Bridging the ensemble Kalman and particle filters

In many applications of Monte Carlo nonlinear filtering, the propagation step is computationally expensive, and hence the sample size is limited. With small sample sizes, the update step becomes crucial. Particle filtering suffers from the well-known problem of sample degeneracy. Ensemble Kalman filtering avoids this, at the expense of treating non-Gaussian features of the forecast distribution incorrectly. Here we introduce a procedure that makes a continuous transition indexed by γ∈[0,1] between the ensemble and the particle filter update. We propose automatic choices of the parameter γ such that the update stays as close as possible to the particle filter update subject to avoiding degeneracy. In various examples, we show that this procedure leads to updates that are able to handle non-Gaussian features of the forecast sample even in high-dimensional situation

Adriamycin/cyclophosphamide and adriamycin/melphalan in advanced L1210 leukaemia.

Adriamycin and cyclophosphamide are active agents in human and experimental tumours. Using the L1210 murine leukaemia, their effectiveness alone and in combination was studied. The combination is highly synergistic in this tumour, resulting in a greater than 50% survival rate when the agents used alone at optimal doses are not curative. DNA synthesis by tumour cells is substantially inhibited and the total ascitic population much reduced. In contrast, DNA synthesis in sensitive host tissues is less disturbed. There is no major difference in the pharmacology of the agents whether given alone or in combination. In very advanced disease the combination is no better than treatment with cyclophosphamide alone. The combination of adriamycin and melphalan in L1210 leukaemia also produces superior results to those obtained using either drug alone at its optimal dosage

Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy

Aristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, is associated with tumor development in patients suffering from Chinese herbs nephropathy (now termed aristolochic acid nephropathy, AAN) and may also be a cause for the development of a similar type of nephropathy, the Balkan endemic nephropathy (BEN). Major DNA adducts [7-(deoxyadenosin-N-6-yl)-aristolactam and 7-(deoxyguanosin-N-2-yl)aristolactam] formed from AA after reductive metabolic activation were found in renal tissues of patients with both diseases. Understanding which human enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual's susceptibility to this plant carcinogen. This paper reviews major hepatic and renal enzymes responsible for AA-DNA adduct formation in humans. Phase I biotransformation enzymes play a crucial role in the metabolic activation of AA to species forming DNA adducts, while a role of phase II enzymes in this process is questionable. Most of the activation of AA in human hepatic microsomes is mediated by cytochrome P450 (CYP) 1A2 and, to a lower extent, by CYP1A1; NADPH:CYP reductase plays a minor role. In human renal microsomes NADPH:CYP reductase is more effective in AA activation. Prostaglandin H synthase (cyclooxygenase, COX) is another enzyme activating AA in human renal microsomes. Among the cytosolic reductases, NAD(P)H:quinone oxidoreductase (NQO I) is the most efficient in the activation of AA in human liver and kidney. Studies with purified enzymes confirmed the importance of CYPs, NADPH:CYP reductase, COX and NQO1 in the AA activation. The orientation of AA in the active sites of human CYP1A1, -1A2 and NQO1 was predicted from molecular modeling and explains the strong reductive potential of these enzymes for AA detected experimentally. We hypothesized that inter-individual variations in expressions and activities of enzymes activating AA may be one of the causes responsible for the different susceptibilities to this carcinogen reflected in the development of AA-induced nephropathies and associated urothelial cancer. (c) 2007 Elsevier B.V. All rights reserved

Stronger correlation between antibiotic use and the incidence of Clostridium difficile determined by culture results instead of faecal toxin detection only

