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1. Among the different in vitro studies recommended by the regulatory agencies, no gold-standard model can easily and directly measure the quantitative CYP450 contributions to drug biotransformation. In this article, we propose an original strategy, called SilensomesTM, to produce human liver microsomes silenced for one specific CYP450, thanks to specific mechanism-based inhibitors (MBI). 2. Using azamulin as a specific CYP3A4 MBI, we demonstrated the proof of concept that CYP3A4 can be totally, specifically (even against 3A5) and permanently (at least for six years) inhibited by our process. Thus, comparing clearance in control and CYP3A4-SilensomesTM, CYP3A4 contributions were determined for 11 CYP3A4 substrates which correlated with known in vivo contributions and revealed accuracy with less than 10% error. In comparison, contributions determined using recombinant human CYP450 (rhCYP450s) were less accurate (more than 10% error for 30% of the tested CYP3A4 substrates). 3. This easy and ready-to-use in vitro method combines the advantages of existing models (specificity of rhCYP450s and representativeness of HLM) without their drawbacks. The same strategy could be used to silence other major CYP450s one-by-one to provide a complete direct CYP450 quantitative phenotyping kit.

The micronucleus assay in the 3D human reconstructed EpiDerm™ skin model (RSMN) is a promising new assay for evaluating genotoxicity of dermally applied chemicals. To complement the testing of metabolically activated chemicals, such as cyclophosphamide (CPA) and benzo[a]pyrene (B[a]P), we measured phase 1 (ethoxyresorufin O-deethylation (EROD) and testosterone metabolism) and 2 activities (UGTs and GSTs) in non-treated and genotoxin treated EpiDerm™ models in a study design which mimics the RSMN assay. The assay involved a three-dose dosing regimen over 72 h to take into account effects e.g. enzyme induction, which requires longer than the standard 2 dose 48-h assay. These studies demonstrated the presence of basal phase 1 and 2 activities of EpiDerm™ models. With the exception of GST, all of the activities measured did not reproducibly change over time. It was possible to measure enzyme induction using this assay design. EROD activity was significantly induced by B[a]P but not by CPA. CPA and B[a]P had little or no reproducible effects on GST and UGT activities. In conclusion, a number of metabolic enzyme activities were present in the EpiDerm™ skin model and at least the CYP1 family was inducible.

The office-based preparticipation evaluation for older adults addresses cardiovascular status, muscle strength, flexibility, balance, and agility. The Kasch pulse-recovery test and the sit-and-reach test are practical methods for evaluating aerobic capacity and flexibility, respectively. Other measures, such as assessment of body composition or bone density, help establish goals and provide baselines for measuring exercise progress. The prescription for older people is aimed at maintaining current function and moving patients to the next activity level. The prescription specifies type, frequency, duration, and intensity of exercise. Case reports describe how key pieces of information from the preparticipation exam can lead to specific exercise recommendations.

Aromatic amines and heterocyclic amines are widely used ingredients in permanent hair dyes. However, little has been published on their potential for oxidation via hepatic cytochrome P450s. Therefore, the authors screened nine such compounds for their potential to undergo oxidative metabolism in human liver microsomes. Toluene-2,5-diamine (TDA), p-aminophenol, m-aminophenol, p-methylaminophenol, N,N'-bis(2-hydroxyethyl)-p-phenylenediamine, and 1-hydroxyethyl-4,5-diaminopyrazole showed no evidence of oxidative metabolism. Oxidized metabolites of 4-amino-2-hydroxytoluene (AHT), 2-methyl-5- hydroxyethylaminophenol (MHEAP), and phenyl methyl pyrazolone (PMP) were detected, but there was no evidence of beta-nicotinamide adenine dinucleotide phosphate (NADPH)-dependent covalent binding to microsomal protein, suggesting that these are not reactive metabolites. Metabolism of AHT, MHEAP, PMP, and TDA was further studied in human hepatocytes. All these compounds underwent conjugation, but no oxidative metabolites were found. The results suggest that none of the hair dye ingredients tested showed evidence of hepatic metabolism to potentially biologically reactive oxidized metabolites.

