Soluble murine IL-1 receptor type I induces release of constitutive IL-1 alpha.
(25/2974)
IL-1 alpha and IL-1 beta are proinflammatory cytokines involved in the pathogenesis of many infectious and noninfectious inflammatory diseases. To reduce IL-1 toxicity, extracellular domains of the soluble (s) IL-1R are shed from cell membranes and prevent triggering of cell-bound receptors. We investigated to what extent murine sIL-1RI can neutralize the IL-1 produced by LPS-stimulated macrophages. When mouse peritoneal macrophages were incubated with LPS, addition of sIL-1RI significantly inhibited the bioactivity of IL-1. Stimulation of cells with sIL-1RI alone induced no bioactive IL-1. When immunoreactive cytokine concentrations were measured with specific radioimmunoassays, sIL-1RI alone appeared to induce a significant release of IL-1 alpha in a concentration-dependent manner. This effect was independent of new protein synthesis. The production of IL-1 beta or TNF-alpha was not influenced by sIL-1RI. There was no interference of sIL-1RI with the IL-1 alpha radioimmunoassay. In mice, an i.v. injection of sIL-RI alone induced a rapid release of IL-1 alpha, but not of TNF-alpha or IL-1 beta. Treatment of mice with sIL-1RI improved the survival during a lethal infection with Candida albicans. In conclusion, sIL-1RI induces a rapid release of IL-1 alpha from cells, as well as into the systemic circulation. Although this IL-1 alpha may be inactivated in circulation by the same sIL-1RI, this phenomenon probably has immunostimulatory effects at local levels where the sIL-1RI-induced IL-1 alpha acts in a paracrine or autocrine manner. (+info)
Phase I trial of docetaxel with filgrastim support in pediatric patients with refractory solid tumors: a collaborative Pediatric Oncology Branch, National Cancer Institute and Children's Cancer Group trial.
(26/2974)
Neutropenia is the dose-limiting toxicity of docetaxel in children. This Phase I trial was designed to determine the maximum tolerated dose, the dose-limiting toxicities, and the incidence and severity of other toxicities of docetaxel with filgrastim (G-CSF) support in children with refractory solid tumors. Docetaxel was administered as an i.v. infusion for 1 h every 21 days with a starting dose of 150 mg/m2 and an escalation to 185 mg/m2 and 235 mg/m2 in subsequent patient cohorts. G-CSF (5 microg/kg/day) was administered s.c., starting 48 h after docetaxel and continuing until the post-nadir neutrophil count reached 10,000/microl. Seventeen patients received 27 courses of docetaxel with G-CSF support. Generalized erythematous desquamating skin rash and myalgias were dose-limiting at 235 mg/m2. Localized and generalized rashes were seen at all of the three dose levels. Neutropenia (median nadir, 95/1microl) occurred at all of the dose levels but was brief in duration and not dose-limiting. Thrombocytopenia was minimal (median platelet count nadir, 139,000/microl), and the severity of neutropenia and thrombocytopenia did not seem to be related to the docetaxel dose. Other docetaxel-related toxicities included hemorrhage (associated with mucositis), sepsis, hypersensitivity reaction, transient elevation of liver enzymes, stomatitis, back pain, asthenia, and neuropathy. One minor response was observed in a patient with colon cancer. The maximum tolerated dose of docetaxel with G-CSF support in children is 185 mg/m2, which is 50% higher than the maximum tolerated dose of docetaxel alone in children and 85 % higher than the recommended adult dose. (+info)
Neutropenic infections in 100 patients with non-Hodgkin's lymphoma or Hodgkin's disease treated with high-dose BEAM chemotherapy and peripheral blood progenitor cell transplant: out-patient treatment is a viable option.
