bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Synthesis of Racemic Parasorbic Acid
Authors: Eicher Theophil , Graf Richard , Pick Rigobert
Published: October 2006

Parasorbinsäure (cis‐5‐Hydroxyhex‐2en‐1‐säurelacton, 6) zeigt eine Reihe von bemerkenswerten biologischen Aktivitäten1). Synthesen sind für das Racemat2,3) und für das S‐Enantiomer4) in der Literatur beschrieben. Wir teilen nachstehend eine Modifikation der Synthese von Lamberti et al.2) mit, die eine ökonomische Darstellung der rac.‐Parasorbinsäure im präparativen Maßstab ermöglicht und über eine Fünf‐Stufen‐Sequenz mit einer Gesamt‐Ausbeute von 45% (Lit.2) ca. 5%) verläuft.
Entzündungshemmende Wirkstoffe, 10. Mitt.1). 1‐(4‐Chlorphenyl)‐2‐pyrazolin‐5‐on‐Derivate
Authors: Kreutzberger Alfred , Kolter Karl
Published: October 2006

Aus der durch s‐Triazin (1) initiierten Aminomethinylierung des 1‐(4‐Chlorphenyl)‐3‐methyl‐2‐pyrazolin‐5‐ons (2) geht das 4‐Aminomethylen‐1(4‐chlorphenyl)‐3‐methyl‐2‐pyrazolin‐5‐on (4) hervor, das einerseits zur C‐Rubazonsäure 5, andererseits in Gegenwart sekundärer Amine 6 zu den Dehydro‐C‐Mannich‐Basen 7 weiterreagieren kann.
Naphtho[2,3‐c]pyrane und Benz[g]isochinoline aus 6‐Methoxy‐2H‐pyran‐3(6H)‐on1)
Authors: Eiden Fritz , Wünsch Bernhard
Published: October 2006

Durch Cycloaddition des Methoxy‐dihydro‐3‐pyranons 2 mit dem Isobenzofuran 1 entsteht 3 (exo/endo), das durch Dehydratisierung, Reduktion und erneute Wasserabspaltung in das Naphtho[2,3‐c]pyran 6 übergeführt werden kann. Reaktion mit Ammoniumacetat/Essigsäure bildet das Benzisochinolin 7, aus dem man durch N‐Alkylierung und Hydrierung das Tetrahydro‐Derivat 9 gewinnen kann.
Prospective multicentre evaluation of adverse outcomes following treatment for complicated diverticular disease
Authors: Constantinides V A , Tekkis P P , Senapati A
Published: October 2006

Background

The choice of operation for complicated diverticular disease is contentious. The aim of this study was to investigate adverse events following restorative (primary resection and anastomosis, PRA) and non-restorative (Hartmann's procedure, HP) surgery for complicated diverticular disease.

Methods

Five hundred and thirty-nine patients who presented with complicated diverticular disease in 42 centres over a 12-month period from January 2003 were considered for the study. Data were collected prospectively from 248 patients (46·0 per cent) who underwent PRA and 167 (31·0 per cent) who had HP. A propensity score was developed for case-mix adjustment. Multifactorial logistic regression was used to evaluate differences in operative outcomes.

Results

Mortality, surgical and medical complication rates were 4·0, 31·0 and 13·7 per cent respectively after PRA, and 23·4, 53·3 and 40·7 per cent for HP (all P < 0·001). After adjusting for the propensity score, the HP group had a 2·1- and 1·9-fold increase in medical and surgical complications respectively compared with those who had PRA, whereas the operative mortality rate was not significantly different. Non-colorectal surgeons performed a significantly higher proportion of HPs in the non-elective setting than colorectal surgeons (80·6 versus 60·4 per cent; χ2 = 8·31, 1 d.f., P = 0·004).

Conclusion

PRA with or without a proximal diversion is more often performed non-electively by specialist colorectal surgeons. It may be a safe procedure for complicated diverticular disease in selected patients as it may be associated with fewer postoperative adverse events.
Relationship between CD38 expression on peripheral blood T‐cells and monocytes, and response to antiretroviral therapy: A one‐year longitudinal study of a cohort of chronically infected ART‐naive HIV‐1+ patients
Authors: Almeida Maria , Cordero Miguel , Almeida Julia , Orfao Alberto
Published: October 2006

Background:

HIV‐1 infection has been associated with high expression of CD38 on peripheral blood (PB) CD8+ and CD4+ T‐cells, which has been related with poor prognosis in untreated HIV‐1+ patients. In turn, CD38 expression on PB monocytes from HIV‐1+ individuals and its behavior after starting antiretroviral therapy (ART) have been poorly studied.

Methods:

CD38 expression on PB CD8+ and CD4+ T‐lymphocytes and monocytes was prospectively analyzed in 30 ART‐naive HIV‐1+ patients, using a quantitative multiparameter flow cytometry approach. Patients were tested prior to therapy, and at weeks +2, +4, +8, +12, and +52 after ART.

Results:

Prior to ART, CD38 expression was significantly increased on PB CD8+ and CD4+ T‐cells and monocytes; despite a significant decrease after ART, CD38 expression remained abnormally high on PB CD8+ T‐cells and monocytes, even after one year of therapy, in the absence of detectable plasma viral load. The ART‐induced early changes on CD38 expression by PB T‐cells and monocytes differed among the cell subsets analyzed and patient groups, probably reflecting an interaction between the direct effects of therapy and a redistribution of the PB compartments of T‐cells and monocytes. Hierarchical clustering analysis showed that the overall pattern of changes in CD38 expression observed early after starting ART was predictive of a better response to therapy, not only for PB CD8+ T‐cells, but also for CD4+ T‐cells and monocytes. Accordingly, those HIV‐1+ patients, who experienced a more pronounced increase in CD38 expression on both PB CD4+ T‐cells and monocytes after 2 weeks of ART, showed a more rapid viral clearance, which might reflect decreased HIV‐1 replication in lymph nodes and other tissues, and a partial restoration of hematopoiesis.