A wind tunnel atomization study was conducted to measure the emission droplet size spectra for water and Glyphos (a glyphosate formulation sold in Colombia) + Cosmo-flux sprays for aerial application to control coca and poppy crops in Colombia. The droplet size spectra were measured in a wind tunnel for an Accu-Flo nozzle (with 16 size 0.085 [2.16 mm] orifices), under appropriate simulated aircraft speeds (up to 333 km/h), using a laser diffraction instrument covering a dynamic size range for droplets of 0.5 to 3,500 microm. The spray drift potential of the glyphosate was modeled using the AGDISP spray application and drift model, using input parameters representative of those occurring in Colombia for typical aerial application operations. The droplet size spectra for tank mixes containing glyphosate and Cosmo-Flux were considerably finer than water and became finer with higher aircraft speeds. The tank mix with 44% glyphosate had a D(v0.5) of 128 microm, while the value at the 4.9% glyphosate rate was 140 microm. These are classified as very fine to fine sprays. Despite being relatively fine, modeling showed that the droplets would not evaporate as rapidly as most similarly sized agricultural sprays because the nonvolatile proportion of the tank mix (active and inert adjuvant ingredients) was large. Thus, longer range drift is small and most drift that does occur will deposit relatively close to the application area. Drift will only occur downwind and, with winds of velocity less than the modeled maximum of 9 km/h, the drift distance would be substantially reduced. Spray drift potential might be additionally reduced through various practices such as the selection of nozzles, tank mix adjuvants, aircraft speeds, and spray pressures that would produce coarser sprays. Species sensitivity distributions to glyphosate were constructed for plants and amphibians. Based on modeled drift and 5th centile concentrations, appropriate no-spray buffer zones (distance from the end of the spray boom as recorded electronically +/-5%) for protection of sensitive plants were 50-120 m for coca spray scenarios and considerably lower for poppy spray scenarios. The equivalent buffer zone for amphibia was 5 m. The low toxicity of glyphosate to humans suggests that these aerial applications are not a concern for human health.

1. We compared the intrinsic clearance (CL(int)) of a number of substrates in suspensions of fresh and cryopreserved human hepatocytes from seven donors. 2. CL(int) values for a cocktail incubation of phenacetin, diclofenac, diazepam, bufuralol, midazolam, and hydroxycoumarin were 4.9 +/- 3.4, 18 +/- 7.2, 5.1 +/- 4.9, 6.3 +/- 3.3, 9.8 +/- 5.8 and 22 +/- 14 microl min(-1)/10(6) cells, respectively, and they correlated well with corresponding CL(int) values using cryopreserved hepatocytes from 25 different donors. 3. CL(int) values of each cocktail substrate and 20 AstraZeneca new chemical entities were compared in fresh and cryopreserved hepatocytes from the same three donors. There was a statistically significant correlation between CL(int) in fresh and cryopreserved hepatocytes for each of the three livers (p0.002) and the geometric mean of the ratio of fresh to cryopreserved CL(int) values was 1.03. 4. In conclusion, the results add further support to the use of cryopreserved human hepatocytes as a screening model for the intrinsic clearance of new chemical entities.

Induction of drug-clearance pathways (Phase 1 and 2 enzymes and transporters) can have important clinical consequences. Inducers can (1) increase the clearance of other drugs, resulting in a decreased therapeutic effect, (2) increase the activation of pro-drugs, causing an alteration in their efficacy and pharmacokinetics, and (3) increase the bioactivation of drugs that contribute to hepatotoxicity via reactive intermediates. Nuclear receptors are key mediators of drug-induced changes in the expression of drug-clearance pathways. However, species differences in nuclear receptor activation make the prediction of cytochrome P450 (CYP) induction in humans from data derived from animal models problematic. Thus, in vitro human-relevant model systems are increasingly used to evaluate enzyme induction. In this review, the authors' current understanding of the mechanisms of enzyme induction and the in vitro methods for assessing the induction potential of new drugs will be discussed. Relevant issues and considerations surrounding proper study design and the interpretation of in vitro results will be discussed in light of the current US Food and Drug Administration (FDA) recommendations.

1: The metabolism by HepG2 cell from two sources (M1, M2) of 12 substrates is reported: ethoxyresorufin, ethoxycoumarin, testosterone, tolbutamide, chlorzoxazone, dextromethorphan, phenacetin, midazolam, acetaminophen, hydroxycoumarin, p-nitrophenol and 1-chloro-2,4-dinitrobenzene (CDNB), and a pharmaceutical compound, EMD68843. 2: Activities varied markedly. Some were present in M1 (CYP1A, CYP2C9, CYP2E1) but absent in M2. M1 had a more complete set of Phase I enzymes than M2. CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A activities were present at levels similar to human hepatocytes. Phase II metabolism differed between M1 and M2. M1 conjugated hydroxycoumarin and p-nitrophenol to glucuronides only, whereas M2 produced sulfates. Glutathione conjugation of CDNB metabolism was 10-fold higher in M1 than in M2, but was still much lower than in human hepatocytes. CYP2E, CYP2C, CYP2B6 and CYP3A (but not CYP1A, glucuronyl S-transferase or S-transferase) were inducible in M1. Metabolites of EMD68843, produced by induced (but not uninduced) M1 were the same as those produced in human hepatocytes. 3: In conclusion, HepG2 cells have both Phase I and II enzymes, which activities and at what levels depend on the source and culture conditions. Therefore, HepG2 cells routinely used in in vitro assays should be characterized for their drug-metabolizing capabilities before any results can be fully interpreted.

