Risk prediction of fever in neutropenia in children with cancer: a step towards individually tailored supportive therapy?

BACKGROUND: Fever in severe chemotherapy-induced neutropenia (FN) is the most frequent manifestation of a potentially lethal complication of current intensive chemotherapy regimens. This study aimed at establishing models predicting the risk of FN, and of FN with bacteremia, in pediatric cancer patients. METHODS: In a single-centre cohort study, characteristics potentially associated with FN and episodes of FN were retrospectively extracted from charts. Poisson regression accounting for chemotherapy exposure time was used for analysis. Prediction models were constructed based on a derivation set of two thirds of observations, and validated based on the remaining third of observations. RESULTS: In 360 pediatric cancer patients diagnosed and treated for a cumulative chemotherapy exposure time of 424 years, 629 FN were recorded (1.48 FN per patient per year, 95% confidence interval (CI), 1.37-1.61), 145 of them with bacteremia (23% of FN; 0.34; 0.29-0.40). More intensive chemotherapy, shorter time since diagnosis, bone marrow involvement, central venous access device (CVAD), and prior FN were significantly and independently associated with a higher risk to develop both FN and FN with bacteremia. The prediction models explained more than 30% of the respective risks. CONCLUSIONS: The two models predicting FN and FN with bacteremia were based on five easily accessible clinical variables. Before clinical application, they need to be validated by prospective studies.

Performance of Interleukin-6 and Interleukin-8 serum levels in pediatric oncology patients with neutropenia and fever for the assessment of low-risk

BACKGROUND: Patients with chemotherapy-related neutropenia and fever are usually hospitalized and treated on empirical intravenous broad-spectrum antibiotic regimens. Early diagnosis of sepsis in children with febrile neutropenia remains difficult due to non-specific clinical and laboratory signs of infection. We aimed to analyze whether IL-6 and IL-8 could define a group of patients at low risk of septicemia. METHODS: A prospective study was performed to assess the potential value of IL-6, IL-8 and C-reactive protein serum levels to predict severe bacterial infection or bacteremia in febrile neutropenic children with cancer during chemotherapy. Statistical test used: Friedman test, Wilcoxon-Test, Kruskal-Wallis H test, Mann-Whitney U-Test and Receiver Operating Characteristics. RESULTS: The analysis of cytokine levels measured at the onset of fever indicated that IL-6 and IL-8 are useful to define a possible group of patients with low risk of sepsis. In predicting bacteremia or severe bacterial infection, IL-6 was the best predictor with the optimum IL-6 cut-off level of 42 pg/ml showing a high sensitivity (90%) and specificity (85%). CONCLUSION: These findings may have clinical implications for risk-based antimicrobial treatment strategies.

Non-classical karyotypic features in relapsed childhood B-cell precursor acute lymphoblastic leukemia

Karyotype analysis of acute lymphoblastic leukemia (ALL) at diagnosis has provided valuable prognostic markers for treatment stratification. However, reports of cytogenetic studies of relapsed ALL samples are limited. We compared the karyotypes from 436 nonselected B-cell precursor ALL patients at initial diagnosis and of 76 patients at first relapse. We noticed a relative increase of karyotypes that did not fall into the classic ALL cytogenetic subgroups (high hyperdiploidy, t(12;21), t(9;22), 11q23, t(1;19), <45 chromosomes) in a group of 29 patients at relapse (38%) compared to 130 patients at presentation (30%). Non-classical cytogenetic aberrations in these 29 patients were mostly found on chromosomes 1, 2, 7, 9, 13, 14, and 17. We also describe six rare reciprocal translocations, three of which involved 14q32. The most frequent abnormalities were found in 9p (12/29 cases) and were associated with a marked decrease in the duration of the second remission, but not of the probability of 10-year event-free survival after relapse treatment. From 29 patients with non-classical cytogenetic aberrations, only 8 (28%) had been stratified to a high risk-arm on the first treatment protocol, suggesting that this subgroup might benefit from the identification of new prognostic markers in future studies.

Problems in the classical calculus of variations

This dissertation concerns convergence analysis for nonparametric problems in the calculus of variations and sufficient conditions for weak local minimizer of a functional for both nonparametric and parametric problems. Newton's method in infinite-dimensional space is proved to be well-defined and converges quadratically to a weak local minimizer of a functional subject to certain boundary conditions. Sufficient conditions for global converges are proposed and a well-defined algorithm based on those conditions is presented and proved to converge. Finite element discretization is employed to achieve an implementable line-search-based quasi-Newton algorithm and a proof of convergence of the discretization of the algorithm is included. This work also proposes sufficient conditions for weak local minimizer without using the language of conjugate points. The form of new conditions is consistent with the ones in finite-dimensional case. It is believed that the new form of sufficient conditions will lead to simpler approaches to verify an extremal as local minimizer for well-known problems in calculus of variations.