Conclusions:

Combined quantitative measurement of CD38 expression on PB monocytes, and CD8+ and CD4+ T‐cells is a more useful tool for monitoring HIV‐1+ patients under ART, rather than quantitation of CD38 expression on PB CD8+ T‐lymphocytes alone. © 2006 International Society for Analytical Cytology
Microstructure and magnetic properties of aerosol‐deposited Sm‐Fe‐N thick films
Authors: Maki Tomohito , Sugimoto Satoshi , Kagotani Toshio , Inomata Koichiro , Akedo Jun
Published: October 2006

In this study, the relationship among magnetic properties, Aerosol Deposition (AD) conditions, and microstructures in Sm‐Fe‐N AD films was investigated. The maximum thickness of 145µm was obtained under AD conditions of gas flow rate (gfr)=6liters/min for 10 min. The density of Sm‐Fe‐N films was in the range of 5.43 to 6.24g/cm3, that is, 71 to 81% of the X‐ray density of the Sm2Fe17N3 compound reported (7.67g/cm3). The Sm‐Fe‐N AD films showed remanence in the range of 0.38 to 0.42 T, that is, 61 to 68% of that of the Sm‐Fe‐N host powder (0.62 T). The coercivities increased from 1.16 to between 1.74 and 1.79 T after the deposition because the grain size decreased from 1.94µm to 0.32µm. © 2006 Wiley Periodicals, Inc. Electr Eng Jpn, 158(1): 8–13, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20214
Transient response of closed‐loop MHD experimental facility
Authors: Takana Hidemasa , Okuno Yoshihiro , Yamasaki Hiroyuki
Published: October 2006

Transient responses of a closed‐loop MHD experimental facility from nonpower generation to power generation have been investigated by means of time‐dependent quasi‐one‐dimensional numerical simulations. For the long‐time continuous power generation experiment, the time required to obtain the steady state for the power generation is estimated to be approximately 20 hours. By increasing the electrical input power to the heater as an exponential function of time, the temperature increment of ceramics can be moderated. When the duration of the experiment is around 10 minutes, argon gas temperature at the exit of the heater hardly changes because of the large heat capacity of structure materials. It is found that the fluid disturbances are induced at the instant of the power generation and they propagate as they repeatedly reflect at the sudden change of duct shape. Since all of the induced disturbances attenuate approximately 0.4 second after the power generation, the time scale that the disturbances exist in the facility is estimated to be 1 second at most. © 2006 Wiley Periodicals, Inc. Electr Eng Jpn, 158(1): 46–52, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20237
A study of economic evaluation of demand‐side energy storage system in consideration of market clearing price
Authors: Furusawa Ken , Sugihara Hideharu , Tsuji Kiichiro , Mitani Yasunori
Published: October 2006

In Japan the electricity market will open on April 1, 2004. Electric utility, Power Producer and Supplier (PPS), and Load Service Entity (LSE) will join the electricity market. LSEs purchase electricity based on the Market Clearing Price (:MCP) from the electricity market. LSEs supply electricity to the customers that contracted with the LSEs on a certain electricity price, and one to the customers that introduced Energy Storage System (:ES) on a time‐of‐use pricing. It is difficult for LSEs to estimate whether they have any incentive to promote customers to introduce ES or not. This paper evaluates the reduction of LSEs' purchasing cost from the electricity market and other LSEs' purchasing cost by introducing ES to customers. It is clarified which kind of customers has the effect of decreasing LSEs' purchasing cost and how much MCP of the whole power system the demand‐side energy storage systems change. Through numerical examples, this paper evaluates the possibility of giving the cost merit to both customers with energy storage systems and LSE by using real data for a year's worth of MCP. © 2006 Wiley Periodicals, Inc. Electr Eng Jpn, 158(1): 22–35, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20447
Does an index futures split enhance trading activity and hedging effectiveness of the futures contract?
Authors: Nordén Lars
Published: October 2006

Recently, several stock index futures exchanges have experimented with an altered contract design to make the contract more attractive and to increase investor accessibility. In 1998, the Swedish futures exchange (OM) split the OMX‐index futures contract with a factor of 4:1, without altering any other aspect of the futures contract design. This isolated contract redesign enables a ceteris paribus analysis of the effects of a futures split. The purpose is to investigate whether the futures split affects the futures market trading activity, as well as hedging effectiveness and basis risk of the futures contract. A bivariate GARCH framework is used to jointly model stock index returns and changes in the futures basis, and to obtain measures of hedging efficiency and basis risk. Significantly increased hedging efficiency and lower relative basis risk is found following the split. In addition, evidence of an increased trading volume is found after the split, whereas the futures bid‐ask spread appears to be unaffected by the split. The results are consistent with the idea that the futures split has enhanced trading activity and hedging effectiveness of the futures contract, without raising the costs of transacting at the futures market. © 2006 Wiley Periodicals, Inc. Jrl Fut Mark 26:1169–1194, 2006
Dynamic trading value at risk: Futures floor trading
Authors: Lee Jongdoo , Locke Peter
Published: October 2006

