The diagnosis of pericardial effusion and cardiac tamponade by 12-lead ECG. A technology assessment

Two types of receptor for tumour necrosis factor-alpha (TNF-R), the 55-kD receptor (TNF-RI) and the 75-kD receptor (TNF-RII), have been identified. Soluble TNF-RI (sTNF-RI) and soluble TNF-RII (sTNF-RII) can be measured in culture supernatants and biological fluids, and the role of sTNF-R has been suggested. In the present study, we measured plasma sTNF-RI and sTNF-RII levels in 19 patients with active sarcoidosis by ELISA in order to assess the state of both types of receptors in this disease. Both plasma sTNF-RI and sTNF-RII levels in patients with active sarcoidosis were significantly higher than those in normal control subjects. A longitudinal evaluation of plasma sTNF-RI and sTNF-RII levels showed that the magnitude of changes in sTNF-RII was closely related with the clinical course of sarcoidosis. These results suggest that plasma sTNF-RII levels may be useful parameters for monitoring the clinical course of sarcoidosis as well as markers for identifying disease activity.     

Soluble tumor necrosis factor alpha receptors in sera from leprosy patients

Serum levels of soluble tumor necrosis factor alpha receptor I (sTNF-RI) were elevated in patients with lepromatous (LL) reactional-state type II leprosy, and sTNF-RII levels were increased in patients with full tuberculoid (TT) or LL type II leprosy. The sTNF-R in sera from patients with type II leprosy, but not other forms of leprosy, inhibited recombinant TNF cytolytic activities in vitro. This suggests that sTNF-R regulatory activities are partially impaired in patients with leprosy.     

Increased serum levels of soluble tumor necrosis factor a-receptors in patients undergoing partial liver resection

BACKGROUND/AIMS: This study was conducted to evaluate the association of tumor necrosis factor-a and soluble receptors as known antagonists in liver surgery with regard to ischemia and reperfusion. METHODOLOGY: Preoperative and perioperative changes of TNF, soluble TNF receptor I and II as well as IL-6 were evaluated in twelve patients with partial liver resection. Before liver ischemia and after reperfusion, the levels were measured in the portal and hepatic vein, as well as systemically. Ten patients with gastrectomy and lymphadenectomy as another major abdominal operation and eight healthy volunteers served as the control groups. RESULTS: Uncomplicated liver resections were associated with a prolonged and significantly increased release of soluble receptors until the third (for soluble receptor I) or the fifth postoperative day (for soluble receptor II). No tumor necrosis factor immunoreactivity could be detected, except in one patient with postoperative sepsis. The pattern of interleukin-6 immunoreactivity during liver resection was characterized by a delayed peak on day 2 (p<0.01 vs preop), compared to an early peak after 8 hours in control patients undergoing gastrectomy (p<0.05 vs preop). Liver resection elicits a release of interleukin-6 and soluble receptors without ischemia/reperfusion-induced effects. A strong correlation of the soluble receptors with interleukin-6 (p<0.01) could be detected in liver resection and gastrectomy. CONCLUSIONS: Uncomplicated liver resections were associated with a prolonged and increased release of soluble tumor necrosis factor receptors while no immunoreactivity could be detected. The strong correlation of soluble receptors with interleukin-6 may suggest an important role in the acute phase response of major operations.     

Systemic release of soluble TNF receptors after high-dose TNF in isolated limb perfusion

