bluuebunny/crossref_metadata_2025 huggingface dataset:
Are spontaneous earthquakes stationary in California?
Authors: Wang Qi , Jackson David. D. , Zhuang Jiancang
Published: August 2010

Aftershocks and some main shocks are triggered, with timing controlled by preceding events. The remaining spontaneous earthquakes presumably respond to tectonic stresses. We consider whether triggered events can be reliably identified, whether the rest are stationary, and whether external phenomena control them. To all three questions, some studies of earthquake physics and hazard assume answers. Many suggest that stress changes from large distant earthquakes can alter the local spontaneous earthquake rate. We demonstrate significant differences in the apparent earthquake rate after declustering by different methods, and we present criteria for assessing the influence of such distant events. The estimated spontaneous earthquake rate depends on the lower magnitude threshold of included events, whether spontaneity is treated in binary or probabilistic form, as well as assumptions about catalog completeness. Different statistical tests give different answers to the question of stationarity. We examine a reported rate change in southern California and the suggestion that it might have resulted from the 1960 Chile and 1964 Alaska earthquakes. The rate change itself is questionable. If it has occurred, it was probably not caused by those distant events, because the rate change is not present in northern California or in all parts of southern California.
Joint inversion for three‐dimensional S velocity mantle structure along the Tethyan margin
Authors: Chang Sung‐Joon , van der Lee Suzan , Flanagan Megan P. , Bedle Heather , Marone Federica , Matzel Eric M. , Pasyanos Michael E. , Rodgers Arthur J. , Romanowicz Barbara , Schmid Christian
Published: August 2010

We construct a new three‐dimensional S velocity model and Moho map by jointly inverting regional S and Rayleigh waveform fits, teleseismic S and SKS arrival times, fundamental mode Rayleigh wave group velocities, and independent Moho depth estimates for the region that extends from the mid‐Atlantic ridge through northern Africa, southern Europe, and western Asia. The joint inversion benefits from both better resolution and wider data coverage than when using only individual data sets. Resolution tests confirm that the joint inversion yields good resolution ranging from the Moho to a depth of 1400 km. The complementary and overlapping nature of the different data sets' resolving power has reduced disparities in resolving power that exist for individual data sets, for example between resolving power for crustal and lower‐mantle structure. This increases the utility of the new tomographic model for explaining and predicting a variety of observations and dynamics. The new model derived from the joint inversion assembles a large number of mantle structures known from a wide variety of previous studies into one model and in some cases reconciles different local studies that previously seemed contradictory. Finally, the model shows that shallow low‐velocity anomalies beneath the Pannonian basin and the Iranian plateau are connected to similar anomalies in the transition zone, the latter possibly related to a deep dehydration process in the subducted lithosphere of the Neo‐Tethys Ocean. The model shows the Hellenic slab penetrating the lower mantle, the Calabrian slab extending flatly in the transition zone, and discontinuous slabs beneath the Apennines and the Zagros belt.
Near‐surface dynamics of a separated jet in the coastal transition zone off Oregon
Authors: Koch A. O. , Kurapov A. L. , Allen J. S.
Published: August 2010

Three‐dimensional circulation in the coastal transition zone (CTZ) off Oregon is studied using a 3 km resolution model based on the Regional Ocean Modeling System. The study period is spring and summer 2002, when extensive observations were available from the northeastern Pacific component of the Global Ocean Ecosystems Dynamics project. Our main focus is on near‐surface transports, particularly in an area off Cape Blanco where an energetic coastal current is separated in the CTZ. Comparisons with available observations (velocities from midshelf moorings, surface velocities from high‐frequency radars, satellite sea surface temperature maps, along‐track sea surface height altimetry, and SeaSoar hydrography) show that the model reproduces qualitatively correctly the flow structure and variability in the study area. The near‐surface flow behavior during 26 July to 21 August, a late‐summer time period of strong, time‐variable southward winds, is examined. During that period the coastal jet separates from the continental shelf around Cape Blanco (43°N). The energetic separated jet continues to flow southward in a near‐coastal region between 42.2°N and 43°N. It subsequently turns around 42°N to flow westward offshore past 127°W. Relatively vigorous up‐ and downwelling is found concentrated in the region of the separated jet. Frontogenesis secondary circulation, nonlinear effects of the relative vorticity on the ageostrophic Ekman transport, and submesoscale instabilities contribute to the vertical circulation within the jet. Vertical velocities are found to reach 50 m d−1 in the offshore part of the jet and 100 m d−1 in the near‐coastal part, where the jet is aligned with the wind direction.
Differences in cyclonic raindrop size distribution from southwest to northeast monsoon season and from that of noncyclonic rain
Authors: Radhakrishna B. , Narayana Rao T.
Published: August 2010

