Plasma interleukin-1beta, -6, -8 and tumor necrosis factor-alpha as highly informative markers of pelvic inflammatory disease

BACKGROUND: The role of proinflammatory cytokines in pelvic inflammatory disease (PID) is unclear. We therefore determined whether plasma proinflammatory cytokines, interleukin-1beta (IL-1beta), IL-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) were useful plasma markers in PID patients. METHODS: Multiplex bead array analysis was used to measure the plasma levels of proinflammatory cytokines in 50 healthy controls as well as in 41 PID patients before and after routine protocol treatments. RESULTS: IL-1beta, IL-6, IL-8 and TNF-alpha were significantly elevated in PID patients before antibiotic treatment than after treatment. However, IL-8 was not significantly different between healthy controls and PID patients. The relative increase in ratio of IL-6 was significantly correlated with white blood cell count (r=0.448, p=0.003), neutrophil count (r=0.472, p=0.002) and C-reactive protein level (r=0.412, p=0.008). CONCLUSIONS: IL-1beta, IL-6, IL-8 and TNF-alpha may play an important role in the pathogenesis of PID. These biomarkers, particularly IL-6, could be useful adjuncts for the clinical diagnosis of PID.     

Biological variation of interleukin-1beta, interleukin-8 and tumor necrosis factor-alpha in serum of healthy individuals.

Components of biological variation can be used to assess the usefulness of reference values, to evaluate the significance of changes in serial results from an individual and to define objective analytical goals. The aim of the study was to assess, in 15 healthy subjects studied at regular monthly intervals over a period of 6 consecutive months, the biological variation of interleukin-1beta (IL-1beta), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha). Biological variation data (within-subject and between-subject coefficient of variation (CV)) were determined using a simple nested analysis of variance. Derived parameters (index of individuality, reliability coefficient and critical diferences) were calculated from within-subject and between-subject CV. The mean and standard deviation (SD), within-subject CV, between-subject CV, index of individuality and reliability coefficient were as follows: for IL-1beta, 0.67 (0.32) pg/ml, 30%, 36%, 0.85, and 0.76; for IL-8, 3.68 (1.45) pg/ml, 24%, 31%, 0.85 and 0.75; and for TNF-alpha, 3.14 (1.87) pg/ml, 43%, 29%, 1.56 and 0.50, respectively. We conclude that between-subject variation and within-subject variation are quite similar for IL-1beta and IL-8 and are relatively high for the three cytokines studied. Index of individuality is less than 1.4 for IL-1beta and IL-8, and thus reference intervals based on population studies are of limited value. On the contrary, the index of individuality for TNF-alpha is greater than 1.4 and reference values can be used for diagnosis. Quality goals for imprecision are easily achieved for the three cytokines with current methodology.     

Tumour necrosis factor-alpha, interleukin-1beta and interleukin-8 induce persistent mechanical nociceptor hypersensitivity

It has been previously described that daily intraplantar (i.pl.) injections of prostaglandin E2 (PGE2) and dopamine in rats for 14 days cause the development of a persistent mechanical nociceptor hypersensitivity state lasting more than 30 days. Considering that during inflammation, the release of these hyperalgesic agents are mediated by cytokines, we investigated in the present study whether interleukin-1beta (IL-1beta), IL-8 and tumour necrosis factor-alpha (TNF-alpha) are able to induce persistent mechanical nociceptor hypersensitivity. Daily i.pl. administration of TNF-alpha, IL-1beta or IL-8 for 18 days led to persistent mechanical nociceptor hypersensitivity, which lasted at least 30 days after the cessation of treatment. The co-treatment of the animals with IL-1beta plus indomethacin, but not with atenolol, prevented the induction of persistent mechanical nociceptor hypersensitivity. The co-treatment of the animals with IL-8 plus atenolol, but not with indomethacin, prevented the induction of persistent mechanical nociceptor hypersensitivity. The daily co-treatment of TNF-alpha with either indomethacin or atenolol partially inhibited (+/-50%) the induction of persistent mechanical nociceptor hypersensitivity. However, the combined treatment with indomethacin plus atenolol abolished the induction of the persistent mechanical nociceptive hypersensitivity by TNF-alpha.A single injection of cytokines in the contralateral paws of the animals with persistent hypersensitivity caused only an acute nociceptive response. This observation, together with the demonstration of undetectable levels of immunoglobulins against TNF-alpha, IL-1beta or IL-8 in the sera of animals after the development of the persistent hypersensitivity induced by those cytokines, indicate that this event is not due to an ongoing immunological response against the cytokines. In conclusion, our results support the suggestion that IL-1beta- and IL-8-induced persistent mechanical nociceptor hypersensitivity results from the endogenous release of eicosanoids and sympathetic amines, respectively. However, TNF-alpha-induced mechanical nociceptor hypersensitivity results from the concomitant endogenous release of eicosanoids and sympathomimetic mediators.     