Speculative traders' dynamic trading strategies are not easy to model, because they depend on latent information flows and preferences. As a result, the risks involved in such strategies may only be revealed by examining empirical distributions of ex post returns to traders engaged in speculative activities. The authors' comprehensive data from futures floor trader's proprietary trading allows for an empirical examination of one prominent type of speculative trader risk. It is shown that floor trader “value at risk” can be predicted somewhat, using simple market variables such as volume and volatility. Although some predictability for the crosssectional distribution of floor trader income, and hence risk was found, not much was determined in terms of trader‐specific characteristics. © 2006 Wiley Periodicals, Inc. Jrl Fut Mark 26:1217–1234, 2006
Effect of entrapped gas on peatland surface level fluctuations
Authors: Strack M. , Kellner E. , Waddington J. M.
Published: October 2006

Peat is a highly compressible medium and changes in peat surface level in response to shifts in water storage and entrapped gas volume have been reported previously. Since both peat compressibility and capacity to entrap gas are related to peat structure, we hypothesize that the relationship between water table and surface level may vary across a peatland. The objective of this study is to investigate the relationships between peat surface level positions, water table positions and subsurface gas pools at local topographic low‐lying areas within a poor fen, which differ in peat properties and vegetation cover. Three sites were investigated, two with highly movable surfaces (FA and FB) and one which was more stable (NF). Deviations from the water table position–surface level position relationship (residuals) appear to be related to changes in atmospheric pressure. However, this relationship varied between FA and NF. The differences in these relationships were supported by distinct patterns of gas dynamics between these sites. Ebullition tended to occur only during periods of falling atmospheric pressure at FA, whereas it occurred much more frequently at NF without atmospheric pressure being the primary control. Evidence of ebullition based on changes in volumetric water content below the water table were supported by ebullition measured by surface gas traps and by shifts in pore water pressure deviation. These different responses of surface level fluctuations to changes in atmospheric pressure between sampling locations are likely related to variations in peat properties between the sites. Copyright © 2006 John Wiley & Sons, Ltd.
Tributyltin compounds induce male characteristics on female mud snails Nassarius obsoletus = Ilyanassa obsoleta
Authors: Smith Blakeman S.
Published: October 2006

Superimposition of male characteristics on to normal females of this dioecious snail is prevalent near marinas in estuaries. In the laboratory it can be caused by exposure to parts per billion concentrations of three organotin biocides: tributyltin oxide, tributyltin resinate and tributyltin chloride. Occurrence of such abnormalities in natural populations is thus an indicator of organotin pollution which might present an environmental hazard.
Safety evaluation of cimetidine: 54 month interim report on long‐term study in dogs
Authors: Crean G. P. , Leslie G. B. , Walker T. F. , Whitehead S. M. , Roe F. J. C.
Published: October 2006

Cimetidine [N″‐cyano‐N‐methyl‐N′‐2[(5‐methylimidazol‐4‐yl)methylthio]ethyl guanidine] was administered orally to eight male and four female beagle dogs at a dose level of 144 mg per kg body weight per day. Four males and two females received placebo tablets. Dosing began in March 1976. During the first 26 months of dosing the animals became obese – the control animals more so than the cimetidine‐treated. Since month 27 feeding time was restricted and there has been an overall weight loss. Some control animals are still obese. One control male and one dosed female have been killed because they developed convulsions. No treatment‐related effects on haematology, clinical biochemistry, urinalysis, electrocardiography or clinical condition have been seen. Three out of the five surviving control animals but none of the 11 surviving cimetidine‐dosed animals have developed cataracts. Biopsies of gastric mucosa taken during endoscopy in months 41, 47 and 53 have shown no changes attributable to cimetidine treatment.
Reproduction and teratology study of 1,3‐butanediol in rats
Authors: Hess Frederick G. , Cox George E. , Bailey David E. , Parent Richard A. , Becci Peter J.
Published: October 2006

The effect of 1,3‐butanediol on reproductive performance as well as its teratogenic, dominant lethal and cytogenetic effects were studied in five generations of Wistar rats. Animals of both sexes were fed either control diet or diet supplemented with 1,3‐butanediol at dose levels of 5, 10 or 24% of the diet by weight. Reproduction and lactation parameters were comparative to controls for four of five generations of dams and pups. In contrast, the pregnancy rate of F1A rats decreased during five successive mating cycles; no pups were obtained in the high‐dose level group of the fifth series of litters (F2E generation). Excluding this group, the viability of F2 generation pups revealed no significant differences between litters or between control and test groups. No definitive dose‐related teratological findings were found in either soft or skeletal tissue examinations of F3B generation rats. However, incomplete ossification of sternebrae occurred frequently in mid‐ and high‐dose fetuses, whereas missing sternebrae were noted especially in high‐level fetuses. Both skeletal tissue findings suggest slight delayed fetal growth. For the dominant lethal assay of the F1B generation, the mutagenic index (percentage resorptions per implant sites) revealed no dose‐related trend. In the three‐generation cytogenetic study, no 1,3‐butanediol related chromosomal aberrations were noted.
Methylmercury poisoning in the Iraqi suckling infant: A longitudinal study over five years
Authors: Amin‐Zaki Laman , Majeed M. A. , Greenwood Michael R. , Elhassani Sami B. , Clarkson Thomas W. , Doherty Richard A.
Published: October 2006

In a five‐year longitudinal study of mothers and infants exposed to methylmercury during the Iraq epidemic of 1972, the frequencies of signs and symptoms exhibited by the mothers were typical of methylmercury poisoning. When blood concentrations of mercury are corrected to 1 March 1972, mothers with the most severe signs and symptoms had an average blood mercury concentration significantly higher (p < 0.01) than either the milder or asymptomatic groups. Analytical data indicate that the predominant route of exposure for the infant was through breast milk in which approximately 60% of total mercury was determined, by cold vapor atomic absorption, to be organic mercury. Abnormal neurological signs in these infants became more obvious with time: hyperreflexia was observed in 8 of 22 infants at first examination, and in 17 of 22 at second examination. Delayed motor development became evident at the second and third examinations. The frequency of pathological reflexes and delayed motor developmental milestones was so high as to be considered significant even in the absence of a controlled study. There was no increase in mortality as compared to a control group.
Considerations on the carcinogenicity of the mushroom poison gyromitrin and its metabolites
Authors: Braun R. , Dittmar W. , Greeff U.
Published: October 2006