(27/2974)
A retrospective analysis was performed on 100 patients with non-Hodgkin's lymphoma (NHL, n = 75) or Hodgkin's disease (HD, n = 25) who underwent peripheral blood progenitor cell transplant (PBPCT) following high-dose chemotherapy (HDCT) with BCNU, etoposide, cytarabine and melphalan (BEAM) between March 1994 and June 1997. Following PBPCT and until engraftment all patients received oral ciprofloxacin and fluconazole, patients with positive Herpes simplex virus serology received acyclovir and 91 patients received filgrastim. The median days of neutropenia and days to an absolute neutrophil count (ANC) >500/mm3 were 6 and 9, respectively. Febrile neutropenia occurred in 68 patients. Gram-positive bacteremia occurred in 14 patients. No gram-negative infections, invasive fungal infections, intensive care visits or deaths occurred during the period of neutropenia or in the first 30 days following transplant. In multivariate logistic regression the risk of development of any infection was associated only with the duration of neutropenia (P = 0.02) and the risk of bacteremia was associated only with the number of CD34+ cells infused (P = 0.046). Among 49 patients treated in the outpatient setting, 14 (28%) were never admitted. High-dose chemotherapy with BEAM supported by PBPCT, prophylactic antibiotics and filgrastim resulted in a low incidence of infections and no acute mortality. WBC engraftment occurred rapidly allowing for a predictable course during which lengthy hospital stays and amphotericin therapy could be avoided. (+info)
Increased apoptotic peripheral blood neutrophils in systemic lupus erythematosus: relations with disease activity, antibodies to double stranded DNA, and neutropenia.
(28/2974)
OBJECTIVE: To quantify the percentage of apoptotic peripheral blood neutrophils in systemic lupus erythematosus (SLE) and to determine the relations with disease activity and neutropenia. METHODS: Neutrophil apoptosis in SLE patients (n =50) was assessed by flow cytometry using annexin V binding and fluorescent labelled anti-fas. Rheumatoid arthritis (RA, n =20) and inflammatory bowel disease patients (IBD, n =20) were studied as disease controls. RESULTS: The percentage of apoptotic neutrophils, determined by annexin V binding, was increased in peripheral blood of SLE patients (median = 3.25%) compared with normal healthy donors (n =20, median = 1.20%) and disease controls (RA: median = 1.15%) (IBD: median = 1.15%). SLE neutrophil apoptosis correlated positively with lupus disease activity measured by SLAM score. SLE patients with increased antibodies to dsDNA (>10 mg/ml) had increased apoptotic neutrophils. Eight of 14 neutropenic SLE patients had increased apoptotic neutrophils. Increased neutrophil fas expression compared with normal controls was observed in SLE, RA, and IBD. CONCLUSION: Neutrophil fas expression is increased non-specifically in inflammatory disease. Increased circulating apoptotic neutrophils in SLE correlate positively with disease activity (SLAM) and may contribute to autoantigen excess including dsDNA. (+info)
Additive effects of human recombinant interleukin-11 and granulocyte colony-stimulating factor in experimental gram-negative sepsis.
(29/2974)
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to promote granulocyte recovery from a variety of pathologic states. Recombinant human interleukin-11 (rhIL-11) has recently become available clinically as a platelet restorative agent after myelosuppressive chemotherapy. Preclinical data has shown that rhIL-11 limits mucosal injury after chemotherapy and attenuates the proinflammatory cytokine response. The potential efficacy of combination therapy with recombinant human forms of rhIL-11 and rhG-CSF was studied in a neutropenic rat model of Pseudomonas aeruginosa sepsis. At the onset of neutropenia, animals were randomly assigned to receive either rhG-CSF at a dose of 200 micrograms/kg subcutaneously every 24 hours for 7 days; rhIL-11 at 200 micrograms/kg subcutaneously every 24 hours for 7 days; the combination of both rhG-CSF and rhIL-11; or saline control. Animals were orally colonized with Pseudomonas aeruginosa 12.4.4 and then given a myelosuppressive dose of cyclophosphamide. rhG-CSF resulted in a slight increase in absolute neutrophil counts (ANC), but did not provide a survival advantage (0 of 12, 0% survival) compared with the placebo group (1 of 12, 8% survival). rhIL-11 was partially protective (4 of 10, 40% survival); the combination of rhG-CSF and rhIL-11 resulted in a survival rate of 80% (16 of 20; P <.001). rhIL-11 alone or in combination with rhG-CSF resulted in preservation of gastrointestinal mucosal integrity (P <.001), lower circulating endotoxin levels (P <.01), and reduced quantitative levels of P. aeruginosa in quantitative organ cultures. These results indicate that the combination of rhIL-11 and rhG-CSF is additive as a treatment strategy in the prevention and treatment of experimental Gram-negative sepsis in immunocompromised animals. This combination may prove to be efficacious in the prevention of severe sepsis in neutropenic patients. (+info)
Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation.