Isolated limb perfusion (ILP) with high dose tumour necrosis factor (TNF), interferon gamma and melphalan (TIM) is an efficient treatment for patients with regionally advanced melanoma and sarcoma. In 44 patients, we determined the kinetics of soluble TNF receptors (sTNF-RI and RII) plasma concentrations, and correlated them with systemic TNF and interleukin 6 (IL-6) levels and shock. Seven patients treated conventionally by ILP without cytokine served as controls. Elevated levels of both sTNF-Rs were observed within 30 min after beginning of the TIM-ILP. A first peak of sTNF-Rs levels was observed 3 h after ILP and was followed by a rapid decrease reaching a nadir at 12-14 h post ILP. This first peak was followed by a second, long-lasting elevation of both sTNF-Rs levels persisting for 4 to 5 days after TIM-ILP. Patients treated by ILP without TNF/interferon gamma (IFN-gamma) had no detectable increase in either sTNF-Rs or in circulating TNF, demonstrating that the release of TNF-Rs was dependent upon the administration of TNF/IFN-gamma. High plasma levels of TNF and IL-6 were observed in patients that had more than 5% leakage during the TIM-ILP, but no significant correlation between TNF levels and the peak values of both sTNF-Rs was observed. The levels of TNF and IL-6 were, however, significantly related to each other. TNF systemic levels, but not sTNF-Rs concentrations, correlated significantly with the severity of the shock observed after TIM-ILP. Patients in which sTNF-RII concentration was in excess over circulating TNF, had no shock or grade I shock only, suggesting that sTNF-RII may play a protective, although limited, role in inhibiting activity of circulating TNF.     

The potential of serum levels of soluble tumour necrosis factor receptor I as a biochemical marker in cervical cancer

OBJECTIVES: To investigate the significance of serum levels of soluble tumour necrosis factor receptor I (sTNF-RI) as a potential biochemical marker in women with cervical cancer. DESIGN: A prospective, case-controlled study. PARTICIPANTS: Seventy-one women with cervical cancer and 33 women with myoma were enrolled in this study. METHODS: Pre-operative serum levels of sTNF-RI were measured with a standard enzyme-linked immunosorbent assay utilising murine monoclonal antibody against sTNF-RI. MAIN OUTCOME MEASURES: All data in both groups were evaluated and correlated with the pre-operative serum levels of sTNF-RI. Data analysis was carried out using ANOVA with multiple comparison and linear regression. RESULTS: The mean serum level of sTNF-RI in the cervical cancer group was significantly lower than that in the myoma group (P < 0.001). The sTNF-RI levels decreased sequentially with disease progression from Stage Ia to IIb in women with cervical cancer. The mean serum level of sTNF-RI was also significantly lower in women with positive lymph node (P < 0.05) or recurrent cancer (P < 0.001). A negative correlation was observed between serum levels of sTNF-RI and tumour size (r = -0.622, P < 0.0001). CONCLUSIONS: Decreased pre-operative serum levels of sTNF-RI are observed in women with cervical cancer. The results do not support that the use of sTNF-RI as a biochemical marker for cervical cancer.     

Angiographic evaluation of culprit lesions in acute coronary syndrome: relation to the original site on previous coronary angiography

Recent studies suggest that release of cytokines during inflammatory states such as septic shock leads to hypocholesterolemia. To examine whether tumor necrosis factor alpha (TNF), which is the major cytokine in inflammatory disease, causes hypocholesterolemia, we measured serum levels of total (bioactive and receptor-bound) TNF, cholesterol, Apo B, and Apo A1 in seven patients with septic shock over a period of 8 days. Since elevated serum TNF levels are accompanied by the release of soluble TNF receptors, levels of TNF receptors p55 and p75 were also measured. Patients with septic shock had significantly higher serum TNF and TNF receptor levels compared with healthy controls. Increased cytokine levels were accompanied by a significant decline in total serum cholesterol apolipoprotein A1 and B. In vitro studies with cultured human skin fibroblasts, human umbilical vein endothelial cells, and HepG2 hepatoma cells showed that TNF increased the degradation of 125I-labeled low-density lipoprotein in all the cell lines tested. Recombinant soluble TNF receptors inhibited the TNF-induced stimulation of low-density lipoprotein receptor in a concentration-dependent manner. However, the calculated ratio of TNF receptors to total TNF measured in serum of these patients was not able to counteract the stimulatory effect of TNF, possibly due to the higher molar excess of TNF receptors required to achieve this effect in vitro. Our data strengthen the hypothesis that serum values of total TNF determine the extent of hypocholesterolemia during sepsis and septic shock despite the presence of a high concentration of TNF receptors. Studies with recombinant TNF also confirm the role of TNF in hypocholesterolemia in inflammation.     