The raindrop size distributions (RSDs) measured with an impact‐type disdrometer have been utilized to study the differences in cyclonic RSD (1) from southwest monsoon (SWM) to northeast monsoon (NEM), (2) from that of noncyclonic rain, and (3) from cyclonic rain elsewhere. The stratified (based on rainfall rateR) cyclonic RSD exhibits significant seasonal variation, with more large drops and fewer small drops in SWM than in NEM. The big drops are almost absent in cyclonic RSD, whereas the small and medium‐sized drops are larger in number than they are in noncyclonic rain. The average cloud effective radius in cyclones is nearly equal in SWM and NEM, suggesting that the nature of the cyclonic cloud may be similar (oceanic) in both seasons. The cyclonic RSD in the Bay of Bengal is consistent qualitatively with that observed elsewhere, but there exist some differences in rainfall bulk parameters. Implications of the observed seasonal and cyclonic to noncyclonic differences in RSD on quantitative rainfall estimation and cloud‐modeling studies are also discussed.
Sand transport by wind on complex surfaces: Field studies in the McMurdo Dry Valleys, Antarctica
Authors: Lancaster Nicholas , Nickling William G. , Gillies John A.
Published: August 2010

Field experiments on boundary layer winds and sand transport in the Victoria Valley, Antarctica have provided information on the spatial and temporal variability of sand transport across coarse sand surfaces covered with isolated roughness elements (rock clusters). Five sand transport events, with a duration ranging between 9.6 and 22 h, were studied. Sand transport threshold velocity was determined using the time faction equivalence method and varied between 0.30 and 0.35 m s−1. Mean rates of sand transport ranged from 0.008 to 0.072 g cm s−1. Sand transport was variably intermittent, with continuous saltation (intermittency (γ) = 1) occurring from 11% to as much as 31% of the time. For all events, there is a close temporal correspondence between intermittency values, shear velocity (u*, m s−1) and the ratio u*/u*t (u*t is threshold shear velocity), sand flux, and sand transport intensity as measured by piezoelectric saltation sensors. Although the roughness density of this site is low, partitioning of shear stress between the rock clusters and the intervening sand surface is important to the spatial pattern of sand transport and acts to increase the mean threshold wind shear velocity or shear stress for sediment transport by approximately 1.2 times compared to a bare sand surface. The effective local threshold wind shear velocity, however, varies by up to 6 times from the smoother sand areas to the most protected areas of the rock clusters. As a result, continuous and widespread sand transport will only occur at this site when the overall wind shear velocity exceeds 0.58 m s−1 (1.6 × u*t minimum).
Temperature sensitivity of forest soil organic matter decomposition along two elevation gradients
Authors: Schindlbacher Andreas , de Gonzalo Carlos , Díaz‐Pinés Eugenio , Gorría Pilar , Matthews Bradley , Inclán Rosa , Zechmeister‐Boltenstern Sophie , Rubio Agustín , Jandl Robert
Published: August 2010