Immunoglobulin M-enriched intravenous immunoglobulin inhibits classical pathway complement activation, but not bactericidal activity of human serum

Acute or even hyperacute humoral graft rejection, mediated by classical pathway complement activation, occurs in allo- and xenotransplantation due to preformed anti-graft antibodies. Intravenous immunoglobulin (IVIg) preparations can prevent complement-mediated tissue injury and delay hyperacute xenograft rejection. It is known that IgM-enriched IVIg (IVIgM) has a higher capacity to block complement than IVIgG. Different IVIgs were therefore tested for specificity of complement inhibition and effect on anti-bacterial activity of human serum. IVIgM-I (Pentaglobin), 12% IgM), IVIgM-II (IgM-fraction of IVIgM-I, 60% IgM), and three different IVIgG (all >95% IgG) were used. The known complement inhibitor dextran sulfate was used as control. Hemolytic assays were performed to analyze pathway-specificity of complement inhibition. Effects of IVIg on complement deposition on pig cells and Escherichia coli were assessed by flow cytometry and cytotoxicity as well as bactericidal assays. Complement inhibition by IVIgM was specific for the classical pathway, with IC50 values of 0.8 mg/ml for IVIgM-II and 1.7 mg/ml for IVIgM-I in the CH50 assay. Only minimal inhibition of the lectin pathway was seen with IVIgM-II (IC50 15.5 mg/ml); no alternative pathway inhibition was observed. IVIgG did not inhibit complement in any hemolytic assay. Classical pathway complement inhibition by IVIgM was confirmed in an in vitro xenotransplantation model with PK15 cells. In contrast, IVIgM did not inhibit (mainly alternative pathway mediated) killing of E. coli by human serum. In conclusion, IgM-enriched IVIg is a specific inhibitor of the classical complement pathway, leaving the alternative pathway intact, which is an important natural anti-bacterial defense, especially for immunosuppressed patients.

H-ficolin serum concentration and susceptibility to fever and neutropenia in paediatric cancer patients

H-ficolin (Hakata antigen, ficolin-3) activates the lectin pathway of complement similar to mannose-binding lectin. However, its impact on susceptibility to infection is currently unknown. This study investigated whether the serum concentration of H-ficolin at diagnosis is associated with fever and neutropenia (FN) in paediatric cancer patients. H-ficolin was measured by time-resolved immunofluorometric assay in serum taken at cancer diagnosis from 94 children treated with chemotherapy. The association of FN episodes with H-ficolin serum concentration was analysed by multivariate Poisson regression. Median concentration of H-ficolin in serum was 26 mg/l (range 6-83). Seven (7%) children had low H-ficolin (< 14 mg/l). During a cumulative chemotherapy exposure time of 82 years, 177 FN episodes were recorded, 35 (20%) of them with bacteraemia. Children with low H-ficolin had a significantly increased risk to develop FN [relative risk (RR) 2.24; 95% confidence interval (CI) 1.38-3.65; P = 0.004], resulting in prolonged duration of hospitalization and of intravenous anti-microbial therapy. Bacteraemia occurred more frequently in children with low H-ficolin (RR 2.82; CI 1.02-7.76; P = 0.045). In conclusion, low concentration of H-ficolin was associated with an increased risk of FN, particularly FN with bacteraemia, in children treated with chemotherapy for cancer. Low H-ficolin thus represents a novel risk factor for chemotherapy-related infections.