The effect of agitation intensity during standard brewing fermentations, using a lager strain of yeast, Saccharomyces cerevisiae NCYC 1324, and a model lager wort was investigated. A series of repr...

In 1995 Western Sydney Area Health Service (WSAHS) and University of Western Sydney Nepean (UWSN) entered a strategic alliance to develop a nursing research culture in Western Sydney. As a result, the WSAHS/UWSN Professorial Nursing Unit (PNU) was established in 1996: Its mandate was to develop a variety of strategies to promote a nursing research culture in the area. One of these strategies was to encourage mentored research projects between personnel in the PNU and inexperienced clinical nurses. This paper describes one such project. In addition, it contextualises the study in relevant literature relating to mentored research and outlines both the issues and the benefits associated with such projects.

Cells of a heavy metal-accumulating Citrobacter sp. appeared electron-opaque under the electron microscope when pre-grown in medium containing lactose and inorganic phosphate as the respective carbon and phosphorus sources, compared to cells supplied with glycerol and glycerol 2-phosphate. This was attributable to a greater proportion of bound metal cations, as analysed using proton induced X-ray emission analysis of extracted extracellular polymeric material (EPM). This was associated with a greater content of EPM-associated phosphorus and also an enhanced activity of isolated EPM to accumulate uranyl ion, to 23% of the polymer dry weight. EPM from glycerol 2-phosphate-grown cells, analysed using 31P nuclear magnetic resonance spectroscopy, gave several major phosphorus resonances between −1 and 2 ppm, in accordance with published spectra for enterobacterial lipopolysaccharide. Addition of Cd2+ promoted a shift downfield of the P resonances to a new, common, resonance at 3 ppm which was similar to that o...

1. The effect of cryopreservation on the metabolic capacity of monkey hepatocytes over 4 h in suspension and 24 h in culture was determined. Hepatocytes were diluted in a buffer containing 10% DMSO and frozen in a computer-controlled chamber. 2. Initial ethoxyresorufin and ethoxycoumarin O-deethylase (ECOD) activities were the same in fresh and cryopreserved (CP) hepatocytes. ECOD activity in suspensions declined over 4 h but was the same in fresh and CP hepatocytes. 3. The formation of testosterone hydroxy (OHT) metabolites (namely 6beta-OHT, 2beta-OHT, 16beta-OHT, 16alpha-OHT, 15beta-OHT, 2alpha-OHT and 6beta-OHT) was unaffected by cryopreservation. The loss of OHT activities over 4 h in CP and fresh whole cell suspensions was attributed to a loss of cofactor. CP hepatocyte cultures had equivalent OHT activities to freshly isolated hepatocytes. 4. Initial UDP-glucuronyltransferase (UGT) activities, using the substrates 4-methylumbelliferone, ethoxycoumarin and hydroxycoumarin, were equivalent in fresh and CP whole hepatocytes. At later times, UGT activity was lower in CP than fresh hepatocytes but this was due to a loss of UDPGA. Initial sulphotransferase (SULT) activities, using the substrates 2-naphthol, ethoxycoumarin and hydroxycoumarin, were equivalent in fresh and CP hepatocytes. SULT activities were less stable than UGT activities but were the same in fresh and CP hepatocytes throughout the 4-h incubation. 5. Initial glutathione S-transferase activities (using 1-chloro-2,4-dinitrobenzene) were the same in fresh and CP hepatocytes and both did not decrease over 4 h. 6. CP monkey hepatocytes are a useful model for metabolic and cytotoxicity studies. These cells can be can be used either in suspension or in culture.