Serum levels of tumor necrosis factor alpha and soluble tumor necrosis factor-receptor I in asthmatic patients and patients with chronic respiratory tract infection

In order to investigate the role of tumor necrosis factor alpha (TNF-alpha) in bronchial asthma or chronic respiratory infection, we measured serum levels of TNF-alpha and serum soluble tumor necrosis factor-receptor I (sTNF-RI) in asthmatic patients (n = 11) and patients (n = 10) with chronic respiratory infection by Pseudomonas aeruginosa. We also measured serum levels of eosinophil cationic protein (ECP) in the asthmatic patients. The serum levels of TNF-alpha in the asthmatic patients, patients with chronic respiratory tract infection and control group were 2.864 +/- 0.719 g/ml, 2.564-1.384 pg/ml and 0.681 +/- 0.453 pg/ml respectively. The levels of the former two groups were higher than those of the control group (p < 0.05). The serum levels of sTNF-RI in the asthmatic patients, the patients with chronic respiratory tract infection, and the control group was 758 +/- 268 pg/ml, 999 +/- 242 pg/ml and 909 +/- 268 pg/ml respectively. The levels of the former two groups did not differ significantly from those of the control group. There were significant correlations between TNF-alpha and sTNF-RI in the control group and in the patients with chronic respiratory tract infection, but there was no significant correlation in the asthmatic patients. In the asthmatic patients. TNF-alpha/s TNF-RI correlated with %best of PEF (r = 0.691, n = 9, p 0.0373). The serum levels of ECP correlated significantly with TNF-alpha, but not with sTNF-RI in the asthmatic patients. It is suggested that TNF-alpha plays a significant role in the pathogenesis of bronchial asthma and chronic respiratory tract infection as a factor causing inflammation and that the increase of TNF-alpha/sTNF-RI reflects the activation of eosinophil functions in an asthmatic attack.     

Prothymosin alpha 1 effects in vitro on chemotaxis, cytotoxicity and oxidative response of neutrophils from melanoma, colorectal and breast tumor patients

Immunoregulatory effects of thymic peptides on functions of polymorphonuclear leukocytes (PMNs) are poorly investigated. We studied the effects of prothymosin alpha 1 (Pro alpha 1) on PMNs from patients with colorectal tumors, breast tumors and melanoma (total n = 37) in comparison with healthy donors (n = 18), with respect to chemotaxis, cytotoxicity against HCT-116 colon tumor cells, oxidative response (chemiluminescence reaction) as well as expression of surface marker molecules. We found that Pro alpha 1 was equally effective in stimulating the chemotactic activity of PMNs from tumor patients and healthy donors (43% increase). PMNs from tumor patients, especially with breast tumor, showed a significant enhancement of cytotoxicity against the tumor target cells in comparison with healthy donors. With respect to the PMNs cytotoxicity, only about 50% of the colorectal tumor patients and healthy donors responded to Pro alpha 1 and FMLP. As to the oxidative response of PMNs, elevated levels were found only among colorectal tumor patients. Pro alpha 1 significantly increased the oxidative response in breast and colorectal tumor patients by 55% and 25%, respectively. Pro alpha 1 decreased the expression of CD16 on PMNs of healthy donors, but not that of CD11a, CD11b, CD11c, CD13, CD14, CD15 and CD32. Therefore, we suggest, that Pro alpha 1 may improve some PMN functions of tumor patients, associated with the proposed role in host-tumor interaction.     

Development of Neostrongylus linearis in Cernuella (Cernuella) virgata experimentally infected and maintained in the subhumid climate of Galicia in northwest Spain

