Fluconazole for empiric antifungal therapy in cancer patients with fever and neutropenia

BACKGROUND: Several clinical trials have demonstrated the efficacy of fluconazole as empiric antifungal therapy in cancer patients with fever and neutropenia. Our objective was to assess the frequency and resource utilization associated with treatment failure in cancer patients given empiric fluconazole antifungal therapy in routine inpatient care. METHODS: We performed a retrospective cohort study of cancer patients treated with oral or intravenous fluconazole between 7/97 and 6/01 in a tertiary care hospital. The final study cohort included cancer patients with neutropenia (an absolute neutrophil count below 500 cells/mm(3)) and fever (a temperature above 38°C or 100.4°F), who were receiving at least 96 hours of parenteral antibacterial therapy prior to initiating fluconazole. Patients' responses to empiric therapy were assessed by reviewing patient charts. RESULTS: Among 103 cancer admissions with fever and neutropenia, treatment failure after initiating empiric fluconazole antifungal therapy occurred in 41% (95% confidence interval (CI) 31% – 50%) of admissions. Patients with a diagnosis of hematological malignancy had increased risk of treatment failure (OR = 4.6, 95% CI 1.5 – 14.8). When treatment failure occurred the mean adjusted increases in length of stay and total costs were 7.4 days (95% CI 3.3 – 11.5) and $18,925 (95% CI 3,289 – 34,563), respectively. CONCLUSION: Treatment failure occurred in more than one-third of neutropenic cancer patients on fluconazole as empiric antifungal treatment for fever in routine clinical treatment. The increase in costs when treatment failure occurs is substantial

Development and optimization of quantitative PCR for the diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid

Background: The diagnosis of invasive pulmonary aspergillosis (IPA) remains challenging. Culture and histopathological examination of bronchoalveolar lavage (BAL) fluid are useful but have suboptimal sensitivity and in the case of culture may require several days for fungal growth to be evident. Detection of Aspergillus DNA in BAL fluid by quantitative PCR (qPCR) offers the potential for earlier diagnosis and higher sensitivity. It is important to adopt quality control measures in PCR assays to address false positives and negatives which can hinder accurate evaluation of diagnostic performance. Methods: BAL fluid from 94 episodes of pneumonia in 81 patients was analyzed. Thirteen episodes were categorized as proven or probable IPA using Mycoses Study Group criteria. The pellet and the supernatant fractions of the BAL were separately assayed. A successful extraction was confirmed with a human 18S rRNA gene qPCR. Inhibition in each qPCR was measured using an exogenous DNA based internal amplification control (IAC). The presence of DNA from pathogens in the Aspergillus genus was detected using qPCR targeting fungal 18S rRNA gene. Results: Human 18S rRNA gene qPCR confirmed successful DNA extraction of all samples. IAC detected some degree of initial inhibition in 11 samples. When culture was used to diagnose IPA, the sensitivity and specificity were 84.5% and 100% respectively. Receiver-operating characteristic analysis of qPCR showed that a cutoff of 13 fg of Aspergillus genomic DNA generated a sensitivity, specificity, positive and negative predictive value of 77%, 88%, 50%, 96% respectively. BAL pellet and supernatant analyzed together resulted in sensitivity and specificity similar to BAL pellet alone. Some patients did not meet standard criteria for IPA, but had consistently high levels of Aspergillus DNA in BAL fluid by qPCR. Conclusion: The Aspergillus qPCR assay detected Aspergillus DNA in 76.9% of subjects with proven or probable IPA when the concentrated BAL fluid pellet fraction was used for diagnosis. There was no benefit from analyzing the BAL supernatant fraction. Use of both extraction and amplification controls provided optimal quality control for interpreting qPCR results and therefore may increase our understanding of the true potential of qPCR for the diagnosis of IPA.Supported by NIH grant R01 AI054703 from the National Institute of Allergy and Infectious Diseases

One size fits all? High frequency trading, tick size changes and the implications for exchanges: market quality and market structure considerations

This paper offers a systematic review of the empirical literature on the implications of tick size changes for exchanges. Our focus is twofold: first, we are concerned with the market quality implications of a change in the minimum tick size. Second, we are interested in the implications of changes in the minimum tick size on market structure. We show that there is a large body of empirical literature that documents a decrease in transaction costs following a decrease in the minimum tick size. However, even though market liquidity increases, the incentive to provide market making activities decreases. We document a strong link between the minimum tick size regulations and the recent increase in high frequency trading activity. A smaller tick enhances the price discovery process. However, the question of how multiple tick size regimes affect market liquidity in a fragmented market remains to be answered. Finally, we identify topics for future research; we discuss the empirical literature on the minimum trade unit and the recent calls for a minimum resting time for quotes

The evaluation of lipid peroxidation and adenosine deaminase activity in patients with Behcet's disease