Immunogenicity and safety of yellow fever vaccination for 102 HIV-infected patients

BACKGROUND: Yellow fever vaccine (17DV) has been investigated incompletely in human immunodeficiency virus (HIV)-infected patients, and adequate immunogenicity and safety are of concern in this population. METHODS: In the Swiss HIV Cohort Study, we identified 102 patients who received 17DV while they were HIV infected. We analyzed neutralization titers (NTs) after 17DV administration using the plaque reduction neutralization test. NTs of 1:>or=10 were defined as reactive, and those of 1:<10 were defined as nonreactive, which was considered to be nonprotective. The results were compared with data for HIV-uninfected individuals. Serious adverse events were defined as hospitalization or death within 6 weeks after receipt of 17DV. RESULTS: At the time of 17DV administration, the median CD4 cell count was 537 cells/mm(3) (range, 11-1730 cells/mm(3)), and the HIV RNA level was undetectable in 41 of 102 HIV-infected patients. During the first year after vaccination, fewer HIV-infected patients (65 [83%] of 78; P = .01) than HIV-uninfected patients revealed reactive NTs, and their NTs were significantly lower (P < .001) than in HIV-uninfected individuals. Eleven patients with initially reactive NTs lost these reactive NTs

Bone-marrow derived progenitor cells are associated with psychosocial determinants of health after controlling for classical biological and behavioral cardiovascular risk factors

BACKGROUND: Circulating progenitor cells have been implicated with maintaining vascular integrity. Low counts are found in adults with high cardiovascular risk and are associated with impaired endothelial function. It remains unknown whether psychosocial risk factors are independently related to counts of circulating progenitor cells. METHODS: We investigated a random sample of 468 adult industrial employees (mean age 41.2 years, 89% men) of Caucasian origin. Cardiovascular risk factors (blood pressure, LDL, HDL and C-reactive protein), health behavior (smoking, alcohol and physical exercise), psychological variables (effort-reward imbalance social support, negative affectivity) and interaction terms served as predictors of circulating progenitor cells (CD34+ CD31dim) as enumerated by flow-cytometry. FINDINGS: Psychosocial variables were independently associated with progenitor cell counts. The association with risk factors increased with age (explained variance in 18-36 year olds R(2)=0.17, p=0.55; age 36.1-46 R(2)=0.32, p=0.001; age>46 R(2)=0.27, p<0.001). Data revealed a shift from a larger association between behavioral and psychosocial variables and cell counts to a stronger association between biological variables and cell counts in older individuals. A significant interaction was observed between smoking and effort-reward imbalance in middle-aged subjects, those with both risk factors present had lower cell counts. In older employees, the interaction between biological risk factors and smoking was related to lower cell counts. INTERPRETATION: In working middle-aged and older men, psychosocial risk factors were related to circulating counts of progenitor cells. Smoking interacted negatively with psychosocial risk factors (middle-aged men) or with biological risk factors (older employees).

[Fever of unknown origin as a sign of calcium pyrophosphate deposition disease]

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease may manifest clinically as septic fever (40 degrees C), acute pseudogout attack of knee, wrist and shoulders, or as a variety of patterns of chronic inflammatory or degenerative joint disease. The association of pseudogout with fever is less widely recognised and may lead to over-investigation, delay in appropriate treatment and disproportionate costs. We report on a 67-year-old woman with a history of recurrent episodes of fever and polyarthritis every 2 months for the last 3 years. Because of this she was hospitalised several times, finally with suspected culture-negative endocarditis, and was treated for 6 weeks with gentamicin, rifampicin and vancomycin. During this therapy the patient again developed septic fever and acute arthritis of the right wrist. Radiographs of the wrist, knee and symphysis pubis revealed prominent chondrocalcinosis and destructive arthropathy.

From Classical Terrorism to “Global” Terrorism

This article examines the history and the development of terrorism as a research subject for social sciences. It gives an impression of how the subject’s theoretical remit has changed over the last decades—explicitly taking into account the characteristics of a modern and global world and their impact on current understandings of terrorism.

[Occurrence of Clostridium perfringens type A and type C in piglets of the Swiss swine population]

Necrotizing enteritis (NE) of newborn piglets still represents an economical problem in Swiss pig breeding and production. The aim of our study was to identify risk factors for NE and evaluate the prevalence of C. perfringens with the toxingenes cpb and cpb2 in Swiss pig breeding farms. The prevalence of theses C. perfringens was investigated using fecal swabs followed by bacteriological culturing and genotyping. Close proximity to other breeding farms and large herd sizes were shown to predispose to NE. C. perfringens type C, carrying the genes cpa, cpb and cpb2 were frequently identified in herds with acute outbreaks of NE. Farms not affected by NE or those using prophylactic vaccination against NE were predominantly positive for C. perfringens type A strains with cpb2 and showed much lower prevalence of C. perfringens type C, compared to acutely affected herds. Our results demonstrate that C. perfringens type A strains with cpb2 are not associated with NE. Besides typical necropsy finding, only the identification of cpb can be used for the diagnosis of NE in affected herds.