The temperature sensitivity of the soil organic matter (SOM) decomposition along the slopes of mountain forests in Austria and Spain was analyzed. High‐altitude forest soils store large quantities of organic carbon (C) and are particularly vulnerable to global warming if the decomposition of the SOM is more temperature sensitive than at lower altitude. Mineral soil and O‐layer material was incubated in the laboratory at temperatures increasing from 5°C to (20°C) 25°C. The temperature sensitivity (Q10) was determined by fitting different temperature response functions to the measured CO2 efflux. Bulk soil and density fractions were analyzed for organic C and nitrogen (N) contents. C and N stocks along the elevation gradients were estimated. Q10 over the whole incubation temperature range varied between 1.5 and 2.5 but did not show any altitudinal trends for O‐layer material and mineral soils along both gradients. Besides that, Q10 generally increased with decreasing soil temperatures. SOM decomposition at higher elevation forests will be more responsive to global warming because it will be affected in a more sensitive (cooler) temperature range compared to lower elevation sites. This effect was modeled by the Lloyd and Taylor function and Gaussian but not by the frequently used exponential temperature function. Both soil C and N contents increased with increasing altitude. Density fractionation showed deviating altitudinal C and N patterns of labile and recalcitrant SOM pools along the Spanish gradient. Soil C stocks along both gradients did not resemble the trend in C contents and were determined by other site‐specific factors. This, and significantly low C and N contents and stocks of a site that was used as a forest pasture, indicates that both forest management and land use can play equally important roles in the development of soil C as climatic factors.
Modeling advection in geophysical flows with particle level sets
Authors: Samuel H. , Evonuk M.
Published: August 2010

We have applied, for the first time in geodynamical flows, the Particle Level Set method for advecting compositional fields with sharp discontinuities. This robust and efficient Eulerian‐Lagrangian technique is based on the concept of Implicit Surfaces, which allows the use of high order accurate numerical schemes in the vicinity of discontinuities. We have tested the Particle Level Set method against the robust and popular Tracer‐in‐Cell method on well‐known 2D thermochemical benchmarks and typical 3D convective flows. The use of Lagrangian tracers in the Particle Level Set method yields accurate solutions of purely advective transport, where sub‐grid scale features can be resolved. In every case we ran we found that the Particle Level Set method accuracy equals or is better than the popular Tracer‐in‐Cell method, and can lead to significantly smaller computational cost, in particular in three‐dimensional flows, where the reduction of computational time for modeling advection processes is most needed.
Widely different characteristics of oxygen and hydrogen ion escape from Venus
Authors: Jarvinen R. , Kallio E. , Dyadechkin S. , Janhunen P. , Sillanpää I.
Published: August 2010

We study the solar wind induced escape of O+ and H+ ions from Venus' atmosphere in the HYB‐Venus hybrid simulation. Most of the previous Venus global plasma modelling studies have concentrated only on the O+ escape. According to the hybrid simulation, planetary O+ and H+ ions behave very differently from each other in the Venusian induced magnetosphere. Both species are asymmetrically distributed in the direction of the interplanetary electric field and in the dawn‐dusk plane. The H+ flow can be understood by E × B drift motion but finite Larmor radius (FLR) effects are essential to the behavior of O+ ions. These differences result in different H+/O+ escape ratios globally and in the plasma wake. Further, the energy ratio of the escaping planetary ions was found to be consistent with the observations made in the near Venus wake by the ASPERA‐4 instrument onboard the Venus Express spacecraft.
Distribution of present‐day vertical deformation across the Southern Alps, New Zealand, from 10 years of GPS data
Authors: Beavan J. , Denys P. , Denham M. , Hager B. , Herring T. , Molnar P.
Published: August 2010

We use ten years of GPS data from nine continuous and six semi‐continuous GPS stations in a transect across the Southern Alps to measure rates of relative vertical movement with typical 1σ uncertainties of 0.3–0.5 mm/yr. The estimated vertical rates define a fairly smooth profile across the range, with the highest rates of ∼5 mm/yr found near the crest of the mountains and ∼20–30 km southeast of the Alpine Fault. The distribution of vertical rates supports models based on horizontal velocities from GPS surveys in which interseismic coupling on the Alpine Fault decreases from 100% near the surface to zero by 13–18 km depth.
Endocrine‐Disrupting Agents on Healthy Human Tissues
Authors: Paganetto Guglielmo , Campi Franca , Varani Katia , Piffanelli Adriano , Giovannini Gloria , Borea Pier Andrea
Published: August 2010