Circulating interleukin-1 beta and tumor necrosis factor-alpha concentrations after burn injury in humans.

OBJECTIVES: To measure plasma interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) concentrations after burn injury and to determine if these concentrations relate to clinical status. DESIGN: Prospective assessment. SETTING: Hospital burn unit. PATIENTS: Thirty-one patients with second- or third-degree burns, covering 10% to 95% of body surface area. MEASUREMENTS AND MAIN RESULTS: Initial concentrations of IL-1 beta were increased (mean 188 +/- 31 pg/mL), and the concentrations for each patient correlated with body temperature at the time of the blood sample (rho = 0.51, p < .015) (rho is a nonparametric statistical measure; a nonparametric analysis is mandatory for data that is categorical [Acute Physiology and Chronic Health Evaluation, APACHE, scores] and data that are not normally distributed [IL-1 beta and tumor necrosis factor, TNF, data]). Mean TNF alpha concentrations were initially 264 +/- 132 pg/mL, and these concentrations were positively related to body temperature (rho = 0.41, p < .05) and inversely related to the total WBC count (rho = -0.45, p < .025). Through the course of hospitalization, plasma cytokine levels fluctuated, but transient increases (sometimes into the nanogram/mL range) did not consistently correspond to changes in clinical signs or severity of illness, as determined by APACHE II scores. The maximum plasma cytokine levels in any patient were not related to age, but maximum IL-1 beta concentrations were inversely related to burn size (rho = -0.46, p < .015). The final IL-1 beta concentrations measured in the patients who died (n = 7) were significantly less than measurements in surviving patients matched for burn size and age taken at approximately the same time after admission. CONCLUSIONS: These results indicate that early after burn injury there is a correspondence of IL-1 beta and TNF alpha with certain host responses, but these correlations disappear with the progression of illness. In general, IL-1 beta and TNF alpha appear to be poor indicators of prognosis during burn injury; however, the association of mortality with low circulating IL-1 beta values supports the concept of IL-1 beta as being an essential mediator of host defenses.     

Determination of diagnostic and prognostic values of urinary interleukin-8, tumor necrosis factor-alpha, and leukocyte arylsulfatase-A activity in patients with bladder cancer

OBJECTIVES: This study was planned to evaluate the feasibility of the assay of leukocyte arylsulfatase-A (AS-A) activity, and some urinary cytokine levels (tumor necrosis factor-alpha [TNF-alpha] and interleukin-8 [IL-8]), as noninvasive diagnostic tools in different stages of bladder cancer patients. DESIGN AND METHODS: Blood and urine samples of 79 subjects were analyzed, including 28 healthy volunteers, 27 patients with superficial bladder cancer (SBC), and 24 patients with muscle invasive bladder cancer (MIBC). RESULTS: In SBC patients, the mean leukocyte AS-A activity was slightly higher (11.4%) than healthy subjects without reaching statistical significance. On the other hand, the enzyme activity in MIBC patients was significantly higher than those of controls (38.9%) and SBC patients (18.3%). Urinary TNF-alpha levels in both cancer groups were not significantly different from the control group. Urinary IL-8 levels of MIBC patients were significantly increased when compared with the levels of SBC patients and healthy subjects (P < 0.001). CONCLUSIONS: Based on our results, it may be concluded that measurement of leukocyte AS-A activity is not a sufficiently reliable noninvasive diagnostic test in distinguishing early stage bladder cancer from healthy subjects as well as detecting disease progression. Whereas measurement of urinary IL-8 may be valuable as a noninvasive diagnostic and prognostic test especially in patients with advanced bladder cancer. It also appears that complementary biochemical information may be obtained about the prognosis of the disease by monitoring urinary IL-8 profile. However, further confirmatory clinical trials about the prognostic value of the measurement of urinary IL-8 are needed.     

