Age-related differences in the use of guideline-recommended medical and interventional therapies for acute coronary syndromes: a cohort study.

OBJECTIVES: To compare the use of guideline-recommended medical and interventional therapies in older and younger patients with acute coronary syndromes (ACSs). DESIGN: Prospective cohort study. SETTING: Fifty-five hospitals in Switzerland. PARTICIPANTS: Eleven thousand nine hundred thirty-two patients with ACS enrolled between March 1, 2001, and June 30, 2006. ACS definition included ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina pectoris (UA). MEASUREMENTS: Use of medical and interventional therapies was determined after exclusion of patients with contraindications and after adjustment for comorbidities. Multivariate logistic regression models were used to calculate odds ratios (ORs) per year increase in age. RESULTS: Elderly patients were less likely to receive acetylsalicylic acid (OR=0.976, 95% confidence interval (CI)=0.969-0.980) or beta-blockers (OR=0.985, 95% CI=0.981-0.989). No age-dependent difference was found for heparin use. Elderly patients with STEMI were less likely to receive percutaneous coronary intervention (PCI) or thrombolysis (OR=0.955, 95% CI=0.949-0.961). Elderly patients with NSTEMI or UA less often underwent PCI (OR=0.943, 95% CI=0.937-0.949). CONCLUSION: Elderly patients across the whole spectrum of ACS were less likely to receive guideline-recommended therapies, even after adequate adjustment for comorbidities. Prognosis of elderly patients with ACS may be improved by increasing adherence to guideline-recommended medical and interventional therapies.

The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies.

APO866 inhibits nicotinamide phosphoribosyltransferase (NMPRTase), a key enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis from the natural precursor nicotinamide. Intracellular NAD is essential for cell survival, and NAD depletion resulting from APO866 treatment elicits tumor cell death. Here, we determine the in vitro and in vivo sensitivities of hematologic cancer cells to APO866 using a panel of cell lines (n = 45) and primary cells (n = 32). Most cancer cells (acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], mantle cell lymphoma [MCL], chronic lymphocytic leukemia [CLL], and T-cell lymphoma), but not normal hematopoietic progenitor cells, were sensitive to low concentrations of APO866 as measured in cytotoxicity and clonogenic assays. Treatment with APO866 decreased intracellular NAD and adenosine triphosphate (ATP) at 24 hours and 48 to72 hours, respectively. The NAD depletion led to cell death. At 96 hours, APO866-mediated cell death occurred in a caspase-independent mode, and was associated with mitochondrial dysfunction and autophagy. Further, in vivo administration of APO866 as a single agent prevented and abrogated tumor growth in animal models of human AML, lymphoblastic lymphoma, and leukemia without significant toxicity to the animals. The results support the potential of APO866 for treating hematologic malignancies.

Ultra high performance supercritical fluid chromatography coupled with tandem mass spectrometry for screening of doping agents. II: Analysis of biological samples.

The potential and applicability of UHPSFC-MS/MS for anti-doping screening in urine samples were tested for the first time. For this purpose, a group of 110 doping agents with diverse physicochemical properties was analyzed using two separation techniques, namely UHPLC-MS/MS and UHPSFC-MS/MS in both ESI+ and ESI- modes. The two approaches were compared in terms of selectivity, sensitivity, linearity and matrix effects. As expected, very diverse retentions and selectivities were obtained in UHPLC and UHPSFC, proving a good complementarity of these analytical strategies. In both conditions, acceptable peak shapes and MS detection capabilities were obtained within 7min analysis time, enabling the application of these two methods for screening purposes. Method sensitivity was found comparable for 46% of tested compounds, while higher sensitivity was observed for 21% of tested compounds in UHPLC-MS/MS and for 32% in UHPSFC-MS/MS. The latter demonstrated a lower susceptibility to matrix effects, which were mostly observed as signal suppression. In the case of UHPLC-MS/MS, more serious matrix effects were observed, leading typically to signal enhancement and the matrix effect was also concentration dependent, i.e., more significant matrix effects occurred at the lowest concentrations.

Predicting hematologic toxicity in patients undergoing radioimmunotherapy with 90Y-ibritumomab tiuxetan or 131I-tositumomab.