Abstract: A vast number of substances have been suggested as possibly contributing to perturbation of the endocrine system. Several have been tested with different approaches ranging from yeast expression system of human oestrogenic receptors to human breast cancer cells assays. Surprisingly, no inhibition‐binding experiments to steroid receptors on healthy human tissue have been performed so far. Our study provides inhibition binding experiments to oestrogens, progesterone, testosterone and retinoic acid receptors in prostate and uterine human tissue of organochlorine pesticides, phthalate esters, oestrogenic constituents derived from plants and phenol derivates. Affinities of significant extent of phthalates on oestrogenic, progestinic and androgenic receptors have not been detected. As for retinoic acid receptors, mono(2‐ethylexyl)phthalate provokes a notable reduction of the binding of the tritiated retinoic acid, phtalic acid ethyl‐n‐butyl ester and 4‐octylphenol show an affinity comparable to that of isoflavonoid genistein, whereas 4‐nonylphenol reduces the binding of retinoic acid in prostate.
Differential Activities of CYP1A Isozymes in Hepatic and Intestinal Microsomes of Control and 3‐Methylcholanthrene‐Induced Rats
Authors: Spatzenegger Margit , Horsmans Yves , Verbeeck Roger K.
Published: August 2010

Abstract: Differences in expression of CYP1A isoforms (CYP1A1 and CYP1A2) in liver and small intestine of male Wistar rats and their inducibility by 3‐methylcholanthrene as well as the effect of different CYP1A1/1A2 expression on caffeine metabolism were investigated. In rat liver, CYP1A2 is the predominant isoform and CYP1A1 protein expression in liver is significantly increased after treatment by 3‐methylcholanthrene. In contrast, only CYP1A1 was detected in control and 3‐methylcholanthrene induced small intestine microsomes. Treatment with 3‐methylcholanthrene (40 mg/kg intraperitoneally daily during 1, 2, 3 or 4 days) demonstrated that liver CYP1A1 is more sensitive for the induction effects than CYP1A2 and also that significant induction of CYP1A1 in rat small intestine only occurred after 3 to 4 days pretreatment. Caffeine metabolism and inhibition studies by furafylline, CYP1A1 antiserum and ketoconazole revealed that the differences in the expression of CYP1A1 and CYP1A2 in the two tissues led to significant changes in the contribution of the various isoenzymes involved in the biotransformation of caffeine. Whereas in liver paraxanthine formation was almost exclusively catalyzed by CYP1A2, in rat proximal intestine it was formed by CYP1A1. In addition, other CYP enzymes (most probably CYP3A) play a significant role in theobromine and theophylline formation from caffeine in rat intestine. Overall, this study shows different expression and inducibility of CYP1A1/1A2 by 3‐methylcholanthrene in rat liver and small intestine. Furthermore in rat intestine cytochrome P450 isozymes such as CYP1A1 and CYP3A replace CYP1A2 in the caffeine metabolism.
Effect of Loperamide on Mucosal Guanylyl Cyclase Activity in Rat Jejunum Following Escherichia coli Heat‐Stable Toxin‐Induced Fluid Accumulation
Authors: Farack Ulrich M. , Asher Angela , Elsenhans Bernd , Schütte‐Lückenga Barbara , Gerzer Rupert
Published: August 2010

Abstract: Loperamide has antidiarrhoeal activities against secretagogues with different mechanisms of action. Besides its opioid‐like effect on intestinal motility and secretion it might exhibit additional antisecretory properties which may not be completely elucidated yet. Direct effects of loperamide on mucosal guanylyl cyclase have never been observed. We therefore investigated the effect of loperamide on intestinal fluid transport altered by heat‐stable Escherichia coli enterotoxin which acts by stimulating mucosal guanylyl cyclase. Net fluid movement was determined during a 1 hr incubation period in ligated jejunal loops of anaesthetised female Wistar rats. Transport rates of net fluid movement were calculated from the loop contents measured gravimetrically at the beginning and the end of the experiments. Addition of heat‐stable Escherichia coli enterotoxin to the luminal solution resulted in a net secretion of water which was significantly reversed into net absorption by loperamide. The specific activity of the particulate guanylyl cyclase was determined in mucosal scrapings of the jejunum without and with the addition of heat‐stable Escherichia coli enterotoxin and/or loperamide. Additions of loperamide of up to 10 μmol/l did not change guanylyl cyclase activity. We conclude that the effect of loperamide counteracting heat‐stable Escherichia coli enterotoxin induced changes of intestinal fluid transport does not involve a direct effect on guanylyl cyclase.
Induction of Apoptosis by Lovastatin through Activation of Caspase‐3 and DNase II in Leukaemia HL‐60 Cells
Authors: Wang Ing‐Kae , Lin‐Shiau Shoei‐Yn , Lin Jen‐Kun
Published: August 2010