急性脑梗死患者S100蛋白B及炎症介质的变化

目前，对脑梗死进行早期诊断、指导治疗、判断预后的血清标记物研究已引起广泛重视。本研究通过分析S100蛋白B（S100B）、白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF—α）水平与临床神经功能缺损症状的关系，探讨其在脑梗死中的临床意义。     

阿尔茨海默病患者血清和脑脊液中肿瘤坏死因子α及白细胞介素8的水平

目的：观察炎症因子肿瘤坏死因子α与白细胞介素8在阿尔茨海默病患者和血管性痴呆患者脑脊液和血清中的表达. 方法：收集白求恩医科大学第一临床学院1999-05／10和大连医科大学第一临床学院1999-07／2000-05收治住院的阿尔茨海默病患者11例，血管性痴呆患者13例，采集静脉血和脑脊液，采用双抗体夹心酶联免疫吸附方法检测肿瘤坏死因子α和白细胞介素8水平，应用直线相关分析分析阿尔茨海默病患者的血和脑脊液中肿瘤坏死因子α和白细胞介素8水平的关系。并以同期体检的正常人做对照组进行比较。 结果：3组37例被试者全部进入结果分析。①肿瘤坏死因子α水平：脑脊液中阿尔茨海默病组明显高于血管性痴呆组及对照组[（142．58&;#177;11.46），（115．46&;#177;19．52），（106．23&;#177;26．13）ng／L，P〈0．01，0.051；血清中3组间比较差异不显著。②白细胞介素8水平：脑脊液中阿尔茨海默病组和血管性痴呆组明显高于对照组[（188．58&;#177;52．66），（176．36&;#177;48）．（139．63&;#177;47．01）ng／L，P〈0．01，0.05]；血清中阿尔茨海默病组和血管性痴呆组也明显高于对照组[（67．16&;#177;19．82），（59．64&;#177;22．40）．（42．08&;#177;17．61）ng／L，P〈0．01，0.05]。③阿尔茨海默病组患者血清和脑脊液中的肿瘤坏死因子α呈正相关（r=0．71，P〈0．05）。 结论：肿瘤坏死因子α、白细胞介素8在阿尔茨海默病患者脑脊液中异常增高，可能起到神经毒性作用。对神经元丧失，小胶质细胞增生，认知障碍形成及发展起到重要作用。     

阿尔茨海默病患者血清和脑脊液中肿瘤坏死因子α及白细胞介素8的水平

目的:观察炎症因子肿瘤坏死因子α与白细胞介素8在阿尔茨海默病患者和血管性痴呆患者脑脊液和血清中的表达。方法:收集白求恩医科大学第一临床学院1999-05/10和大连医科大学第一临床学院1999-07/2000-05收治住院的阿尔茨海默病患者11例,血管性痴呆患者13例,采集静脉血和脑脊液,采用双抗体夹心酶联免疫吸附方法检测肿瘤坏死因子α和白细胞介素8水平,应用直线相关分析分析阿尔茨海默病患者的血和脑脊液中肿瘤坏死因子α和白细胞介素8水平的关系。并以同期体检的正常人做对照组进行比较。结果:3组37例被试者全部进入结果分析。①肿瘤坏死因子α水平:脑脊液中阿尔茨海默病组明显高于血管性痴呆组及对照组[(142.58±11.46),(115.46±19.52),(106.23±26.13)ng/L,P<0.01,0.05];血清中3组间比较差异不显著。②白细胞介素8水平:脑脊液中阿尔茨海默病组和血管性痴呆组明显高于对照组[(188.58±52.66),(176.36±48),(139.63±47.01)ng/L,P<0.01,0.05];血清中阿尔茨海默病组和血管性痴呆组也明显高于对照组[(67.16±19.82),(59.64±22.40),(42.08±17.61)ng/L,P<0.01,0.05]。③阿尔茨海默病组患者血清和脑脊液中的肿瘤坏死因子α呈正相关(r=0.71,P<0.05)。结论:肿瘤坏死因子α、白细胞介素8在阿尔茨海默病患者脑脊液中异常增高,可能起到神经毒性作用。对神经元丧失,小胶质细胞增生,认知障碍形成及发展起到重要作用。     

Intra-abdominal sepsis alters tumor necrosis factor-alpha and interleukin-1 beta binding to human neutrophils.