Monomethylhydrazine (MMH) and unsymmetrical dimethylhydrazine (UDMH), but not N‐methyl‐N‐formylhydrazine (MFH), a mushroom poison, can be oxidized by the weak oxidant 2,6‐dichlorophenol‐indophenol Hydrogen peroxide is formed by this oxidation, and has been found to cause decay of DNA in aqueous solution as measured by the decreased viscosity of a DNA solution in the presence of the hydrazines. Furthermore, MMH and UDMH but not MFH inhibit the incorporation of [3H]thymidine and [3H]uridine into DNA and RNA of Ehrlich ascites carcinoma (EAC) cells. These experiments show that MFH is an inactive compound in contrast to MMH and UDMH. Since the hydrolysis rate of MFH, to produce MMH, is low, it is concluded that MFH must be activated in vivo into toxic metabolites which are ultimately responsible for the known high carcinogenicity of MFH.
The acute toxicity of some organolead and organotin compounds in the rat, with particular reference to a gastric lesion
Authors: Verschoyle R. D. , Little R. A.
Published: October 2006

The acute toxicity of triphenyl, tributyl and dibutyllead in the rat appears to result from their irritating properties to membranes regardless of their route of administration. A more detailed examination of their oral toxicity has shown that a single dose inhibits gastric emptying with resulting fluid distension. A similar effect was observed with a number of other organolead and organotin compounds. Analysis of gastric fluid from pyloric ligated rats following an oral organolead dose showed increased concentrations of Na+ and glucose and decreased concentrations of H+ and K+. Dilation of the gastic mucosal microcirculation was also observed along with desquamation of surface mucous cells which resulted in shallow erosions of the upper portions of the gastric glands. It is suggested that oral dosing with a number of organoleads and, possibly, organotins has an effect on mucosal membranes that results in erosion of the gastric mucosa and increases permeability of the mucosal microcirculation. This would allow leakage of plasma constituents into interstitial fluid and ultimately the gastric lumen with back‐diffusion of H+ into the gastric mucosa. Such a lesion would impair gastric function and reduce normal food and water consumption. The starvation and dehydration may then be the important factors for death that follows oral dosing with organolead and organotin compounds.
The murine aromatic hydrocarbon responsiveness locus: A comparison of receptor levels and several inducible enzyme activities among recombinant inbred lines
Authors: Bigelow Sanford W. , Nebert Daniel W.
Published: October 2006

The aromatic hydrocarbon responsiveness (Ah) locus has been correlated with genetic differences in the risk of drug toxicity, teratogenesis, chemical carcinogenesis, and mutagenesis. Hepatic cytosolic Ah receptor levels, 2‐amino‐5‐chlorobenzoxazole (zoxazolamine) paralysis time following β‐naphthoflavone treatment and aryl hydrocarbon hydroxylase (AHH),3 acetanilide 4‐hydroxylase (Ac4H), and NAD(P)H:menadione oxidoreductase (NMOR);4 induction by 3‐methylcholanthrene were studied in (a) the progenitors C57BL/6J (Ahb/Ahb) and DBA/2J (Ahd/Ahd) and 25 BXD recombinant inbred lines, (b) the progenitors C57BL/6N and C3H/HeN and 14 B6NXC3N recombinant inbred lines, and (c) the progenitors C57BL/6J and C3H/HeJ and 12 BXH recombinant inbred lines. The Ahb phenotype exhibits >5 femtomole receptor/mg of cytosolic protein, ≤15 minutes zoxaxolamine paralysis time, and twofold to 15‐fold induction of these three hepatic enzyme activities; the Ahd phenotype exhibits ≤2 fmol receptor/mg protein, >15 minutes zoxazolamine paralysis time, and <30% induction of these three activities. Among the BXD lines but especially among the B6NXC3N and BXH lines, high frequencies of recombination were found; the phenotype of each of the five parameters did not segregate with the phenotype of each of the other parameters in four or more recombinant lines. This report shows for the first time that AHH induction by 3‐methylcholanthrene can occur in the Ahd phenotype mouse. These data underline the complexity of this genetic system when genes from C57BL/6 and DBA/2 are combined and particularly when genes from C57BL/6 and C3H/He inbred mouse strains are combined.
Ca2+ homeostasis and cytotoxicity in isolated hepatocytes: Studies with extracellular adenosine 5′‐triphosphate
Authors: Mirabelli Francesca , Bellomo Giorgio , Nicotera Pierluigi , Moore Margo , Orrenius Sten
Published: October 2006

The incubation of isolated rat hepatocytes with extracellular adenosine 5′‐trihosphate (ATP) resulted in an inhibition of Ca2+ efflux. The ATP‐induced Ca2+ accumulation as determined by the increase in phosphorylase a activity and the Ca2+ ‐sensitive fluorescent indicator (2‐[(2‐bis‐[carboxymethyl]‐amino‐5‐methylphenoxy)‐methyl]‐6‐methoxy‐8‐bis‐[carboxymethyl] aminoquinoline‐tetrakis‐[acetoxymethyl]ester) (Quin 2‐AM) was associated with both the hydrolysis of ATP and the phosphorylation of a 110 kDa protein. No significant alteration in the intracellular ATP level was observed.