Abstract: Lovastatin, an HMG‐CoA reductase inhibitor, was found to suppress growth and induce apoptosis in culture human promyelocytic leukaemic cell, HL‐60. However, the mechanisms of lovastatin‐induced apoptosis are still unclear. In this study, we attempted to elucidate the signal transduction pathway for lovastatin‐induced apoptosis in HL‐60 cells in a dose‐ and time‐dependent manner. The features of this apoptosis were attenuated by the presence of mevalonate, a metabolic intermediate of cholesterol synthesis. Treatment of lovastatin caused a rapid release of mitochondrial cytochrome c into cytosol and subsequent induction of caspase‐3, but not caspase‐1 activity. Lovastatin also stimulated proteolytic cleavage of poly‐(ADP‐ribose) polymerase (PARP), and followed by the appearance of caspase activity and DNA fragmentation. Pretreatment with caspase‐3 inhibitors, Ac‐DEVD‐CHO and Z‐VAD‐FMK, inhibited lovastatin–induced caspase‐3 activity and DNA fragmentation. Furthermore, we demonstrated that DNase II was involved in the DNA fragmentation induced by lovastatin. These results suggested that the mechanism of lovastatin induced HL‐60 cells apoptosis through activation of caspase‐3 and DNase II activities.
Toxicity Study of Di(2‐Ethylhexyl)phthalate (DEHP) in Combination with Acetone in Rats
Authors: Dalgaard Majken , Østergaard Grete , Lam Henrik Rye , Hansen Ernst V. , Ladefoged Ole
Published: August 2010

Abstract: In two separate studies with exposure duration 9 weeks or 4 weeks, male Wistar rats were dosed with di(2‐ethylhexyl)phthalate (DEHP) by gavage and exposed to drinking water with or without acetone (0.5% wt/v in the 9‐week study, 1.0% wt/v in the 4‐week study). In the 9‐week study the doses of DEHP were 0, 125, 250, 500 or 1000 mg/kg b.wt. In the 4‐week study the doses of DEHP were increased to 1000, 5000 and 10,000 mg/kg b.wt. In the 9‐week study, the relative liver weight was increased in the rats exposed to 500 and 1000 mg/kg b.wt. No interaction of DEHP and acetone was observed in any of the measured parameters. In the 4‐week study DEHP, at the highest dose level, resulted in severe general toxicity. The group exposed to DEHP in combination with acetone was more affected. Male fertility was decreased. Body weight was decreased, and the relative weight of the liver, kidney, heart, brain and adrenals increased. The relative weight of the testes decreased in the 5000 and 10,000 mg/kg b.wt. groups. The weight of seminal vesicles and epididymals decreased at 10,000 mg/kg b.wt. In animals exposed to 5000 and 10,000 mg DEHP/kg b.wt. a severe atrophy of the seminiferous tubules and a slight diffuse Leydig's cell hyperplasia was observed. The cellular debris and conglomerates of desquamated cells found in the lumen of the seminiferous tubules were immunostained positive for vimentin. This indicates that Sertoli cell cytoplasm is included in the conglomerates – an interesting finding not previously described. No specific interaction of DEHP and acetone was observed in any of the measured parameters.
Paraquat‐Induced Membrane Dysfunction in Pulmonary Microvascular Endothelial Cells
Authors: Tsukamoto Maki , Tampo Yoshiko , Sawada Minoru , Yonaha Masanori
Published: August 2010