OBJECTIVE: To determine the effects of intraabdominal sepsis on polymorphonuclear leukocyte tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) receptor expression. DESIGN: Prospective, randomized comparison between patients undergoing elective colon surgery vs. patients with intra-abdominal sepsis. SETTING: Tertiary-care center with all patients with intra-abdominal sepsis in a surgical ICU environment. PATIENTS: Group 1 (n = 7) represents control patients who underwent elective colon surgery without intra-abdominal sepsis. Group 2 (n = 10) represents patients with intra-abdominal sepsis. MEASUREMENTS AND MAIN RESULTS: Polymorphonuclear leukocyte TNF-alpha and IL-1 beta receptor expression +/- stimulation of the oxidative burst was measured using 125I TNF-alpha and 125I IL-1 beta. Superoxide anion production and candicidal activity were measured in the presence of TNF-alpha and IL-1 beta. Group 2 patients expressed fewer TNF-alpha and IL-1 beta receptors on their cell surface, and stimulation of oxidative burst reduced TNF-alpha and IL-1 beta receptor expression in group 2 more than in group 1. Diminished TNF-alpha and IL-1 beta binding reduced superoxide anion production by group 2 polymorphonuclear leukocytes. Decreased TNF-alpha binding but not IL-1 beta, reduced polymorphonuclear leukocyte candicidal activity by group 2 polymorphonuclear leukocytes. CONCLUSIONS: a) Intra-abdominal sepsis reduces polymorphonuclear leukocyte TNF-alpha and IL-1 beta receptor expression. b) Expression of these surface receptors is altered by stimulation of the polymorphonuclear leukocyte oxidative burst. c) Diminished TNF-alpha and IL-1 beta receptor expression is associated with functional impairments in polymorphonuclear leukocyte activity.     

急性肺损伤兔肺泡灌洗液及血清肿瘤坏死因子α、白细胞介素1β和白细胞介素6浓度变化与小剂量高渗盐水的干预

目的:观察创伤性休克兔经小剂量高渗盐水治疗后肺部炎症反应及病理学损伤的变化情况,进一步研究高渗盐水对创伤应激状态下急性肺损伤的作用及其机制。方法:实验于2005-08/2006-04在华中科技大学同济医学院附属同济医院急诊科实验室完成。①实验分组:新西兰白兔30只随机分为3组:假手术组、生理盐水处理组、高渗盐水治疗组,每组10只。②实验方法:假手术组:局部麻醉下行插管术及肝素化,静脉输注平衡盐80mL。生理盐水处理组:用骨钳致兔一侧股骨中下1/3粉碎性骨折,经股动脉放血至储血瓶内,使平均动脉压降至(40±5)mmHg,45min后输注生理盐水4mL/kg,再回输储血及2倍于失血量的平衡盐液进行复苏。高渗盐水治疗组:除以75g/L的氯化钠溶液代替生理盐水外,其余处理同生理盐水处理组。在休克前、休克末、复苏后2h、4h分别采集静脉血1mL备用。复苏后4h空气栓塞处死动物,进行支气管肺泡灌洗,收集支气管肺泡灌洗液。③评估指标:双抗体夹心ELISA法测定支气管肺泡灌洗液以及血清肿瘤坏死因子α、白细胞介素1β、白细胞介素6的浓度;凝胶电泳迁移率改变分析法检测肺泡巨噬细胞核蛋白提取物中核因子κB的活性;显微镜观察肺组织的病理改变。结果:30只实验动物均进入结果分析。①血清细胞因子浓度的变化:与假手术组比较,生理盐水处理组肿瘤坏死因子α浓度在休克发生后迅速升高(P<0.05),复苏后又进一步上升(P<0.01),白细胞介素1β及白细胞介素6浓度在复苏后4h才有明显增加(P<0.01)。高渗盐水治疗组与生理盐水处理组比较,复苏后2～4h肿瘤坏死因子α、白细胞介素1β及白细胞介素6浓度均有不同程度下降(P<0.05,P<0.01,P<0.05)。②支气管肺泡灌洗液细胞因子浓度的变化:生理盐水处理组肿瘤坏死因子α、白细胞介素1β及白细胞介素6浓度均显著高于假手术组(P均<0.01),高渗盐水治疗组各细胞因子的浓度虽然也高于假手术组(P<0.05,P<0.01,P<0.01),但与生理盐水处理组比较均有明显降低(P<0.05,P<0.01,P<0.01)。③肺泡巨噬细胞核因子κB的活性变化:生理盐水处理组核因子κB的活性远高于假手术组(P<0.01),而高渗盐水治疗组核因子κB的活性虽然也高于假手术组(P<0.01),但与生理盐水处理组比较有显著降低(P<0.01)。④肺组织病理学改变:高渗盐水治疗组肺水肿及炎性细胞浸润明显减轻;Ⅰ、Ⅱ型肺泡上皮细胞内仅有少量空泡,上皮基本完整,基底膜增厚不明显。结论:小剂量高渗盐水治疗可抑制创伤性休克时核因子κB的活化,减少促炎细胞因子的合成与分泌,减轻肺部的炎症反应,从而发挥对急性肺损伤的保护作用。     