BACKGROUND: The outcome of breast cancer is usually determined by multiple factors. Serum tumor necrosis factor alpha concentration has been found to be increased in the circulation of patients with malignancy. This study was designed with the aim to investigate any correlation between the serum tumor necrosis factor alpha and the clinicopathological features and furthermore evaluate the prognostic significance of serum tumor necrosis factor alpha concentration in breast cancer. METHODS: Forty consecutive patients with invasive breast cancer undergoing modified radical mastectomy were prospectively included and evaluated. Venous blood samples were collected before the surgery. Sera were obtained by centrifugation, and stored at -70 degrees C until assayed. The control group consisted 30 healthy, age-matched subjects. Serum concentrations of tumor necrosis factor alpha were measured by the quantitative sandwich enzyme immunoassay technique. The data on tumor size, age, estrogen receptor status, lymph node status and TNM staging were reviewed and recorded. RESULTS: The mean value of serum tumor necrosis factor alpha in patients with invasive breast cancer was 1.47 +/- 0.58 pg/ml and that of the control group was 0.98 +/- 0.37 pg/ml, and the difference was significant (P < 0.01). With univariable analysis, patients with maximum tumor size of 5 cm or larger (P = 0.03), more advanced TNM staging (P < 0.01); and more advanced lymph node status (P < 0.01) were shown to have significantly higher serum concentrations of tumor necrosis factor alpha. However, with multivariable analysis, TNM staging appeared as the only independent factor (P < 0.01) predicting the significant, higher serum concentrations of tumor necrosis factor alpha. CONCLUSION: Preoperative evaluation of serum tumor necrosis factor alpha concentrations may be a valuable parameter for reflecting the severity of staging for invasive breast cancer.     

Prestorage versus bedside white blood cell filtration of red blood cell concentrates: effects on the content of cytokines and soluble tumor necrosis factor receptors

BACKGROUND: The cytokine network has important implications for the systemic inflammatory and metabolic response in trauma and infection. The objective of this study was to investigate the influence of white blood cell (WBC) filtration on the cytokine content in red blood cell concentrates (RBCs). STUDY DESIGN AND METHODS: Tumor necrosis factor-alpha (TNF), interleukin-1-beta (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), and soluble TNF receptors I and II (sTNF-RI, sTNF-RII) were investigated in filtered and nonfiltered RBCs during storage. After 40 days of storage the originally nonfiltered units were filtered. RESULTS: On day 1 prestorage filtered RBCs had lower concentrations of WBCs (p < 0.001), TNF (p < 0.01), sTNF-RI (p < 0.01) and sTNF-RII (p < 0.05) compared to nonfiltered units. IL-1 concentrations increased from day 1 to day 40 (p < 0.05) in nonfiltered RBCs and were higher in nonfiltered units compared to prestorage filtered ones on day 40 (p < 0.05). An increase of IL-8 was found in nonfiltered RBCs as well as prestorage filtered units from day 1 to day 40 (p < 0.05) but the concentrations of IL-8 were higher in nonfiltered units on day 40 compared to prestorage filtered units (p < 0.05). Filtration at the end of the 40-day storage period had no influence on the concentrations of cytokines and soluble TNF receptors. CONCLUSION: The present results suggest that prestorage WBC filtration may be more efficient in reducing the cytokine content of RBCs compared to filtration at the the end of the storage period. The clinical impact of passive transfer of components of the cytokine network via RBCs, e.g., in critically ill patients, is however unclear and needs further investigations.     

Progressive growth of human papillomavirus type 16-transformed keratinocytes is associated with an increased release of soluble tumour necrosis factor (TNF) receptor

Analysis of conditioned media generated by weakly and highly tumorigenic SKv-1 keratinocyte lines harbouring integrated human papillomavirus type 16 (HPV16) DNA sequences revealed a factor inhibiting TNF-alpha and TNF-beta cytotoxic activity. This inhibitory activity was specifically blocked by htr-9 monoclonal antibody (MAb) recognising 55/60 kDa type I TNF receptor suggesting that it is related to a soluble form of this particular receptor (sTNF-RI). The presence of sTNF-RI was confirmed by Western blot analysis of SKv-1 cell-conditioned medium showing a band of 31.5 kDa as well as by the specific enzyme-linked immunobiological assay (ELIBA). Release of sTNF-RI was a result of shedding because Northern blot analysis showed that SKv-1 cells expressed a full-length TNF-RI mRNA, and radioimmunoprecipitation of TNF-RI from [32S]cysteine-labelled cell extracts demonstrated the presence of normal 55 kDa molecule. Evaluation by ELIBA showed that highly tumorigenic SKv-12 cells released significantly more sTNF-RI than their weakly tumorigenic SKv-11 parental cells. Furthermore, human recombinant as well as SKv cell-derived sTNF-RI stimulated proliferation of weakly tumorigenic SKv-11 cells. This suggests that a progressive growth of some neoplastic cells may be, at least partially, a result of an increased spontaneous release of sTNF-RI that enables the cells to escape from local TNF-alpha-mediated growth inhibition.     