Membrane dysfunction monitored by lactate dehydrogenase release from cultured pulmonary microvascular endothelial cells of pigs, which were exposed to paraquat at different concentrations (0.1–2 mM), was examined. Paraquat caused a time‐dependent increase in lactate dehydrogenase release. Lactate dehydrogenase releases after 72 hr, 32, 58, and 84% by 0.1, 0.5, and 2 mM paraquat, respectively, were well correlated with cell viability measured by cell adherence. In contrast, reductions of two tetrazolium compounds were depleted profoundly by 72 hr after exposure to 0.5 mM paraquat, suggesting depletion of intracellular reductive substances. Extracellular hydrogen peroxide began to significantly increase 56 hr or 32 hr after exposure to 0.5 mM or 1.5 mM paraquat, respectively, preceding the initial increase of lactate dehydrogenase release (64 hr by 0.5 mM or 48 hr by 1.5 mM). Lactate dehydrogenase release 72 hr after exposure to 0.5 mM paraquat was prevented strongly by catalase (1000 units/ml), but weakly by superoxide dismutase (1000 units/ml). These enzymes failed to restore the reduced acid phosphatase activity. Also, 0.1 mM desferal or α,α′‐dipyridyl protected lactate dehydrogenase release. Similarly, 1 mM thiourea or dimethylthiourea, and 0.5 mM α‐tocopherol or trolox, were effective, but diethylenetriaminepentaacetic acid (0.1 mM) and probucol (5 or 10 μM) were ineffective. Exposure of 0.5 or 1.5 mM paraquat suppressed levels of lipid peroxidation. These results indicate that membrane dysfunction by paraquat is ascribed to an iron‐catalyzed reaction of extracellularly increased hydrogen peroxide. A deleterious species for the membrane dysfunction is discussed.
The Preservatives Ethyl‐, Propyl‐ and Butylparaben are Oestrogenic in an in vivo Fish Assay
Authors: Pedersen Knud L. , Pedersen Søren N. , Christiansen Lisette B. , Korsgaard Bodil , Bjerregaard Poul
Published: August 2010

The widely used phenolic preservatives ethylparaben, propylparaben, butylparaben and their common metabolite p‐hydroxybenzoic acid were tested for their ability to evoke an oestrogenic response in vivo. Yolk protein induction in sexually immature rainbow trout was used as an oestrogen‐specific endpoint after repeated injections of the compounds. All tested parabens were oestrogenic in doses between 100 and 300 mg/kg, while the metabolite showed no activity. Ethylparaben was found to be approximately sixty times weaker than propyl‐ and butylparaben which had oestrogenic potencies comparable to those previously found for bisphenol A.
Minimal Toxicity to Myeloid Progenitor Cells of Weekly24‐Hr Infusion of High‐Dose 5‐Fluorouracil: Direct Evidence from Colony Forming Unit‐Granulocyte andMonocyte (CFU‐GM) Clonogenic Assay
Authors: Yeh Kun‐Huei , Yeh Shiou‐Hwei , Chang Yu‐Shiahn , Cheng Ann‐Lii
Published: August 2010

Although very high doses of 5‐fluorouracil was used in the weekly 24‐h infusion, high‐dose 5‐fluorouracil (2600 mg/m2/week) and leucovorin (500 mg/m2/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit‐granulocyte and monocyte clonogenic assay; and 2 representative modes of 5‐fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5‐fluorouracil in the bone marrow to be 200–400 μM and 1–2 μM for the 30 min. infusion (600–900 mg/m2) and the 24 hr‐infusion (1000–2000 mg/m2) regimens, respectively. The results of our colony‐forming unit‐granulocyte and monocyte clonogenic assay showed that 24‐hr exposure to 5‐fluorouracil (2 μM) and 30 min. exposure to 5‐fluorouracil (100 μM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.
Antioxidative and Prooxidative Action of Stilbene Derivatives
Authors: Miura Toshiaki , Muraoka Sanae , Ikeda Nahoko , Watanabe Miki , Fujimoto Yukio
Published: August 2010