The detection of Clostridium difficile in previous studies evaluating antibiotic use as a risk factor was limited to toxin assay tests. The reported associations may have been misleading due to the low sensitivity of toxin assay tests compared to culture results. Antibiotic use and the incidence of C. difficile of 19 units (wards) over 5years were analysed. Stool samples were tested for toxin A/B and cultured. The correlation of antibiotic use with the incidence of C. difficile determined by culture results was compared to the correlation determined by toxin assay results. Additionally, single antibiotics were analysed as risk factors. Of 5,772 faecal samples tested for C. difficile, 154 single-first cases were detected by the toxin assay and 251 additional single-first cases by culture. Antibiotic use was a significantly stronger risk factor in the correlation based on the culture results (R 2 = 0.63) versus toxin assay results (R 2 = 0.40). Multivariate analysis did not improve the correlation significantly and only the group of broad-spectrum beta-lactams was identified as an independent risk factor. The correlation between antibiotic use and C. difficile incidence rates significantly improves if detection is not limited to faecal toxin assays. Therefore, antibiotic pressure was previously underestimated as a risk facto

Complexity-based learning and teaching: a case study in higher education

This paper presents a learning and teaching strategy based on complexity science and explores its impacts on a higher education game design course. The strategy aimed at generating conditions fostering individual and collective learning in educational complex adaptive systems, and led the design of the course through an iterative and adaptive process informed by evidence emerging from course dynamics. The data collected indicate that collaboration was initially challenging for students, but collective learning emerged as the course developed, positively affecting individual and team performance. Even though challenged, students felt highly motivated and enjoyed working on course activities. Their perception of progress and expertise were always high, and the academic performance was on average very good. The strategy fostered collaboration and allowed students and tutors to deal with complex situations requiring adaptation

IS THE END-TIDAL PARTIAL PRESSURE OF ISOFLURANE A GOOD PREDICTOR OF ITS ARTERIAL PARTIAL PRESSURE?

End-tidal partial pressure of isoflurane (PE′iso) may be used as a measure of anaesthetic depth. During uptake, an arterial partial pressure (Paiso) which is considerably less than PE′iso(Paiso/PE′iso<<1) leads to underestimation of depth of anaesthesia and, during elimination, PE′iso/Paiso<<1 will lead to an overestimation of anaesthetic depth. We measured Paiso/PE′iso during a 60-min uptake period of 1% isoflurane and PE′iso/Paiso during the subsequent 60-min elimination period in 26 patients (age 13-88 yr, ASA I-III) undergoing various surgical procedures. After 15 min of isoflurane uptake, Paiso/PE′iso of 26 patients was mean 0.78 (SD 0.10) and this increased only marginally at 60 min (0.79 (0.09)), whereas during elimination, PE′iso/Paiso was in the range 0.79 (0.14)-0.83 (0.11). Predictability of Paiso in a given patient is hindered by the high SD of Paiso/PE′iso and PE′iso/Paiso, but it may be improved by taking into account age, ASA physical status category, vital capacity, inspired minus end-tidal isoflurane partial pressure and arterial minus end-tidal carbon dioxide partial pressure during uptake; and obesity, end-tidal isoflurane partial pressure and arterial minus end-tidal carbon dioxide partial pressure during elimination. However, even with multiple regression analysis (to account for the various possible variables), clinically useful prediction of Paiso/PE′iso and PE′iso/Paiso in a particular patient is not possible (residual SD 0.084 and 0.113, respectively

Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches

Abstract: This review summarizes the results found in studies investigating the enzymatic activation of two genotoxic nitro-aromatics, an environmental pollutant and carcinogen 3-nitrobenzanthrone (3-NBA) and a natural plant nephrotoxin and carcinogen aristolochic acid I (AAI), to reactive species forming covalent DNA adducts. Experimental and theoretical approaches determined the reasons why human NAD(P)H:quinone oxidoreductase (NQO1) and cytochromes P450 (CYP) 1A1 and 1A2 have the potential to reductively activate both nitro-aromatics. The results also contributed to the elucidation of the molecular mechanisms of these reactions. The contribution of conjugation enzymes such as N,O-acetyltransferases (NATs) and sulfotransferases (SULTs) to the activation of 3-NBA and AAI was also examined. The results indicated differences in the abilities of 3-NBA and AAI metabolites to be further activated by these conjugation enzymes. The formation of DNA adducts generated by both carcinogens during their reductive activation by the NOQ1 and CYP1A1/

