A convenient method to discriminate between cytochrome P450 enzymes and flavin-containing monooxygenases in human liver microsomes

Liver microsomes are a frequently used probe to investigate the phase I metabolism of xenobiotics in vitro. Structures containing nucleophilic hetero-atoms are possible substrates for cytochrome P450 enzymes (P450) and flavin-containing monooxygenases (FMO). Both enzymes are located in the endoplasmatic reticulum of hepatocytes and both need oxygen and NADPH as cofactors. The common method to distinguish between the two enzyme systems is to use the thermal inactivation of FMO and to inhibit P450 completely with carbon monoxide, N-octylamine or N-benzylimidazole. In the literature no indication could be found that the heat inactivation of FMO does not affect any of the human P450 enzymes or that the overall P450 inhibitors inhibit the different human P450 enzymes sufficiently and do not affect the FMO. The effect of N-benzylimidazole and heat inactivation was tested on specific activities of seven P450 enzymes in human liver microsomes, 1A2, 2A6, 2C9, 2C19, 2D6, 3A4/5, and 2E1, using methoxyresorufin O-demethylation, coumarin 7-hydroxylation, (S)-warfarin 4-hydroxylation, (S)-(+)-mephenytoin 4-hydroxylation, dextrometorphan O-demethylation, oxidation of denitronifedipine, and chlorzoxazone 6-hydroxylation respectively. The sulfoxidation of methimazole (MMI) was used as a specific probe for the determination of FMO activity. Methimazole sulfoxidation was compared with the well known assay for FMO metabolism, the formation of N,N-dimethylaniline (DMA) N-oxide, to be confirmed as an exclusively FMO mediated reaction. The participation of P450 and FMO in the sulfoxidation of four sulfur containing peptides, ametryne; terbutryne, prometryne and methiocarb was investigated using human liver microsomes. All four reactions were demonstrated to be catalysed predominantly by cytochrome P450.     

Noninvasive assessment of the direct action of oral nifedipine and nicardipine on left ventricular contractile state in patients with systemic hypertension: importance of reflex sympathetic responses

BACKGROUND: Alveolar macrophages from patients with sarcoidosis were analyzed for their ability to secrete tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1-beta), and interleukin-6 (IL-6). RESULTS: Constitutive release of all three monokines in these patients was concomitantly increased in the active state of disease in comparison with inactive sarcoidosis or healthy control subjects. Alveolar macrophages from patients with inactive sarcoidosis compared with cells from healthy subjects showed increased spontaneous secretion of TNF-alpha and IL-6 only, whereas the constitutive release of IL-1-beta was similar as in healthy volunteers. In vitro stimulation of alveolar macrophages from healthy control subjects with lipopolysaccharide or pokeweed mitogen led to a time- and dose-dependent enhanced secretion of TNF-alpha, IL-1-beta, and IL-6. In a similar manner, with corresponding cells from patients with sarcoidosis the secretion of all three cytokines could be further increased by stimulation with lipopolysaccharide or pokeweed mitogen. CONCLUSIONS: The data presented indicate that an increased release of TNF-alpha, IL-1-beta, and IL-6 correlates to disease activity and may play a critical part in the pathogenesis of sarcoidosis.     

North sea oil: Responses to employment opportunities

Britain's new offshore oil industry might have generated much additional employment especially in the building, manning and supply of rigs. But there was a failure at first to take proper advantage; little was done to train people in new skills. Consequently the oil companies brought in equipment and skilled personnel from abroad. Eventually efforts were made to improve matters and the paper examines the steps taken to bring more of the employment benefits to Britain, but finds only partial success.     

Blood-flow sensing by anionic biopolymers

The purpose of this study was to compare local recurrence, distant metastases, and survival rate in 350 patients with cancer of the middle and low rectum who underwent a radical abdominoperineal resection (APER) or a sphincter-saving resection (SSR) in our Institute. There were 257 APER patients and 93 SSR patients, with a median follow-up of 77 months. At 5 years, the estimates in APER and SSR patients were respectively 11% and 30% for the incidence of pelvic recurrence, 18% and 8% for the incidence of distant metastases, and 64% and 73% for overall survival. In the multivariate analysis it was found that Dukes' stage significantly affected pelvic recurrences, distant metastases rate and overall survival; histologic type affected only the pelvic recurrence rate. However, the final outcome of patients following APER or SSR was similar, suggesting that local failure per se does not affect long-term survival.     

Field Measurements with a 5.25 GHz Broadband MIMO-OFDM Communication System

Theoretical capacity calculations and corresponding simulations show significant capacity/throughput gains from MIMO systems. Whether these gains are achievable in a real system, deployed in a practical environment, depends on a variety of factors, such as the choice of the communication algorithms, analog impairments and the "quality" of the wireless channel to sustain MEMO communications. In this paper, a 5.25 GHz broadband MIMO-OFDM testbed is described along with field measurements conducted with it. The MIMO-OFDM communication algorithms and also the impact of analog impairments on the performance of the system are described. Detailed system calibration results are described which serve as a baseline for results of field measurements. The results of wireless measurements are compared with the theoretical capacity, computed with the channel estimates obtained during the demodulation process. The average achievable capacity in the indoor wireless environment is shown to be 9.97 bps/Hz (bits per sec per Hz) while the capacity loss due to analog impairments and the choice of algorithms is about 2.33 bps/Hz. Also, field measurements conducted with the system in various environments are presented comparing the average throughput/capacity achieved in each of these environments.     

Incorporating If...Then...Personality Signatures in Person Perception: Beyond the Person-Situation Dichotomy.

Three studies investigated conditions in which perceivers view dispositions and situations as interactive, rather than independent, causal forces when making judgments about another's personality. Study 1 showed that perceivers associated 5 common trait terms (e.g., friendly and shy) with characteristic if...then... (if situation a, then the person does x, but if situation b, then the person does y) personality signatures. Study 2 demonstrated that perceivers used information about a target's stable if...then... signature to infer the target's motives and traits; dispositional judgments were mediated by inferences about the target's motivations. Study 3 tested whether perceivers draw on if...then... signatures when making judgments about Big Five trait dimensions. Together, the findings indicate that perceivers take account of person-situation interactions (reflected in if...then... signatures) in everyday explanations of social behavior and personality dispositions. Boundary conditions are also discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A sensitivity analysis of the linear complementarity programming model: Appalachian steam coal and the natural gas market

There have been extensive attempts in recent years to perform spatial equilibrium analysis of commodity markets, particularly that of energy. Most of these attempts have been based on linear programming transportation models, and more recently quadratic programming models. Unfortunately, neither of these modelling approaches can deal with the case of multi-commodity analysis with non-symmetric regression coefficients. In this paper, we overcome this problem by employing the linear complementarity programming model. In addition, we show how the model can be applied to coal and gas energy flows within a single region. Future potential applications of the model are also implied.