The effects of stilbene derivatives, including resveratrol, diethylstilboestrol and stilbene, as antioxidants or prooxidants were examined. Resveratrol and diethylstilboestrol, but not stilbene, strongly inhibited NADPH‐ and adenosine 5′‐diphosphate (ADP)‐Fe3+‐dependent lipid peroxidation at the initial and propagation stages. In addition, phenolic stilbenes also inhibited ultraviolet light‐induced lipid peroxidation. Resveratrol and diethylstilboestrol efficiently scavenged 2,2′‐azobis‐(2‐amidinopropane)‐dihydrochloride peroxyl radicals. However, 2,2′‐diphenyl‐p‐picrylhydrazyl radicals were trapped only by resveratrol, but not by diethylstilboestrol. These results suggest that the inhibitory effect of phenolic stilbenes on lipid peroxidation was due to their scavenging ability of lipid peroxyl and/or carbon‐cantered radicals. Resveratrol efficiently reduced ADP‐Fe3+, but not EDTA‐Fe3+. Stilbenes and diethylstilboestrol did not reduce either ADP‐Fe3+ or EDTA‐Fe3+. The strand breaks of DNA were stimulated during the interaction of resveratrol with ADP‐Fe3+ in the presence of H2O2. These results suggest that phenolic stilbenes act as antioxidants of membrane lipids and that resveratrol has a prooxidative effect DNA damage during interaction with ADP‐Fe3+ in the presence of H2O2.
Selegiline Metabolism and Cytochrome P450 Enzymes:In vitro Study in Human Liver Microsomes*
Authors: Taavitsainen Päivi , Anttila Markku , Nyman Leena , Karnani Hari , Salonen Jarmo S. , Pelkonen Olavi
Published: August 2010

Although being a drug therapeutically used for a long time, the enzymatic metabolism of selegiline has not been adequately studied. In the current work we have studied the cytochrome P450 (CYP)‐catalyzed oxidative metabolism of selegiline to desmethylselegiline and l‐methamphetamine and the effects of selegiline, desmethylselegiline and l‐methamphetamine on hepatic CYP enzymes in human liver microsomes in vitro. The apparent Km values for desmethylselegiline and l‐methamphetamine formation were on an average 149 μM and 293 μM, and the apparent Vmax values, 243 pmol/min./mg and 1351 pmol/min./mg, respectively. Furafylline and ketoconazole, the known reference inhibitors for CYP1A2 and CYP3A4, respectively, inhibited the formation of desmethylselegiline with Ki value of 1.7 μM and 15 μM. Ketoconazole inhibited also the formation of l‐methamphetamine with Ki of 18 μM. Fluvoxamine, an inhibitor of CYP1A2, CYP2C19 and CYP3A4, inhibited the formation of desmethylselegiline and l‐methamphetamine with Ki values of 9 and 25 μM, respectively. On the basis of these results we suggest that CYP1A2 and CYP3A4 contribute to the formation of desmethylselegiline and that CYP3A4 participates in the formation of l‐methamphetamine. In studies with CYP‐specific model activities, both selegiline and desmethylselegiline inhibited the CYP2C19‐mediated S‐mephenytoin 4′‐hydroxylation with average IC50 values of 21 μM and 26 μM, respectively. The Ki for selegiline was determined to be around 7 μM. Selegiline inhibited CYP1A2‐mediated ethoxyresorufin O‐deethylation with a Ki value of 76 μM. Inhibitory potencies of selegiline, desmethylselegiline and l‐methamphetamine towards other CYP‐model activities were much lower. On this basis, selegiline and desmethylselegiline were shown to have a relatively high affinity for CYP2C19, but no evidence about selegiline metabolism by CYP2C19 was obtained.
Hydrolytic and Metabolic Characteristics of the Esters of1‐(3′‐Hydroxypropyl)‐2‐methyl‐3‐hydroxypyridin‐4‐one (CP41), Potentially Useful Iron Chelators
Authors: Liu Ding Y. , Liu Zu D. , Lu Shu L. , Hider Robert C.
Published: August 2010