Function following stroke is often measured using the Functional Independence Measure (FIM). Independence occurs when the patient achieves certain levels of functions. SPECT imaging assesses the regional cerebral blood flow (rCBF). Is it possible to correlate the FIM scores with SPECT imaging and predict functional return? We evaluated total of 69 stroke patients with SPECT imaging using Iofetamine (I-123). Patients were scanned within 14-21 days post-stroke. CT scans were evaluated and correlated with the SPECT images. This information was compared with the admission and discharge FIM scores. The rCBF reperfusion changes and region of stroke were evaluated and correlated with discharge functional status. The right parietal areas demonstrated a strong correlation with SPECT and FIM changes as predictors of return of functional living status (p-value = 0.0438). The right parietal area demonstrated an improvement in ambulation (p-value = 0.0578); the right brain correlated with overall improvement in FIM scores and change in SPECT imaging (p-value = 0.0833); the left brain did not exhibit significant values. Our conclusion was that there were trends seen with the predictive value of stroke recovery using SPECT imaging. The current sample number was not large enough to provide an adequate study, especially for the left brain; a larger study is needed. This information could be useful to help determine patient placement for rehabilitation.

(1995). Evaluation of residential exposure to arsenic in soil near a superfund site. Human and Ecological Risk Assessment: An International Journal: Vol. 1, No. 3, pp. 323-335.

A series of wind tunnel atomization studies were carried out to investigate the effects of polymer and invert suspension oil “drift control adjuvants” upon the droplet size distribution spectra produced by nozzles typically used in aerial and ground based spraying of pesticides. A D8–46 disc and core was used as a typical aerial application nozzle, and an 8003 fan nozzle was used for the ground based sprayers simulation. The droplet size spectra were evaluated in a wind tunnel using a Malvern 2600 laser particle size analyzer immediately upon mixing and at 15 minutes after re‐circulation through a pumping system. The addition of the polymer‐based adjuvants significantly increased the droplet size spectra parameters of the spray cloud, but all the polymer products showed signs of breakdown of their molecular arrangements in the liquid medium, as a result of agitation. The invert suspension oil adjuvant did not change the droplet size spectra markedly, nor did it show signs of breakdown of the inte...

A wind tunnel was used to characterize the droplet size spectra of liquid sprays from several different atomizers and nozzles used under simulated aerial application conditions. The atomizers included a D8–46 nozzle, a Through Valve Boom (TVB) nozzle, and rotary cage and drum atomizers. The D8–46 hydraulic nozzle was evaluated, using water, at orientations of 0, 10, 20, 30, 40, 50, 60, 70, 80 and 90° relative to 145 and 180 km/h airstreams. The TVB nozzle was evaluated using water, water with isopropyl alcohol, and water with a non‐ionic surfactant at airstream velocities between 130 and 180 km/h. The rotary atomizers were evaluated at different rotation rates, flow rates of water and an insecticide, in 130 and 180 km/h airstreams. The volumetric droplet size spectra parameters (Dvo.x) decreased as the angle of the D8–46 nozzle and the airstream velocity increased. Empirical models were developed to predict these values for different windspeed and nozzle angle conditions. The TVB nozzle produced ...

Production of the feedstock for steel rolling mills is shown to be a complex procedure. The problems associated with both ingot production and continuous casting are discussed and the two are compared from different aspects, e.g. quality, yield, etc. It is demonstrated that the feedstock must be examined as an integral part of the steelmaking and rolling operations, and several examples are given of the needfor optimization. The various types of steel are described, and analytical, defect, and yield control are fully discussed. Finally, recent innovations are outlined andfuture trends are considered. The paper is designed to enable those in non-ferrous industries to draw comparisons (or contrasts) with their own practices.

Discharge tubes containing argon, and NH3 separated from atmospheric N2 by condensation in a liquid‐nitrogen—cooled trap, are used to determine 15N: 14N ratios in ammonium solutions. Reduction of NH3 to N2 during sample preparation is not required; the dissociation of NH3 in the discharge tube produces sufficiently intense N2 band spectra for the isotope analysis. The method can be readily applied to the analysis of ammonium solutions derived from Kjeldahl digests of plant material.

Evidence is presented that fumes generated from stainless steels by high temperature processes, can continue to evolve chemically for several minutes. In some cases their hexavalent chromium content appears to rise to a maximum some time after formation of the aerosol and then partly decay again. This finding has important implications for the monitoring of metallic aerosols produced, for example, during the manufacture, cutting, grinding and welding of chromium alloy steels.

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(1954). The Effects of Deficiencies and Excesses of Some Mineral Nutrients on the Growth of Tulip and Daffodil Bulbs in Sand Culture. Journal of Horticultural Science: Vol. 29, No. 4, pp. 237-244.

(1913). A LIST OF SOUTH AFRICAN LACERTILIA, OPHIDIA, AND BATRACHIA IN THE McGREGOR MUSEUM, KIMBERLEY; WITH FIELD-NOTES ON VARIOUS SPECIES. Transactions of the Royal Society of South Africa: Vol. 3, No. 1, pp. 147-176.