Prospective navigator-echo-based real-time triggering of fetal head movement for the reduction of artifacts

The purpose of this study was to evaluate the neuroimaging quality and accuracy of prospective real-time navigator-echo acquisition correction versus untriggered intrauterine magnetic resonance imaging (MRI) techniques. Twenty women in whom fetal motion artifacts compromised the neuroimaging quality of fetal MRI taken during the 28.7 ± 4week of pregnancy below diagnostic levels were additionally investigated using a navigator-triggered half-Fourier acquired single-shot turbo-spin echo (HASTE) sequence. Imaging quality was evaluated by two blinded readers applying a rating scale from 1 (not diagnostic) to 5 (excellent). Diagnostic criteria included depiction of the germinal matrix, grey and white matter, CSF, brain stem and cerebellum. Signal-difference-to-noise ratios (SDNRs) in the white matter and germinal zone were quantitatively evaluated. Imaging quality improved in 18/20 patients using the navigator echo technique (2.4 ± 0.58 vs. 3.65 ± 0.73 SD, p < 0.01 for all evaluation criteria). In 2/20 patients fetal movement severely impaired image quality in conventional and navigated HASTE. Navigator-echo imaging revealed additional structural brain abnormalities and confirmed diagnosis in 8/20 patients. The accuracy improved from 50% to 90%. Average SDNR increased from 0.7 ± 7.27 to 19.83 ± 15.71 (p < 0.01). Navigator-echo-based real-time triggering of fetal head movement is a reliable technique that can deliver diagnostic fetal MR image quality despite vigorous fetal movemen

Induction of biotransformation enzymes by the carcinogenic air-pollutant 3-nitrobenzanthrone in liver, kidney and lung, after intra-tracheal instillation in rats

3-Nitrobenzanthrone (3-NBA), a carcinogenic air pollutant, was investigated for its ability to induce cytochrome P450 (CYP) 1A1/2 and NAD(P)H:quinone oxidoreductase (NQO1) in liver, kidney and lung of rats treated by intra-tracheal instillation. The organs used were from a previous study performed to determine the persistence of 3-NBA-derived DNA adducts in target and non-target tissues (Bieler et al., Carcinogenesis 28 (2007) 1117-1121, [22]). NQO1 is the enzyme reducing 3-NBA to N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) and CYP1A enzymes oxidize a human metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), to yield the same reactive intermediate. 3-NBA and 3-ABA are both activated to species forming DNA adducts by cytosols and/or microsomes isolated from rat lung, the target organ for 3-NBA carcinogenicity, and from liver and kidney. Each compound generated the same five DNA adducts detectable by P-32-postlabelling. When hepatic cytosols from rats treated with 0.2 or 2 mg/kg body weight of 3-NBA were incubated with 3-NBA, DNA adduct formation was 3.2- and 8.6-fold higher, respectively, than in incubations with cytosols from control animals. Likewise, cytosols isolated from lungs and kidneys of rats exposed to 3-NBA more efficiently activated 3-NBA than those of control rats. This increase corresponded to an increase in protein levels and enzymatic activities of NQO1. Incubations of hepatic, pulmonary or renal microsomes of 3-NBA-treated rats with 3-ABA led to an 9.6-fold increase in DNA-adduct formation relative to controls. The highest induction in DNA-adduct levels was found in lung. The stimulation of DNA-adduct formation correlated with expression of CYP1A1/2 induced by the intra-tracheal instillation of 3-NBA. The results demonstrate that 3-NBA induces NQO1 and CYP1A1/2 in livers, lungs and kidneys of rats after intra-tracheal instillation, thereby enhancing its own genotoxic and carcinogenic potential. (c) 2010 Elsevier B.V. All rights reserved