This study aimed at identifying clinical factors for predicting hematologic toxicity after radioimmunotherapy with (90)Y-ibritumomab tiuxetan or (131)I-tositumomab in clinical practice. Hematologic data were available from 14 non-Hodgkin lymphoma patients treated with (90)Y-ibritumomab tiuxetan and 18 who received (131)I-tositumomab. The percentage baseline at nadir and 4 wk post nadir and the time to nadir were selected as the toxicity indicators for both platelets and neutrophils. Multiple linear regression analysis was performed to identify significant predictors (P < 0.05) of each indicator. For both platelets and neutrophils, pooled and separate analyses of (90)Y-ibritumomab tiuxetan and (131)I-tositumomab data yielded the time elapsed since the last chemotherapy as the only significant predictor of the percentage baseline at nadir. The extent of bone marrow involvement was not a significant factor in this study, possibly because of the short time elapsed since the last chemotherapy of the 7 patients with bone marrow involvement. Because both treatments were designed to deliver a comparable bone marrow dose, this factor also was not significant. None of the 14 factors considered was predictive of the time to nadir. The R(2) value for the model predicting percentage baseline at nadir was 0.60 for platelets and 0.40 for neutrophils. This model predicted the platelet and neutrophil toxicity grade to within ±1 for 28 and 30 of the 32 patients, respectively. For the 7 patients predicted with grade I thrombocytopenia, 6 of whom had actual grade I-II, dosing might be increased to improve treatment efficacy. The elapsed time since the last chemotherapy can be used to predict hematologic toxicity and customize the current dosing method in radioimmunotherapy.

Polysomy 8 defines a clinico-cytogenetic entity representing a subset of myeloid hematologic malignancies associated with a poor prognosis: report on a cohort of 12 patients and review of 105 published cases.

Tetrasomy, pentasomy, and hexasomy 8 (polysomy 8) are relatively rare compared to trisomy 8. Here we report on a series of 12 patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative disorder (MPD) associated with polysomy 8 as detected by conventional cytogenetics and fluorescence in situ hybridization (FISH). In an attempt to better characterize the clinical and hematological profile of this cytogenetic entity, our data were combined with those of 105 published patients. Tetrasomy 8 was the most common presentation of polysomy 8. In 60.7% of patients, polysomy 8 occurred as part of complex changes (16.2% with 11q23 rearrangements). No cryptic MLL rearrangements were found in cases in which polysomy 8 was the only karyotypic change. Our study demonstrates the existence of a polysomy 8 syndrome, which represents a subtype of AML, MDS, and MPD characterized by a high incidence of secondary diseases, myelomonocytic or monocytic involvement in AML and poor overall survival (6 months). Age significantly reduced median survival, but associated cytogenetic abnormalities did not modify it. Cytogenetic results further demonstrate an in vitro preferential growth of the cells with a high level of aneuploidy suggesting a selective advantage for polysomy 8 cells.

Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-TNF agent?

BACKGROUND: Patients with rheumatoid arthritis (RA) with an inadequate response to TNF antagonists (aTNFs) may switch to an alternative aTNF or start treatment from a different class of drugs, such as rituximab (RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit. OBJECTIVE: To analyse the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients. METHODS: A prospective cohort study of patients with RA who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA) was carried out. The primary outcome, longitudinal improvement in 28-joint count Disease Activity Score (DAS28), was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders. RESULTS: Of the 318 patients with RA included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than with an alternative aTNF (p = 0.03; at 6 months, -1.34 (95% CI -1.54 to -1.15) vs -0.93 (95% CI -1.28 to -0.59), respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar for RTX and alternative aTNFs (p = 0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of co-treatment with a disease-modifying antirheumatic drug. CONCLUSION: This observational study suggests that in patients with RA who have stopped a previous aTNF treatment because of ineffectiveness changing to RTX is more effective than switching to an alternative aTNF.

Fast screening and confirmation of doping agents by UHPLC-QTOF-MS/MS

Introduction: The general strategy to perform anti-doping analysis starts with a screening followed by a confirmatory step when a sample is suspected to be positive. The screening step should be fast, generic and able to highlight any sample that may contain a prohibited substance by avoiding false negative and reducing false positive results. The confirmatory step is a dedicated procedure comprising a selective sample preparation and detection mode. Aim: The purpose of the study is to develop rapid screening and selective confirmatory strategies to detect and identify 103 doping agents in urine. Methods: For the screening, urine samples were simply diluted by a factor 2 with ultra-pure water and directly injected ("dilute and shoot") in the ultrahigh- pressure liquid chromatography (UHPLC). The UHPLC separation was performed in two gradients (ESI positive and negative) from 5/95 to 95/5% of MeCN/Water containing 0.1% formic acid. The gradient analysis time is 9 min including 3 min reequilibration. Analytes detection was performed in full scan mode on a quadrupole time-of-flight (QTOF) mass spectrometer by acquiring the exact mass of the protonated (ESI positive) or deprotonated (ESI negative) molecular ion. For the confirmatory analysis, urine samples were extracted on SPE 96-well plate with mixed-mode cation (MCX) for basic and neutral compounds or anion exchange (MAX) sorbents for acidic molecules. The analytes were eluted in 3 min (including 1.5 min reequilibration) with a S1-25 Ann Toxicol Anal. 2009; 21(S1) Abstracts gradient from 5/95 to 95/5% of MeCN/Water containing 0.1% formic acid. Analytes confirmation was performed in MS and MS/MS mode on a QTOF mass spectrometer. Results: In the screening and confirmatory analysis, basic and neutral analytes were analysed in the positive ESI mode, whereas acidic compounds were analysed in the negative mode. The analyte identification was based on retention time (tR) and exact mass measurement. "Dilute and shoot" was used as a generic sample treatment in the screening procedure, but matrix effect (e.g., ion suppression) cannot be avoided. However, the sensitivity was sufficient for all analytes to reach the minimal required performance limit (MRPL) required by the World Anti Doping Agency (WADA). To avoid time-consuming confirmatory analysis of false positive samples, a pre-confirmatory step was added. It consists of the sample re-injection, the acquisition of MS/MS spectra and the comparison to reference material. For the confirmatory analysis, urine samples were extracted by SPE allowing a pre-concentration of the analyte. A fast chromatographic separation was developed as a single analyte has to be confirmed. A dedicated QTOF-MS and MS/MS acquisition was performed to acquire within the same run a parallel scanning of two functions. Low collision energy was applied in the first channel to obtain the protonated molecular ion (QTOF-MS), while dedicated collision energy was set in the second channel to obtain fragmented ions (QTOF-MS/MS). Enough identification points were obtained to compare the spectra with reference material and negative urine sample. Finally, the entire process was validated and matrix effects quantified. Conclusion: Thanks to the coupling of UHPLC with the QTOF mass spectrometer, high tR repeatability, sensitivity, mass accuracy and mass resolution over a broad mass range were obtained. The method was sensitive, robust and reliable enough to detect and identify doping agents in urine. Keywords: screening, confirmatory analysis, UHPLC, QTOF, doping agents