Sensitivity and specificity of various markers of inflammation for the prediction of tumor necrosis factor-alpha and interleukin-6 in patients with sepsis.

OBJECTIVES: To determine correlations and predictive strength of surrogate markers (body temperature, leukocyte count, C-reactive protein [CRP], and procalcitonin [PCT]) with elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in septic patients. DESIGN: Prospective consecutive case series. SETTING: Surgical intensive care unit (ICU) of a university hospital. PATIENTS: A total of 175 patients experiencing intensive care unit stays >48 hrs categorized for sepsis according to ACCP/ SCCM Consensus Conference criteria. MEASUREMENTS AND MAIN RESULTS: CRP and PCT were both significantly correlated with TNF-alpha and IL-6. Based on the area-under-the-curve of the receiver operating characteristics curves, predicting capability was highest for PCT (0.814 for TNF-alpha >40 pg/mL and 0.794 for IL-6 >500 pg/mL), moderate with CRP (0.732 and 0.716, respectively), and lowest for leukocyte count (0.493 and 0.483, respectively) and body temperature (0.587 and 0.589, respectively). Sensitivity, specificity, positive, and negative predictive values and test effectiveness all followed this same pattern of being highest for PCT followed by CRP, with leukocyte count and body temperature being lowest. CONCLUSION: PCT may be an early and better marker of elevated cytokines than the more classic criteria of inflammation.     

Polymorphisms of genes encoding tumor necrosis factor-alpha,interleukin-10, cluster of differentiation-14 and interleukin-1ra in critically ill patients

Purpose

The aim of the study was to determine whether distributions of tumor necrosis factor (TNF)-α₃₀₈, interleukin (IL)-10₁₀₈₂, CD14₁₅₉, and IL-1ra gene intron 2 genotypes in critically ill patients are associated with outcome, underlying cause of sepsis, and type of microorganism.

Materials and Methods

Blood samples from 106 critically ill white patients were genotyped by method based on polymerase chain reaction for TNF-α₃₀₈, IL-10₁₀₈₂, CD14₁₅₉, and IL-1ra gene intron 2.

Results

All patients with TNF-α₃₀₈AA genotype survived; relative risk (RR) of death in patients with AG was 3.250 and with GG, 1.923 (P < .01). In patients with Gram-positive sepsis, IL-10₁₀₈₂AA and then AG genotypes were the most frequent ones (odds ratio [OR], 18.67 and 7.20, respectively; P < .01). When comparing IL-10₁₀₈₂AA with AG, RR of pancreatitis was 1.80 and OR was 3.40. When AA and GG were compared, RR was 7.33 and OR was 20.00. In patients with GG, RR of peritonitis was 4.07 and OR was 5.88 (P < .01). In patients with Gram-positive sepsis, CD14₁₅₉CT was the most frequent one with OR of 5.25. Distribution of 6 IL-1ra gene intron 2 genotypes showed no significant association.

Conclusions

Distribution of TNF-α₃₀₈ genotypes is associated with outcome, IL-10₁₀₈₂ with type of microorganism and underlying cause of sepsis, and CD14₁₅₉ with type of microorganism.     

Assessment of tumor markers in cerebrospinal fluid

In clinical practice, the examination of cerebrospinal fluid from patients with primary or metastatic brain tumors is commonly limited to cytomorphologic and routine chemistry analysis. The relative lack of sensitivity and specificity of these tests has led to a search for markers that can detect nervous system involvement by neoplasms at an earlier stage and even predict the site of origin of the neoplasms. This article summarizes recent investigators of biochemical tumor markers and cytoplasmic and cell surface markers in cerebrospinal fluid from patients with nervous system tumors.     