Objective: Despite unknown etiology, immunologic alterations and neutrophil hyperfunctions may be involved in the etiopathogenesis of Behcet's Disease (BD). The purpose of the study was to investigate whether adenosine deaminase (ADA) activity, accepted as a nonspecific marker of T lymphocyte activation, may have a potential role in ED. and also may be related to the production of reactive oxygen species (ROS) by neutrophils.Objective: Despite unknown etiology, immunologic alterations and neutrophil hyperfunctions may be involved in the etiopathogenesis of Behcet&#39;s Disease (BD). The purpose of the study was to investigate whether adenosine deaminase (ADA) activity, accepted as a nonspecific marker of T lymphocyte activation, may have a potential role in ED. and also may be related to the production of reactive oxygen species (ROS) by neutrophils.&nbsp;Design and methods: ADA activities and malondialdehyde (MDA; endproduct of lipid peroxidation induced by ROS) levels in both plasma and erythrocytes were spectrophotometrically measured in 25 patients with BD and also in 25 healthy controls.&nbsp;Results: ADA activity was found to be higher in plasma, but lower in erythrocytes; plasma and erythrocyte MDA levels were higher in ED patients than those of controls. In addition, plasma ADA activity was positively related to MDA levels in both plasma (p &lt; 0.05) and erythrocytes (p &lt; 0.01). There was also positive correlation between MDA levels (p &lt; 0.05), but negative correlations between ADA activities (p &lt; 0.01) and also between ADA and MDA values in erythrocytes (p &lt; 0.01) of ED patients.&nbsp;Conclusion: These findings may provide some evidence for a potential role of T lymphocyte activation in ED as reflected by increased plasma ADA activity, and for the presence of possible interrelationship between activated T cells and neutrophil hyperfunctions. such as ROS generation, as reflected by increased MDA levels.&nbsp;</p

Lipid peroxidation and erythrocyte antioxidant enzymes in patients with Behcet's disease

In spite of unknown etiology, it is now accepted that reactive oxygen species (ROS) produced by neutrophils may be related to the pathogenesis of Behcet's Disease (BD). The objective was to investigate whether increased production of ROS may affect erythrocyte oxidant/antioxidant system in patients with BD. The levels of malondialdehyde (MDA), one of the end products of lipid peroxidation, in plasma and erythrocyte, and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), antioxidant enzymes, in erythrocyte, also C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured in 22 patients in active stage of the disease and also in 30 healthy controls. Increased CRP, ESR, and MDA levels in plasma and erythrocyte and. increased SOD but decreased GSH-Px activities in erythrocytes were observed in the patients, when compared to the controls. In addition, significantly positive correlations between plasma and erythrocyte MDA levels, and erythrocyte MDA-CRP, MDA-ESR, MDA-SOD, SOD-ESR and SOD-CRP levels, but negative correlation between plasma MDA and erythrocyte GSH-Px, were found in BD patients. It may be suggested that increased production of ROS in BD, as reflected by higher plasma and erythrocyte MDA levels, may impair erythrocyte membrane integrity and also may lead to the alterations in the erythrocyte antioxidant defense system, as reflected by higher SOD and lower GSH-Px activities in erythrocytes. - Behget's disease; lipid peroxidation; glutathione peroxidase; superoxide dismutase; acute phase reactant (C) 2002 Tohoku University Medical Press

Cutaneous lupoid leishmaniasis: A case report

This article has been peer reviewed and approved by Michael Fisher, MD, Professor of Medicine, Albert Einstein College of Medicine. Review date: December 2005

Micronucleus evaluation in mitogen-stimulated lymphocytes of PUVA treated patients

PUVA describes the treatment of patients with psoralens plus an exposure to a source of UV light of 320-400 nm (UVA). Contradictory results have been reported on the chromosomal damage of PUVA when assayed by sister chromatid exchange (SCE) method. Micronucleus (MN) test is used to detect both clastogenic (breaking) and aneugenic (abnormal segregation) effect of physical/chemical agents on the chromosomes. No data have been found on the MN formation in the cells of PUVA treated patients. Frequency of micronuclei in 72 hours cultivated/mitogen-stimulated lymphocytes of patients have been evaluated at zero time and after 20, 40, 60 sessions of PUVA treatment. While the beginning MN frequency was similar to0.22% (n = 23), it raised to similar to0.32 (n = 23), similar to0.42 (n = 14) and similar to0.53% (n - 10) corresponding respectively to 20, 40 and 60 sessions. These sessions correspond reciprocally to 54+/-23, 172+/-48, 300+/-61 joules/cm(2) of UVA and 13, 26, 39 mg/kg of 8-metoxypsoralen (8-MOP). While large interindividual. variances were apparent, highly significant differences have been observed between initial MN frequency and after that of the 20, 40 and 60 sessions, (p = 0.000, p = 0.004, p = 0.005, reciprocally, Wilcoxon two-related samples test). The coefficient of correlation between MN frequency and UVA doses starting from zero to 60 sessions of treatment has been found as r = 0.61. This indicates a significant relationship between UVA doses and MN frequencies. However, MN inducibility and synergistic property of 8-MOP with UVA should be taken into account. Gradual MN increase during different sessions of PUVA treatment shows that -once appeared-, a part of MN at least persist in the cells of patients from a few days to a few weeks. Smoking as a confounding factor seems to increase MN frequency (p = 0.053, Mann-Whitney U-test) in the beginning population, taken as the control population. This is the first report on the kinetics of MN formation during different sessions of PUVA treatment. Based on our results, we concluded that PUVA treatment causes a detectable chromosome damaging effect on the relatively profound cells/tissues of its human users. Therapists should be careful with its use, especially on the patients who may be more susceptible to carcinogenesis (e.g. immunosuppressed and/or elderly subjects)