Interphase analysis of X-aneuploidy using fluorescent in situ hybridization in various tissues of healthy individuals]

We hypothesized that in patients with chronic heart failure mesenteric venous congestion leads to increased bowel permeability, bacterial translocation, and thereby endotoxin release; the increased endotoxin challenge then causes immune activation with increased soluble CD14 levels and tumor necrosis factor (TNF)-alpha production. Patients with high soluble CD14 levels (indicative of endotoxin-cell interaction) have markedly increased plasma levels of TNF-alpha, soluble TNF receptors 1 and 2, and intracellular adhesion molecule-1, supporting this hypothesis.     

Modulation of cytokine release and neutrophil function by granulocyte colony-stimulating factor during endotoxemia in humans

In this double-blind, cross-over, placebo-controlled, randomized study, two groups of eight healthy male volunteers were challenged with endotoxin (4 ng/kg) on two occasions, once in conjunction with placebo and once with granulocyte colony-stimulating factor (G-CSF; 5 microg/kg). In group 1, G-CSF was administered intravenously 2 hours before endotoxin challenge; in group 2, G-CSF was administered subcutaneously 24 hours before endotoxin challenge. In group 1, G-CSF significantly enhanced the release of tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-8, IL-1 receptor antagonist (IL-1ra), and soluble TNF receptors. In group 2, G-CSF significantly reduced IL-8 concentrations and modestly attenuated TNF and IL-6 levels. In this group, IL-1ra and soluble TNF receptors were enhanced by G-CSF pretreatment and lipopolysaccharide (LPS)-induced soluble TNF receptor release was further augmented, whereas LPS-induced IL-1ra concentrations remained unaltered. Both pretreatments with G-CSF increased LPS-induced peripheral neutrophilia; the expression of CD11b, CD18, and CD67; and the release of elastase and lactoferrin. Both pretreatments also down-regulated neutrophil L-selectin expression and prevented the endotoxin-induced pulmonary neutrophil accumulation during the first 2 hours after endotoxin challenge. These data indicate that two different pretreatments with G-CSF result in differential effects on LPS-induced cytokine release but similar effects on LPS-induced neutrophil activation and changes in expression of cell surface molecules. Finally, regardless of the effects of G-CSF on LPS-induced cytokine release, G-CSF blocks LPS-induced pulmonary granulocyte accumulation.     

Changes of immunological markers after autologous peripheral blood stem cell transplantation

PURPOSE: Recently high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) has become an important treatment for hematological and solid tumors. METHODS: Immunological parameters were examined before and after PBSCT in 9 patients with lung cancer and 13 patients with malignant lymphoma. Findings were compared with those for bone marrow transplantation (BMT). Peripheral blood cells were analyzed for phenotype and the levels of cytokines and soluble factors were measured. RESULTS: After PBSCT, activated T cells (CD3+HLA-DR+ cells, CD8+HLA-DR+ cells) and suppressor/cytotoxic T cells (CD8+CD11b- cells) were significantly higher in the patients with lung cancer than in those with malignant lymphoma. Serum levels of interleukin-4 and soluble interleukin-2 receptor were also significantly higher in the patients with lung cancer than in those with lymphoma. On the other hand, the serum levels of interferon gamma, tumor necrosis factor alpha, interleukin-6, soluble human leukocyte antigen class 1, and soluble thrombomodulin were significantly increased after bone marrow transplantation. The transfused peripheral stem cells of lung cancer and lymphoma patients had a similar number of granulocyte/macrophage-colony-forming units, but lung cancer patients had significantly more CD34-positive cells. CONCLUSION: By reinfusing large numbers of autologous immune cells, PBSCT may accelerate immune reconstitution, with T cells being likely to have a marked therapeutic potential. The changes after PBSCT were greater in patients with lung cancer than in lymphoma patients. These blood cells are potent mediators of anticancer activity and could play an important role in the elimination of autologous malignant cells.     