Interferon-gamma and bacterial lipopolysaccharide act synergistically on human neutrophils enhancing interleukin-8, interleukin-1beta, tumor necrosis factor-alpha, and interleukin-12 p70 secretion and phagocytosis via upregulation of toll-like receptor 4

In human neutrophils, interferon (IFN)-gamma enhanced the expression of toll-like receptor 4 (TLR4), a crucial component of the signaling receptor complex for bacterial lipopolysaccharide (LPS). Lipopolysaccharide alone did not affect TLR4 expression, but costimulation with IFN-gamma and LPS induced higher levels of TLR4 expression than stimulation with IFN-gamma alone. Using the protein synthesis inhibitor cycloheximide and measuring the expression of CD35 in neutrophils stimulated with IFN-gamma and LPS alone or in combination, we could demonstrate that IFN-gamma enhances TLR4 by de novo protein synthesis, whereas the addition of LPS acts synergistically by enhancing vesicular mobilization to the cell surface. Costimulation with IFN-gamma and LPS induced neutrophil activation and enhanced secretion of the cytokines, interleukin (IL)-8, IL-1beta, tumor necrosis factor-alpha, and IL-12 p70, and phagocytosis of latex beads, processes that were blocked by a monoclonal antibody specific for TLR4. These data suggest that IFN-gamma primes neutrophils to respond to LPS.     

Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function.

OBJECTIVE: Proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta have been implicated in the pathogenesis of myocardial dysfunction in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Although circulating TNF-alpha and IL-1beta are both often elevated in septic shock, it remains unknown whether TNF-alpha or IL-1beta are the factors induced during sepsis that directly depress human myocardial function, and if so, whether the combination synergistically depresses myocardial function. Furthermore, the mechanism(s) by which these cytokines induce human myocardial depression remain unknown. We hypothesized the following: a) TNF-alpha and IL-1beta directly depress human myocardial function; b) together, TNF-alpha and IL-1beta act synergistically to depress human myocardial function; and c) inhibition of ceramidase or nitric oxide synthase attenuates myocardial depression induced by TNF-alpha or IL-1beta by limiting proximal cytokine signaling or production of myocardial nitric oxide (NO). DESIGN: Prospective, randomized, controlled study. SETTING: Experimental laboratory in a university hospital. SUBJECTS: Freshly obtained human myocardial trabeculae. INTERVENTIONS: Human atrial trabeculae were obtained at the time of cardiac surgery, suspended in organ baths, and field simulated at 1 Hz, and the developed force was recorded. After a 90-min equilibration, TNF-alpha (1.25, 12.5, 125, or 250 pg/mL for 20 mins), IL-1beta (6.25, 12.5, 50, or 200 pg/mL for 20 mins), or TNF-alpha (1.25 pg/mL) plus IL-1beta (6.25 pg/mL) were added to the bath, and function was measured for the subsequent 100 mins after the 20-min exposure. To assess the roles of the sphingomyelin and NO pathways in TNF-alpha and IL-1beta cross-signaling, the ceramidase inhibitor N-oleoyl ethanolamine (1 microM) or the NO synthase inhibitor N(G)-monomethyl-L-arginine (10 microM) was added before TNF-alpha (125 pg/mL) or IL-1beta (50 pg/mL). MEASUREMENTS AND MAIN RESULTS: TNF-alpha and IL-1beta each depressed human myocardial function in a dose-dependent fashion (maximally depressing to 16.2 + 1.9% baseline developed force for TNF-alpha and 25.7 + 6.3% baseline developed force for IL-1beta), affecting systolic relatively more than diastolic performance (each p < .05). However, when combined, TNF-alpha and IL-1beta at concentrations that did not individually result in depression (p > .05 vs. control) resulted in contractile depression (p < .05 vs. control). Inhibition of myocardial sphingosine or NO release abolished the myocardial depressive effects of either TNF-alpha or IL-1beta. CONCLUSIONS: TNF-alpha and IL-1beta separately and synergistically depress human myocardial function. Sphingosine likely participates in the TNF-alpha and IL-1beta signal leading to human myocardial functional depression. Therapeutic strategies to reduce production or signaling of either TNF-alpha or IL-1beta may limit myocardial dysfunction in sepsis.     