The Archaeological Journal, 24, 222-225

(1926). DESCRIPTION OF A NEW SPECIES OF XENOPUS FROM THE CAPE PENINSULA. Transactions of the Royal Society of South Africa: Vol. 14, No. 3, pp. 343-346.

(1952). Molybdenum as a Plant Nutrient: I. The Influence of Molybdenum on the Growth of Some Brassica Crops in Sand Culture. Journal of Horticultural Science: Vol. 27, No. 4, pp. 245-256.

SummaryThe molybdenum requirement of cauliflower in relation to form of nitrogen supply was reinvestigated using a sterile culture technique to study effects of nitrification where nitrogen was supplied in a reduced form. Plants grown under sterile conditions with ammonium sulphate and in the absence of molybdenum showed no abnormality, and were comparable with those grown with complete nutrient and ammonium sulphate or nitrate. In the absence of molybdenum with ammonium sulphate under non-sterile conditions, or with nitrate, the “whiptail” abnormality appeared.It is concluded that the molybdenum requirement formerly observed with reduced nitrogen compounds, as well as with nitrate, may be associated with the effect of nitrate as a de-repressor of nitrate reductase. When nitrate is excluded, molybdenum may not be required by cauliflower grown with ammonium sulphate.

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SummaryTwo varieties of tulip, Golden Harvest obtained from Cornwall and Lincolnshire and Krelage’s Triumph from Cornwall, were grown in sand culture with deficiency, normal and high levels of major nutrients in various combinations.Symptoms produced by deficiencies of nitrogen, phosphorus, potassium and magnesium mainly resembled those recorded previously with the variety Rose Copland.Leaf measurements and bulb yields showed nitrogen deficiency to have the most significant effect on growth, and symptoms were evident several weeks before flowering.Leaf areas and bulb yields were apparently closely related for Nil, nitrogen and phosphorus deficiency treatments but were less clearly related for other treatments, especially in Krelage’s Triumph.Cornish stock of Golden Harvest tulip was more sensitive than Lincolnshire stock to deficiencies, especially of phosphorus. Krelage’s Triumph was also less sensitive on the whole, and especially in terms of leaf area, than Golden Harvest from the same source, even tho...

(1954). Molybdenum as a Plant Nutrient: IV. The Interrelationships of Molybdenum and Nitrate Supply in Chlorophyll and Ascorbic Acid Fractions in Cauliflower Plants Grown in Sand Culture. Journal of Horticultural Science: Vol. 29, No. 4, pp. 291-300.

PREVIOUS papers in this series described the effects of different levels of molybdenum on the growth and on the ascorbic acid, chlorophyll, molybdenum, sugar, nitrate and total nitrogen contents of cauliflower plants grown in sand cultures with two levels of nitrate (1, 2, 3). A later paper (4) presented the results of similar investigations, on the effects of different molybdenum levels given in the presence of different types of nitrogen supply. It was shown that the appearance of whiptail symptoms in molybdenum-deficient plants was independent of the form of nitrogen supply given. This paper presents results obtained for various nitrogen fractions, which, except for adenine, were determined in the same plants as those for which the results previously reported were obtained. Results of investigations on amino acid constituents by chromatography on filter paper are also given; they relate to plants grown in the experiments described previously and to plants grown on other occasions.

(1952). Molybdenum as a Plant Nutrient: II. The Effects of Molybdenum Deficiency on Some Horticultural and Agricultural Crop Plants in Sand Culture. Journal of Horticultural Science: Vol. 27, No. 4, pp. 257-265.

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(1849). Effigy of a Knight of the Fifteenth Century, Dug up in the Churchyard at Minster, Isle of Sheppey, in 1833, and now Preserved in the Church There. Archaeological Journal: Vol. 6, No. 1, pp. 351-358.

Previous papers have described the effects of molybdenum on the growth (3) and composition (4, 5) of cauliflower plants grown with two levels of nitrate nitrogen. It was found that molybdenum deficiency resulted in decreased contents of chlorophyll, ascorbic acid, sugars and organic nitrogen. This paper describes results obtained with cauliflower plants grown with nitrogen as nitrate, nitrite, ammonium compounds, urea or glutamic acid. The intention was to compare the effects of molybdenum on growth and composition under different conditions of nitrogen nutrition. The results were obtained in two main experiments carried out in 1951 and 1952, of which the first was briefly noted (1), and in other experiments in 1953–54 in which additional confirmation of certain points was obtained.

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