(30/2974)
BACKGROUND: Ticlopidine has been shown to reduce the incidence of stent thrombosis compared with warfarin, but it may cause serious hematological side effects. Clopidogrel, a new thienopyridine derivative, may be a safe alternative to ticlopidine. The aim of this study was to compare the safety and efficacy of clopidogrel and aspirin with those of ticlopidine and aspirin in patients undergoing coronary stent implantation. METHODS AND RESULTS: The population of this study consisted of 2 groups: patients who underwent coronary stenting and were treated with ticlopidine and aspirin (TA group, n=1406), and patients who underwent coronary stenting followed by treatment with clopidogrel and aspirin (CA group, n=283). At 1-month follow-up, there was no difference in stent thrombosis (1.5% versus 1.4%, P=1.0) or major adverse cardiac events (3.1% versus 2.4%, P=0. 85) between the TA and CA groups, respectively. The probability of any side effect (neutropenia, diarrhea, rash) was significantly higher in the TA group (10.6% versus 5.3%, P=0.006; relative risk, 0. 53; CI, 0.32 to 0.86). CONCLUSIONS: These data suggest that clopidogrel may be an effective pharmacological regimen after coronary stent implantation. Furthermore, the simpler dosing regimen, the absence of neutropenia, and the lower frequency of other side effects make it a safe alternative to ticlopidine. (+info)
PCR-restriction enzyme analysis for detection of Candida DNA in blood from febrile patients with hematological malignancies.
(31/2974)
Blood samples were drawn daily from 72 patients who had hematological malignancies, neutropenia, and fever and who had failed to respond to broad-spectrum antibiotics. Each sample was used for conventional fungal blood cultures and for detection and identification of Candida DNA by a PCR method with subsequent restriction enzyme analysis (REA) recently developed in our laboratory. The PCR method was able to detect five CFU of Candida spp. per ml of blood, and subsequent REA of the amplicons allowed the identification of the Candida species most commonly implicated in cases of candidiasis. Thirty-one patients were PCR-REA positive, and four of these patients were also culture positive. The ultimate diagnosis for 13 of these patients and 1 patient who was PCR-REA negative was disseminated candidiasis (confirmed by clinical data, multiple cultures, histology, autopsy, and/or ultrasonographic evidence of hepatosplenic candidiasis). The molecular method is significantly more sensitive than conventional fungal blood cultures and has a high negative predictive value (97.5%) for the development of disseminated candidiasis in neutropenic patients. (+info)
Molecular relationships and antimicrobial susceptibilities of viridans group streptococci isolated from blood of neutropenic cancer patients.
(32/2974)
From January 1995 to May 1998, 57 episodes of bacteremia due to viridans group streptococci were identified in 50 febrile neutropenic patients with hematologic malignancies. Four patients experienced two separate episodes of streptococcal bacteremia, and one patient had four separate episodes of streptococcal bacteremia. Strains were identified to species level as Streptococcus mitis (n = 37), Streptococcus oralis (n = 19), and Streptococcus salivarius (n = 1). Epidemiologic relatedness of these strains was studied by using PCR-based fingerprinting with M13 and ERIC-2 primers and pulsed-field gel electrophoresis with restriction enzyme SmaI. All strains that were isolated from different patients exhibited unique fingerprint patterns, thus suggesting that viridans group streptococcal bacteremia usually derives from an endogenous source. Cross-transmission of strains between patients could not be established. Four S. mitis isolates recovered during four separate bacteremic episodes in a single patient had identical fingerprint patterns. Susceptibility testing was carried out by broth microdilution technique according to National Committee for Clinical Laboratory Standards guidelines. The MICs at which 90% of the isolates are inhibited were (in milligrams per liter) as follows: 0. 5 (penicillin), 0.5 (amoxicillin), 0.25 (cefotaxime), 2 (chloramphenicol), 4 (erythromycin), 0.5 (clindamycin), >/=32 (tetracycline), >/=32 (trimethoprim-sulfamethoxazole), 4 (ciprofloxacin), 0.5 (sparfloxacin), 0.5 (vancomycin), 0.25 (teicoplanin), and 1 (quinupristin-dalfopristin). High-level penicillin resistance (MIC, >/=4 mg/liter) was found in one isolate only, but intermediate penicillin resistance was noted in 11 isolates (19%). Resistance rates to other drugs were as follows: 7% (amoxicillin), 4% (cefotaxime), 4% (chloramphenicol), 32% (erythromycin), 9% (clindamycin), 39% (tetracycline), 68% (trimethoprim-sulfamethoxazole), 23% (ciprofloxacin), 0% (sparfloxacin), 0% (vancomycin), 0% (teicoplanin), and 0% (quinupristin-dalfopristin). (+info)