Levels of inhibitors of tumor necrosis factor alpha and interleukin 1beta in urine and sera of patients with urosepsis

The antiinflammatory cytokine response during urosepsis was determined by measurement of concentrations of soluble tumor necrosis factor receptor (sTNFR) types I and II, interleukin 1 receptor antagonist (IL-1ra), soluble IL-1 receptor type II (sIL-1RII), and interleukin 10 in sera and urine of 30 patients with culture-proven urinary tract infections before and 4, 24, 48, and 72 h after initiation of antibiotic therapy and in 20 healthy individuals. In serum, the levels of sTNFR types I and II, IL-1ra, and IL-10 were higher in patients than in controls. In urine, only sTNFR type I and II levels were elevated in patients. The ratios of concentrations of both types of sTNFR in urine to concentrations in serum were higher in patients than in controls. These findings indicate that during urosepsis, the antiinflammatory cytokine response is generated predominantly at the systemic level.     

Gene expression and secretion of cytokines and cytokine receptors from highly purified CD56+ natural killer cells stimulated with interleukin-2, interleukin-7 and interleukin-12

Interleukin (IL)-2 IL-7 and IL-12 stimulate the generation of lymphokine-activated killer activity and proliferation in natural killer (NK) cells by different mechanisms. In this study, we have compared the ability of IL-2, IL-7 and IL-12 to induce expression of cytokines and cytokine receptors both at the gene and protein level. IL-2 and IL-12 stimulated the CD56+ NK cells to release significant amounts of soluble p55 and p75 tumor necrosis factor receptor (TNFR), whereas less amounts of soluble TNFR were detected in IL-7-stimulated cultures. The p55 and p75 TNFR mRNA were expressed in resting NK cells, and no further induction was observed after cytokine-stimulation. Compared to the effects of IL-2, IL-7 induced lower, but substantial levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA, and IL-7 was a more potent GM-CSF-inducing stimulus than IL-12. IL-12 induced higher levels of interferon-gamma (IFN-gamma) mRNA than did IL-2, and IL-7 only weakly influenced the IFN-gamma expression. In accordance with the mRNA studies, IL-7 induced the secretion of high amounts of GM-CSF and no or low levels of IFN-gamma, whereas high amounts of IFN-gamma and low levels of GM-CSF were detected in supernatants from IL-12-stimulated NK cells. In conclusion, IL-2, IL-7 and IL-12 differentially regulate expression of cytokines and cytokine receptors both at the gene and protein level.     

Soluble cytokine receptors and receptor antagonists are sequentially released after trauma

Cytokine receptors and receptor antagonists (RAs) have been identified in trauma patients. We hypothesized that after traumatic injury, a sequential release of soluble cytokine receptors and RAs may exist that mirrors the release of the primary cytokines themselves. Twenty-two patients were included in the study: 14 males and 8 females. The mean age was 30.1 +/- 12.5 (range, 19 to 71), and the mean Injury Severity Score was 28.7 +/- 12.6 (range, 4 to 57). There were 15 survivors and 7 nonsurvivors. Samples were collected on arrival to the emergency department and at serial intervals for up to 7 days. Monoclonal antibody enzyme-linked immunosorbent assay kits to tumor necrosis factor (TNF), soluble TNF-receptor (sTNF-R) 55 kd and 75 kd, interleukin (IL)-1 and IL-1 RA, and IL-2 and IL-2r were used. Sera from 22 healthy individuals were used as normal controls. No TNF, IL-1, or IL-2 could be detected in any patient sera after injury. Control levels for the soluble cytokine receptors and RAs were as follows: sTNF-R 55 kd, 607 +/- 89 pg/mL; sTNF-R 75 kd, 2,141 +/- 169 pg/mL; IL-1 RA, 291 +/- 35 pg/mL; and IL-2r, 426 +/- 53 U/mL. In trauma patients, both 55 kd and 75 kd sTNF-R were significantly elevated on arrival to the emergency department, with values of 2,441 +/- 506 pg/mL (p < 0.001) and 4,736 +/- 537 pg/mL (p < 0.001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)