The appearance of surface blebs and cytotoxicity followed the rise in cytosolic Ca2+, suggesting that the increased free Ca2+ may be responsible for the loss of viability. When a calmodulin inhibitor, 1‐[bis(4‐chlorophenyl)methyl]‐3‐[2‐(2,4‐dichlorophenyl)‐2‐[(2,4‐dichlorophenyl)methoxy] ethyl]‐1H‐imidazolium chloride (calmidazolium), was included in the medium prior to ATP addition, bleb formation was reduced and the loss of viability was completely prevented, indicating that a Ca2+ ‐calmodulin process may be involved in the initiation of cytotoxicity.
The effects of nonadecafluoro‐n‐decanoic acid on serum retinol and hepatic retinyl palmitate hydrolase activity in male sprague‐dawley rats
Authors: Powers Robert H. , Aust Steven D.
Published: October 2006

The effects of nonadecafluoro‐n‐decanoic acid (NDFDA) on serum retinol levels and hepatic retinyl palmitate hydrolase (RPH) activity were investigated in male Sprague‐Dawley rats given a single intraperitoneal (IP) dose of 0, 50, or 100 mg/kg NDFDA and sacrificed at two, eight, or 11 days. Treated animals exhibited depressed serum retinol levels, lymphoid involution, and failure to gain weight in proportion to the dose. Hepatic RPH activities were depressed in both treatment groups at all time points and correlated with serum retinol levels. Hepatic retinol levels were also depressed by Day 11. Extraction of hepatic homogenates with acetone removed NDFDA and increased RPH activities twofold and threefold for the low‐ and high‐dose groups, respectively. Analysis of partially purified RPH showed both NDFDA and 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) to be noncompetitive inhibitors: K1 = 450 and 750 μM, respectively. We conclude that NDFDA causes a decrease in the mobilization of vitamin A from the liver by noncompetitive inhibition of RPH.
Synthesis and genotoxicity of acetoxyoxirane, the epoxide of vinyl acetate
Authors: Simon P. , Epe B. , Mützel P. , Schiffmann D. , Wild D. , Ottenwälder H. , Fedtke N. , Bolt H. M. , Henschler D.
Published: October 2006

Acetoxyoxirane, the epoxide of vinyl acetate and a potential reactive intermediate, was synthesized and characterized by 13C‐nuclear magnetic resonance (13C‐NMR) and mass spectroscopy. The compound induced lesions (endonuclease‐sensitive and alkali‐labile sites) in supercoiled PM2 DNA in vitro and was directly mutagenic toward Salmonella typhimurium TA100. The mutagenicity of the epoxide in phosphate buffer (pH 7.4, 37 °C) decreased, with an initial half‐life of 2.8 minutes, and mutagenicity was completely abolished by addition of S‐9 mix. Acetoxyoxirane did not induce unscheduled DNA synthesis on incubation with Syrian hamster embryo fibroblasts (SHE cells). These findings may possibly be explained by an effective inactivation of acetoxyoxirane by esterases when these are present in the biological system. This view is consistent with the lack of acetoxyoxirane detected in rat liver microsomal incubations of vinyl acetate.
Identification of S‐1,2,2‐trichlorovinyl‐N‐acetylcysteine as a urinary metabolite of tetrachloroethylene: Bioactivation through glutathione conjugation as a possible explanation of its nephrocarcinogenicity
Authors: Dekant Wolfgang , Metzler Manfred , Henschler Dietrich
Published: October 2006

The elimination and metabolism of [14‐C]‐tetrachloroethylene (Tetra) was studied in female rats and mice after the oral administration of 800 mg/kg [14‐C]‐Tetra. Elimination of unchanged Tetra was the main pathway of elimination in both species and amounted to 91.2% of the dose in rats and 85.1% in mice. [14‐C]‐Carbon dioxide (CO2) was found to be a trace metabolite of [14‐C]‐Tetra. Only a small part of the applied dose was transformed to urinary (rats = 2.3%, mice = 7.1%) and fecal (rats = 2.0%, mice = 0.5%) metabolites. The urinary metabolites were separated and quantified by high performance liquid chromatography (HPLC) and identified by gas liquid chromatography/mass spectrometry (GC/MS). The following metabolites could be identified: oxalic acid (8.0% of urinary radioactivity in rats, 2.9% in mice), dichloroacetic acid (5.1%, 4.4%), trichloroacetic acid (54.0%, 57.8%), N‐trichloroacetyl‐aminoethanol (5.4%, 5.7%), trichloroethanol, free and conjugated (8.7%, 8.0%), S‐1,2,2‐trichlorovinyl‐N‐acetylcysteine (N‐acetyl TCVC) (1.6%, 0.5%), and another conjugate of trichloroacetic acid (1.8%, 1.3%). The structures of the identified metabolites indicate two different pathways operative in Tetra biotransformation: cytochrome P‐450‐mediated epoxidation forming reactive metabolites in the liver and conjugation of Tetra with glutathione (GSH) catalyzed by glutathione transferase(s). The formation of reactive intermediates by renal processing of the glutathione conjugates may provide a molecular mechanism for the nephrotoxicity and nephrocarcinogenicity of Tetra in male rats.
Regulation of hepatic malic enzyme by perfluorodecanoic acid
Authors: Kelling Christopher K. , van Rafelghemp Marc J. , Drake Richard L. , Menahan Lawrence A. , Peterson Richard E.
Published: October 2006

