diabetic patients with PDR compared with control subjects (26 ng/ml [19-118] vs. 22 ng/ml [20-47], P < 0.05). A direct correlation between VCAM-1 and total vitreous proteins was detected in diabetic patients (r = 0.64, P = 0.003), but not in control subjects. After adjusting for total intravitreous proteins, VCAM-1 was significantly lower in diabetic patients with PDR than in control subjects (8.2 ng/ml [4-31.4] vs. 43.1 ng/ml [9.7-100], P < 0.001). Intravitreous VEGF concentrations were higher in patients with PDR than in control subjects in absolute terms (1.34 ng/ml [0.16-6.22] vs. 0.009 ng/ml [0.009-0.044], P < 0.0001) and after correcting for total vitreal proteins (0.33 ng/ml [0.01-2.3] vs. 0.013 ng/ml [0.003-0.035], P = 0.0001). Finally, the vitreous ratio of VCAM-1 to proteins correlated with the vitreous ratio of VEGF to proteins in both diabetic patients (r = 0.74, P = 0.001) and control subjects (r = 0.84, P = 0.005). CONCLUSIONS: The low proportion of VCAM-1 in relation to total vitreal proteins observed in diabetic patients with PDR suggests that VCAM-1 is quenched by diabetic retina. In addition, the direct correlation detected between VCAM-1 and VEGF suggests that cellular adhesion and neovascularization may be linked processes.     

替米沙坦对慢性心衰患者心功能、神经内分泌的影响

[目的]观察替米沙坦对慢性心衰（CHF）患者心功能、神经内分泌的影响。[方法]60例CHF病人随机分为替米沙坦组（30例）和对照组（30例）,对照组予常规治疗,替米沙坦组在常规治疗基础上口服替米沙坦80mg／d,治疗6个月。观察治疗前后两组左室舒张末期内径（LVEDd）和左室射血分数（LVEF）的变化,并用放射免疫法测定血浆血管紧张素Ⅱ（AngⅡ）、内皮素-1（ET-1）和脑钠肽（BNP）含量。[结果]治疗6个月后,替米沙坦组LVEDd及血浆AngⅡ、ET-1和BNP水平均较治疗前明显下降（P〈0．05）,LVEF明显升高（P〈0．05）,与对照组比较,差异有统计学意义（P〈0．05）。[结论]替米沙坦能改善CHF病人心功能和神经内分泌机制失调。     

Vascular endothelial growth factor expression in monocytes from patients with primary antiphospholipid syndrome

BACKGROUND: One of the described mechanisms leading to thrombosis in antiphospholipid syndrome (APS) is overexpression of tissue factor (TF) in the monocytes and endothelial cells of patients with antiphospholipid antibodies (aPL). Vascular endothelial growth factor (VEGF) may stimulate monocyte TF expression through its receptor, the tyrosine kinase Flt-1. OBJECTIVES: This study aimed to analyze the following in monocytes of 55 primary APS patients: VEGF and Flt-1 expression levels, their potential regulation by aPL, and the association of VEGF and Flt-1 expression with the increased TF expression found in APS patients. RESULTS: Purified monocytes from APS patients showed higher levels of VEGF and Flt-1 than healthy donors, which further correlated with immunoglobulin G (IgG) anticardiolipin titers and TF expression rank. Moreover, monocyte VEGF and Flt-1 levels were significantly higher in patients with than in patients without previous thrombosis. In vitro, IgG from APS patients increased monocyte VEGF and Flt-1 expression in a dose-dependent manner. VEGF and Flt-1 expression was significantly inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580; this suggests the involvement of this kinase in the aPL-induced VEGF and Flt-1 upregulation. CONCLUSIONS: Our data show, for the first time in vivo, that monocytes from primary APS patients have an increased expression of VEGF and Flt-1. Furthermore, in vitro results indicated that this cytokine is produced by monocytes when treated with aPL, and that the p38 MAPK signaling pathway plays an important role. Thus, VEGF might act as a regulatory factor in aPL-mediated monocyte activation and TF expression, thereby contributing to the proinflammatory-prothrombotic phenotype of APS patients.     

Increased systemic inflammation and oxidative stress in patients with worsening congestive heart failure: improvement after short-term inotropic support

In the present study, we evaluated circulating pro-inflammatory mediators and markers of oxidative stress in patients with decompensated CHF (congestive heart failure) and assessed whether clinical recompensation by short-term inotropic therapy influences these parameters. Patients with worsening CHF (n=29, aged 61.9+/-2.7 years), NYHA (New York Heart Association) class III-IV, and left ventricular ejection fraction of 23.7+/-1.8% were studied. Controls comprised age-matched healthy volunteers (n=15; 54.1+/-3.2 years). Plasma levels of cytokines [IL (interleukin)-6 and IL-18], chemokines [MCP-1 (monocyte chemotactic protein-1)], adhesion molecules [sICAM (soluble intercellular adhesion molecule), sE-selectin (soluble E-selectin)], systemic markers of oxidation [TBARS (thiobarbituric acid-reactive substances), 8-isoprostaglandin F(2alpha) and nitrotyrosine] and hs-CRP (high-sensitivity C-reactive protein) were measured by ELISA and colorimetric assays at admission and 30 days following 72-h milrinone (n=15) or dobutamine (n=14) infusion. Plasma IL-6, IL-18, sICAM, E-selectin, hs-CRP and oxidative markers were significantly higher in patients on admission before inotropic treatment compared with controls (P<0.05). Short-term inotropic support improved clinical status as assessed by NYHA classification and by the 6-min walk test and significantly decreased plasma levels of IL-6, IL-18, sICAM, hs-CRP and markers of oxidation (P<0.05) at 30 days. The effects of milrinone and dobutamine were similar. In conclusion, our results demonstrate that patients with decompensated CHF have marked systemic inflammation and increased production of oxygen free radicals. Short-term inotropic support improves functional status and reduces indices of inflammation and oxidative stress in patients with decompensated CHF.     

慢性心力衰竭患者血浆D-二聚体与LVEF检测及意义

[目的]通过定量检测慢性心力衰竭患者血浆D-二聚体水平,探讨慢性心力衰竭与高凝状态的关系,为慢性心力衰竭抗凝治疗提供理论依据.[方法]应用散射免疫比浊法分别定量检测慢性心力衰竭患者（心功能Ⅱ～Ⅳ级）组（n=60）和健康对照组（n=30）血浆D-二聚体含量;应用彩色多普勒超声心动图测定慢性心力衰竭患者左心室射血分数（LVEF）;并对心衰患者组按心衰程度、LVEF不同进行分组,分别比较各亚组组间血浆D-二聚体水平,并对结果进行统计学分析.[结果]①慢性心力衰竭患者组血浆D-二聚体含量较健康对照组明显升高,两组比较有显著性差异（P〈0.01）;②随心衰程度加重,D-二聚体水平明显升高,不同心衰程度患者组间比较有显著性差异（P〈0.01）;③随LVEF值降低,D-二聚体水平无明显升高,各不同射血分数（EF）水平患者组间比较无显著性差异（P〉0.05）,两者无明显相关性（r=-0.215,P=0.098）.[结论]①慢性心力衰竭患者体内存在高凝状态;②随心衰程度加重,高凝状态更为严重;③慢性心力衰竭患者左心室射血分数与高凝状态无明显相关性.