Gold nanoparticles functionalized with gadolinium chelates as high-relaxivity MRI contrast agents

Water-dispersible gold nanoparticles functionalized with paramagnetic gadolinium have been fully characterized, and the NMRD profiles show very high relaxivities up to 1.5 T. Characterization using TEM images and dynamic light scattering indicate a particle size distribution from 2 to 15 nm. The gold cores of the nanoparticles do not contribute significantly to the overall magnetic moment.

Less frequent dosing of erythropoiesis stimulating agents in patients undergoing dialysis: a European multicentre cost study.

OBJECTIVE: To calculate the variable costs involved with the process of delivering erythropoiesis stimulating agents (ESA) in European dialysis practices. METHODS: A conceptual model was developed to classify the processes and sub-processes followed in the pharmacy (ordering from supplier, receiving/storing/delivering ESA to the dialysis unit), dialysis unit (dose determination, ordering, receipt, registration, storage, administration, registration) and waste disposal unit. Time and material costs were recorded. Labour costs were derived from actual local wages while material costs came from the facilities' accounting records. Activities associated with ESA administration were listed and each activity evaluated to determine if dosing frequency affected the amount of resources required. RESULTS: A total of 21 centres in 8 European countries supplied data for 142 patients (mean) per hospital (range 42-648). Patients received various ESA regimens (thrice-weekly, twice-weekly, once-weekly, once every 2 weeks and once-monthly). Administering ESA every 2 weeks, the mean costs per patient per year for each process and the estimates of the percentage reduction in costs obtainable, respectively, were: pharmacy labour (10.1 euro, 39%); dialysis unit labour (66.0 euro, 65%); dialysis unit materials (4.11 euro, 61%) and waste unit materials (0.43 euro, 49%). LIMITATION: Impact on financial costs was not measured. CONCLUSION: ESA administration has quantifiable labour and material costs which are affected by dosing frequency.

When nightclub security agents assault clients.

In 2006, a medico-legal consultation service devoted to adult victims of interpersonal violence was set up at the Lausanne University Hospital Centre, Switzerland: the Violence Medical Unit. Most patients are referred to the consultation by the Emergency Department. They are received by forensic nurses for support, forensic examination (in order to establish medical report) and community orientation. Between 2007 and 2009, among community violence, aggressions by security agents of nightclubs on clients have increased from 6% to 10%. Most of the victims are young men who had drunk alcohol before the assault. 25.7% presented one or several fractures, all of them in the head area. These findings raise questions about the ability of security agents of nightclubs to deal adequately with obviously risky situations and ensure client security.

Spondylarthropathies in children--are they different from those in adults?

Juvenile spondylarthropathies (JSpAs) comprise a group of rheumatic diseases distinct from other categories of juvenile arthritis. Several classification systems have been applied, and some are specific for children, such as the seronegative enthesopathy and arthropathy (SEA) syndrome and the enthesitis-related arthritis, diagnostic forms in the International League of Associations for Rheumatism (ILAR) classification. JSpA seems more frequent than was previously believed, but actual epidemiological data show important variations between studies. Compared to adult patients, children with JSpA present with peripheral arthritis and enthesitis early in disease but sacroiliac and spine joints involvement many years later. A multidisciplinary team in a paediatric environment should be responsible for the management of children with spondylarthropathies to ensure the best care for these children with their chronic disease and risk of long-term disability. Recent advances in the treatment of rheumatic diseases with biological agents show promising results in children with JSpA. Further research needs to be conducted to increase our knowledge of the long-term outcome of these patients, to improve management, and to prevent long-term consequences of the disease.