Perfluorodecanoic acid (PFDA) administration to adult male rats increased both the activity of hepatic malic enzyme and liver weight in a dose‐dependent manner. Hepatomegaly and augmented activity of malic enzyme in liver were apparent within one day following PFDA administration and reached a plateau by three days posttreatment. Malic enzyme quantity per liver in PFDA‐treated rats was elevated within one day following dosing and increased continually throughout five days posttreatment. Administration of PFDA to rats in the fed state also led to an increase in the specific activity of hepatic malic enzyme that peaked at three days following dosing. When compared to the fed condition, rats fasted for 48 hours had a decrease in both relative liver weight and the quantity of supernatant protein per liver. The total activity (U/liver) and specific activity of malic enzyme in the liver were also reduced in the fasted state. During the 24 hours after treatment in rats fasted for 48 hours, the body weight as well as the absolute and relative liver weight of animals receiving vehicle declined continuously in the absence of feed. Following the administration of PFDA to fasted rats, body weight was maintained until eight hours posttreatment but then declined at a rate similar to that found with the vehicle‐treated group. Absolute and relative liver weight in PFDA‐treated rats were increased significantly at eight hours posttreatment when compared to those receiving vehicle, and this increment was maintained throughout the rest of the 24 hours following dosing. While the activity and enzyme content of hepatic malic enzyme decreased in the vehicle‐treated group, administration of PFDA to rats fasted for 48 hours prevented their decline. The specific activity of hepatic malic enzyme in 48 hours fasted rats receiving PFDA was also elevated significantly at 16 hours posttreatment. Thus, the administration of PFDA to the adult male rat in both the fed and fasted nutritional states was found to regulate hepatic malic enzyme by not only increasing enzyme quantity but also by augmenting the specific activity, (ie, catalytic state) of the enzyme.
2,3,7,8‐tetrachlorodibenzo‐p‐ dioxin reduces high‐affinity binding of epidermal growth factor to cell surface receptors in C3H 10T1/2 cells
Authors: Moriya Masaaki , Matsumura Fumio , Kalimi Ghulm H.
Published: October 2006

The effect of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) on epidermal growth factor (EGF)‐binding characteristics was studied in a cultured embryonic fibroblast cell line, C3H 10T1/2. At very low concentrations, TCDD was found to cause a persistent decline in EFG binding, the median effective concentration (EC‐50) being 10−12M. This particular effect was most conspicuous when TCDD was added at the time of medium change with fresh Dulbecco's modified Eagle's medium. Cells at an early stage of confluency were more responsive to TCDD than those at a later stage. Although most reported TCDD‐evoked biological changes are recognized to occur slowly during the course of a few days to weeks, the response of C3H 10T1/2 cells to TCDD was swift, showing a sign of decline of EGF binding as early as three hours after TCDD addition. C3H 10T1/2 cells appear to be an excellent in vitro model to study TCDD's biochemical action mechanisms.
Effect of nickel(II) on DNA‐protein binding, thymidine incorporation, and sedimentation pattern of chromatin fractions from intact mammalian cells
Authors: Patierno Steven R. , Sugiyama Masayasu , Costa Max
Published: October 2006

Nuclear uptake and chromatin binding of nickel(II) was investigated in Chinese hamster ovary (CHO) cells. The cytoplasmic:nuclear ratio of nickel immediately following treatment was 5:1, but by 24 and 48 hours this ratio decreased to 4:l and 2:1, respectively, indicating that nickel is retained longer in the nucleus than cytoplasmic nickel. Chromatin was fractionated by sonication and centrifugation into fast‐sedimenting, magnesium‐insoluble, or magnesiumsoluble components. The magnesium‐insoluble portion bound more nickel ions and retained the metal longer than either the magnesium‐soluble or the fastsedimenting fractions. Treatment of cells with nickel chloride (NiCl2) decreased the amount of DNA in the magnesium‐insoluble fraction but increased the amount of DNA in the fast‐ sedimenting chromatin fraction. The magnesium‐insoluble fraction isolated from nickel‐treated cells contained approximately ten times more [35‐S]‐methionine–labeled protein per milligram DNA compared with untreated cells. The magnesium‐soluble and the fast‐sedimenting fractions isolated from the nickel‐treated cells did not exhibit a similar increase in [35‐S]‐methionine–labeled protein per milligram of DNA. Nickel treatment suppressed [14‐C]‐thymidine incorporation into total DNA by 30% compared with untreated cells. However, the magnesium‐insoluble chromatin fraction from nickel‐treated cells had a tenfold to 20‐fold increase in thymidine incorporation, while the other chromatin fractions did not exhibit an increase in thymidine incorporation. These findings indicate that nickel induced widespread alterations in chromatin conformation and preferentially interacted with an Mg‐insoluble component of chromatin.
Characterization of cadmium‐binding proteins detected in rat liver by the western blotting technique
Authors: Aoki Yasunobu , Suzuki Kazuo T.
Published: October 2006

Out of the three cadmium‐binding proteins (CD‐BPs) in rat liver parenchyma (40K, 29K, and 24K CdBPs), the 40K Cd‐BP showed the highest affinity for cadmium (Cd), with a dissociation constant (KD) of 1.2 × 10−8M. This is in between the affinity of human serum albumin KD = 3.8 × 10−5M) and metallothionein (KD = < 10−11). These Cd‐BPs may be responsible for hepatic sequestration of cadmium.
Alterations in platelet aggregation and microsomal benzo‐α‐pyrene hydroxylase activities after exposure of rats to a prudhoe bay crude oil
Authors: Chaudhury Shibani , Martin Marie , Payne Jeremiah F. , Rahimtula Anver
Published: October 2006