The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis

Seventy post-menopausal women with osteoporosis were randomized into two groups: 40 patients received calcitriol (0.5 microg/day) and calcium (1000 mg/day); and 30 control patients received calcium (1000 mg/day) alone. Thirty healthy women formed the healthy control group. Bone mineral density (BMD) and serum interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha (TNF-alpha) concentrations were measured at baseline and after 6 months of treatment. Calcitriol treatment for 6 months significantly increased BMD and reduced serum IL-1 and TNF-alpha concentrations compared with no significant changes in patients treated with calcium alone. Both treatments increased serum calcium and decreased parathyroid hormone concentrations. The healthy control group had a significantly lower IL-6 concentration than the post-menopausal women with osteoporosis. We have shown that calcitriol was an effective treatment for osteoporosis. Significant reductions in serum IL-1 and TNF-alpha concentrations suggest that, in addition to increasing the absorption of calcium, calcitriol may directly affect bone metabolism via cytokines.     

脑脊液乳酸在术后感染中的临床价值

目的：评价脑脊液乳酸水平在神经外科术后颅内感染及预后的临床价值。方法选择重庆市急救医疗中心2008年8月至2013年1月神经外科颅脑术后患者126例为研究对象,根据脑脊液细菌培养结果分为感染者与非感染者,其中感染组46例,非感染组80例,选择未手术的非神经系疾病患者50例作为对照组。126例手术患者在术后7 d分别测定感染组与非感染组和对照组的脑脊液乳酸（csf-LA ）、脑脊液糖（csf-GLU ）、脑脊液蛋白（csf-Pro ）、脑脊液白细胞数（csf-WBC ）。将感染组按预后分为良好组、不良组和死亡组,分别在术后7、9、11、15 d时检测其csf-L A的水平。结果感染组csf-L A水平明显高于对照组和非感染组;非感染组明显高于对照组,差异均有统计学意义（P＜0．01）。感染组不同时相的csf-LA与csf-Pro及csf-WBC显著相关（r＝0．721,P＜0．01;r＝0．654,P＜0．05）,与csf-GLU不相关（r＝0．125,P＞0．05）。良好组不同时相的csf-LA明显低于不良组和死亡组（P＜0．05）,不良组在不同时相的csf-LA明显低于死亡组（P＜0．01）。结论脑脊液乳酸水平在神经外科术后颅内感染患者的诊断、疗效和预后中均有较好的临床价值。     

Transforming growth factor-beta1 blocks in vitro cardiac myocyte depression induced by tumor necrosis factor-alpha, interleukin-1beta, and human septic shock serum

OBJECTIVE: Serum from patients with septic shock induces depression of myocyte contractility in vitro that is proportional the reduction of ejection fraction in vivo. This effect is mediated, in part, by tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Transforming growth factor (TGF)-beta is an immunomodulatory cytokine with a broad range of anti-inflammatory effects. Using an in vitro assay, this study sought to determine the effect of TGF-beta1 on myocyte depression induced by TNF-alpha, IL-1beta, and serum with known depressant activity from patients with septic shock. DESIGN: The maximum extent of shortening of electrically paced rat cardiac myocytes in tissue culture was quantified by a closed-loop video tracking system. Myocytes were exposed to different combinations of TNF-alpha, IL-1beta, septic serum, and TGF-beta1. SETTING: Basic research laboratory. MEASUREMENTS AND MAIN RESULTS: Increasing concentrations of TNF-alpha and IL-1beta each caused significant depression of maximum extent of myocyte shortening in vitro over 30 mins (p<.0001). Similarly, a synergistic combination of TNF-alpha and IL-1beta as well as serum with known depressant activity from five patients with acute septic shock induced significant depression of cardiac myocyte contraction (p<.01). Increasing concentrations of TGF-beta1 alone had no effect on maximum extent of cardiac myocyte contraction. However, myocytes that were co-incubated with increasing concentrations of TGF-beta1 demonstrated dose-dependent reversal of depression induced by TNF-alpha or IL-1beta (p<.0001). Similarly, depressant effects caused by synergistic concentrations of TNF-alpha and IL-1beta and serum from all five patients with septic shock were prevented by co-incubation with TGF-beta1. CONCLUSIONS: These data demonstrate that depression of in vitro cardiac myocyte contraction induced by proinflammatory cytokines and septic serum can be blocked by TGF-beta1. TGF-beta1 may have potential as therapy for sepsis-associated myocardial depression in humans.