Administration of a Prudhoe Bay crude oil (PBCO) to rats has been shown to (a) inhibit platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid, or epinephrine and (b) induce benzo‐α‐pyrene hydroxylase (BPH) in the liver and small intestine. Maximum inhibition of aggregation (90%) was seen 12 to 16 hours subsequent to dosing. However, substantial inhibition was observed as early as four hours and as late as 48 hours after dosing. Of particular interest was the sensitivity of the platelet response compared with the putatively sensitive response of monooxygenase induction in liver. As little as 0.1 ml of PBCO per kilogram body weight (bw) caused an inhibition of aggregation with all three agonists. A similar inhibition of the release of ADP from platelets in the presence of arachidonic acid or epinephrine was also observed. In contrast, hepatic BPH activity showed only a modest increase (67%) over the control value even after administration of 2 ml of PBCO per kilogram body weight. Small intestine BPH activity was more sensitive, showing a gradual increase of up to 19‐fold 24 hours after dosing with 2 ml of PBCO per kilogram body weight. The sensitivity of the platelet response is of general environmental interest and evaluating platelet aggregation in humans may be important as a noninvasive assay for exposure to either accidental or “acceptable” levels of petroleum hydrocarbons in the occupational environment.
Gentamicin‐induced alterations in phospholipid metabolism in cultured human proximal tubular cells
Authors: Chatterjee Subroto
Published: October 2006

The effects of gentamicin on phospholipid levels and metabolism and the uptake of phosphatidylcholine (PC) adsorbed to low‐density lipoprotein (LDL) were investigated in cultured human proximal tubular (PT) cells. Cells incubated with gentamicin (0.3 mM) for one to 21 days had a similar increase in the cell number and protein as compared to control cells. However, the cellular levels of phosphatidylcholine (PC) and sphingomyelin (SM), but not other phospholipids, increased in a time‐dependent manner. Incubation of gentamicin (0.3 to 3.0 mM) resulted in a concentration‐dependent increase in the cellular levels of PC (50% to 320%) and SM (20% to 40%).

Gentamicin stimulated the incorporation of [14C]‐acetate into diacylglycerol, PC, and SM in the order of 300%, 66%, and 20%, respectively, but not into lysophosphatidylcholine (LPC). Similarly, gentamicin stimulated the incorporation of [14C]‐choline into PC and SM in the order of 300% and 172%, respectively, but not into LPC as compared to control cells. In addition, gentamicin also stimulated the incorporation of [14C]‐choline into cytidine diphosphocholine (CDP‐choline). However, the endocytosis of [14C]‐PC‐LDL was lower in cells incubated with gentamicin than in control cells. Thus, exogenously derived PC on LDL does not contribute to the increased cellular levels of PC in PT cells incubated with gentamicin.

The activity of cytidine triphosphate (CTP):phosphocholine cytidyltransferase was moderately lower in cells incubated with gentamicin as compared to control. By contrast, the activity of phospholipase A1 and phospholipase C was twofold lower in cells incubated with gentamicin for 21 days as compared to control. Thus, increased incorporation of [14C]‐acetate and [14C]‐choline into PC in cells incubated with gentamicin may not only be due to increased endogenous synthesis but to decreased catabolism of newly synthesized PC. We conclude that gentamicin impairs the lysosomal catabolism of PC, leading to its accumulation in PT cells. This phenomenon may be an indication of gentamicin‐induced nephrotoxicity in man.
Attenuation of 2‐methoxyethanol and methoxyacetic acid‐induced digit malformations in mice by simple physiological compounds: Implications for the role of further metabolism of methoxyacetic acid in developmental toxicity
Authors: Welsch F. , Sleet R. B. , Greene J. A.
Published: October 2006

The ethylene glycol ether 2‐methoxyethanol (ME) and its oxidation product methoxyacetic acid (MAA) are selective embryotoxins and equipotent as inducers of digit malformations when given by gavage to pregnant CrI:CD‐1 ICR BR mice on gestation day 11. Earlier observations showed that the teratogenic effects were attenuated by delayed administrations of ethanol given at a time when all ME is already converted to MAA. That outcome suggested that acetate from ethanol catabolism might compete with methoxyacetate in biosynthetic reactions relevant to MAA‐induced malformations. Furthermore, 14C derived from [1,2‐14C]‐ME or [1‐14C]‐MAA is incorporated into all marcromolecular fractions of the embryo, and 14C is exhaled by the dam in 14CO2. Those data indicate that 14C derived from 14C‐ME catabolism enters into many metabolic reactions. The present study examined acetate and other simple physiological compounds with close relationships to carbon and one‐carbon moiety metabolic pathways for their ability to attenuate digit malformations upon concomitant dosing with ME. All of the agents examined reduced the teratogenic effect significantly with a potency rank order of formate ≫ acetate = glycine ≫ D‐glucose. The common link for their efficacy may be the one‐carbon moiety oxidation pathway that involves tetrahydrofolic acid as a catalyst of one‐carbon transfer into purines and thymidylate. Carbon from all of the attenuators administered is incorporated into those bases and then into DNA. It appears as if methoxyacetate enters into biochemical reactions analogous to those of acetate. This speculation is supported by the metabolic fate of 14C from 14C‐ME in dam and embryo. Based on the indirect evidence obtained with all of the simple compounds that attenuate the ME‐induced digit malformations, we postulate that abnormal macromolecules are generated by anabolic reactions and that those products disrupt normal paw development.
Age and growth‐related changes in cyclopiazonic acid‐potentiated lipophilic cation accumulation by cultured cells and binding to freeze‐thaw lysed cells
Authors: Riley Ronald T. , Goeger Douglas E. , Norred William P. , Cole Richard J. , Dorner Joe W.
Published: October 2006

In a previous study (1) we demonstrated that increased tetraphenylphosphonium (TPP) uptake by renal epithelial cells (LLC‐PK1) exposed to the fungal metabolite cyclopiazonic acid (CPA) was not a result of hyperpolarization across the plasma membrane even though CPA‐potentiated TPP uptake could be totally inhibited by the depolarizing agent carbonylcyanide‐m‐chlorophenylhydrazone (CCCP). We now demonstrate that CPA potentiates TPP accumulation by proliferating skeletal muscle (L6) and LLC‐PK1 cells but not by nonproliferating primary rat hepatocytes. In LLC‐PK1 cells, CPA‐potentiated TPP accumulation is observed in cells at all ages. In s cells, CPA‐potentiated TPP accumulation is maximal soon after subculturing, and as the cells age they become less sensitive to CPA until TPP accumulation by CPA‐treated cells approaches that of untreated cells. The temporal change in sensitivity of L6 cells to CPA may be related to biochemical and/or metabolic changes which occur as the cells age in culture. Hepatocytes, LLC‐PK1 cells, and L6 cells permeabilized by freeze‐thaw lysis, all exhibit CPA‐potentiated TPP partitioning, even in the presence of CCCP. This result indicates that both TPP and CPA must have access to the intracellular space in order for potentiated TPP partitioning to be observed. We hypothesize that the site of interaction between CPA and TPP is intracellular and probably associated with the cytoplasmic side of the plasma membrane and possibly the mitochondria.
Cerebral glucose and glycogen metabolism in diazinon‐treated animals
Authors: Matin M. A. , Husain K.
Published: October 2006

The intraperitoneal (IP) treatment of rats with diazinon (40 mg/kg) resulted in a variety of changes in the brain. Glycogen was depleted, but there was an increase in the activities of glycogen phosphorylase, phosphoglucomutase, hexokinase, lactate dehydrogenase, and fructose 1,6 diphosphatase. The activity of glucose‐6‐phosphatase was unaffected while that of cholinesterase was significantly reduced. Lactic acid content was increased, while that of pyruvate was not altered. Animals developed tremors and convulsions, which were maximal two hours after treatment. The induced changes may be compensatory mechanisms to provide extra energy to cerebral tissue as a result of the stimulatory effects in diazinon‐treated animals.
Alteration of liver microsomal monooxygenases and substrate competition with aniline hydroxylase from rats chronically fed low‐fat and high‐fat‐containing alcohol diets
Authors: Winston Gary W. , Narayan Satya
Published: October 2006

Male Sprague‐Dawley rats fed ethanol (EtOH) 36% of total calories for four weeks in a liquid diet containing either 34% (HF) or 12% (LF) of calories as fat were studied with respect to induction of microsomal monooxygenases (MFO) and substrate competition with EtOH‐inducible aniline hydroxylase. The specific activity and turnover of aniline hydroxylase were induced to similar extents by HF‐EtOH and LF‐EtOH diets. Whereas, both LF‐EtOH and HF‐EtOH caused a decrease in the turnover of arylhydrocarbon (benzo[a]pyrene) hydroxylase (AHH) and aldrin epoxidase compared to pair‐fed (PF) controls, LF‐EtOH but not HF‐EtOH increased the turnover of ethoxycoumarin and ethoxyresorufin O‐deethylase (ECOD and EROD). The increase in ECOD and EROD and the decrease in AHH by EtOH is contrary to the parallel induction of these activities by J‐methylcholanthrene (3‐MC) and Aroclor 1254 (Aroclor). Benzo(a)pyrene (BaP) stimulated aniline hydroxylase in the HF‐EtOH and PF systems, whereas with LF diet, stimulation was seen only in the EtOH group. Ethoxycoumarin (EC) inhibited aniline hydroxylase by microsomes from EtOH‐ and pyrazole‐treated rats, whereas it stimulated aniline hydroxylase by control microsomes, suggesting that the EC effects were associated with EtOH‐inducible cytochrome P‐450. Ethoxyresorufin (ER) inhibited aniline hydroxylase in EtOH and PF groups, thus the differential effects of EC were not nonspecific O‐deethylase effects. The effects of EtOH feeding on ECOD, EROD, and AHH (ie, substrates for 3‐MC‐inducible cytochrome P‐450) displayed a greater differential between the experimental and control group with the LF‐ than with the HF‐containing diet. The findings suggest that the alteration of certain MFO activities by chronic EtOH ingestion can be modified by the content of dietary fat. Moreover, the competition dynamics of MFO substrates toward EtOH‐inducible aniline hydroxylase are altered by EtOH feeding and, in turn, modified by dietary fat.
Differential Toxicity of Cis and Trans Isomers of Dichlorodiammineplatinum
Authors: Singh Gurmit , Koropatnick James
Published: October 2006

Nephrotoxicity is the dose‐limiting toxic effect of cis‐dichlorodiammineplatinum (cis‐platin) in humans. Its stereoisomer transplatin does not have any toxicity at equimolar concentrations, and it also possesses little antitumor activity. In this study, subcellular localization of both the platinum isomers was examined in the liver and kidney of the mouse 24 hours following the drug administration. Levels of the platinum isomers were measured using flame‐less atomic absorption. The results showed that higher concentrations of the cis isomer were localized in the liver and kidney, while the concentration of the trans isomer was higher in blood. This indicates that trans isomer is sequestered in the central compartment, whereas cis isomer is distributed in the organs.

We also measured metallothionein mRNA and protein levels in both liver and kidney following cisdichlorodiammineplatinum and transdichlorodiammine‐platinum treatment to distinguish if the differential toxicity of the two stereo‐isomers could be related to metallothionein induction. We report here that cisplatin was capable of inducing metallothionein expression in mice in vivo and that there is an inverse relationship between metallothionein expression and the pattern of tissue toxicity induced by the drug.