1‐(3′‐Hydroxypropyl)‐2‐methyl‐3‐hydroxypyridin‐4‐one (CP41) has been extensively investigated as an orally effective iron chelator. In order to improve the pharmacokinetic and metabolic properties of CP41, eleven aromatic esters have been synthesised and tested as potential prodrugs. In the present study, the hydrolytic rates of these CP41 esters in phosphate buffer (pH2.0 and pH7.4), rat blood and rat liver homogenate have been determined and found to cover a wide range. Generally, they possessed relatively slow hydrolytic rates in phosphate buffer (0–50 nmol/ml/hr at pH 2.0 and 0–140 nmol/ml/hr at pH 7.4). The hydrolytic rates in rat blood fell in the range of 9–5766 nmol/ml blood/hr and in rat liver homogenate 1–800 μmol/g liver tissue/hr. All esters possess a higher lipophilicity than that of the parent compound CP41. Although no apparent relationship was observed between the lipophilicities and hydrolytic rates, the esters with relatively higher hydrolytic rates in liver homogenate tend to possess higher iron scavenging efficacies. Further investigation of the metabolism of selected CP41 esters indicates that metabolism is a key factor influencing the efficacy of CP41 esters, as some esters can be metabolically inactivated in the liver in preference to undergoing ester hydrolysis. Ester design, combined with a knowledge of the prodrug metabolism, is a useful strategy for the production of 3‐hydroxypyridin‐4‐ones with enhanced iron scavenging efficacy.
The Effect of Glutathione Modulation on the Concentration of Homocysteine in Plasma of Rats
Authors: Øvrebø Kjell K. , Svardal Asbjørn
Published: August 2010

Elevated plasma homocysteine concentration in humans is associated with increased risk of arteriosclerosis and ischaemic heart disease. We studied whether the plasma homocysteine concentration could be changed by administration of drugs that modulate the concentration of glutathione in both plasma and tissue. Male wistar rats received reduced glutathione (0.5 mmol/kg), N‐acetylcysteine (0.5 mmol/kg), L‐buthionine‐[S,R]‐sulfoximine (2 mmol/kg) or Ringer acetate intravenously. Twenty min. later an arterial blood sample was drawn for the measurement of homocysteine and other thiols in the plasma. The thiols were quantified by reversed‐phase ion‐pair liquid chromatography and fluorescence detection. The total homocysteine concentration in plasma of fasted rats was 6.1±0.5 μM. Intravenous administration of reduced glutathione or N‐acetylcysteine reduced the homocysteine concentration in plasma significantly by 51% to 3.0±0.3 μM and 63% to 2.2±0.2 μM, respectively (P<0.05). In contrast, L‐buthionine‐[S,R]‐sulfoximine increased the concentration of homocysteine by 41% to 8.6±0.6 μM (P<0.05). The glutathione concentration in plasma was 19.5±1.9 μM in controls and was unchanged by N‐acetylcysteine administration. Reduced glutathione increased plasma glutathione to 379.7±22.9 μM (P<0.05), whereas L‐buthionine‐[S R]‐sulfoximine lowered the plasma glutathione concentration to 5.3±0.4 μM. Homocysteine was negatively correlated to the glutathione (r=−0.399, P<0.01) and the cysteine (r=−0.52, P<0.01) concentrations in plasma. Our conclusion is that modulation of the glutathione levels influences the concentration of homocysteine in plasma of rats.
Progesterone and Testosterone Modulate the Convulsant Actions of Pentylenetetrazol and Strychnine in Mice
Authors: Pesce María Ester , Acevedo Ximena , Bustamante Diego , Miranda Hugo F. , Pinardi Gianni
Published: August 2010

The influence of progesterone and testosterone on the incidence of seizures after administration of intraperitoneal pentylenetetrazol and subcutaneous strychnine was evaluated in mice. Pentylenetetrazol and strychnine were administered in doses that induced seizures in 40–50% of control mice in dioestrus (48 and 0.9 mg/kg, respectively). The percentage of seizures induced by pentylenetetrazol and strychnine was significantly lower in female mice in prooestrus/oestrus, when progesterone levels are high, than in dioestrus, when progesterone levels are low. Pretreatment of pentylenetetrazol‐challenged mice with progesterone (250 μg/kg) increased the incidence of seizures in prooestrus/oestrus, without affecting seizures in dioestrus. The same pretreatment in strychnine‐challenged mice also increased the incidence of seizures in prooestrus‐dioestrus, but significantly reduced the incidence of seizures in dioestrus. In addition, progesterone pretreatment significantly increased the percentage of deaths induced by strychnine in prooestrus‐oestrus, reducing deaths in dioestrus. Orchidectomized male mice had a significantly higher incidence of seizures after administration of pentylenetetrazol and strychnine than control mice. Administration of 11 daily doses of 250 μg/kg of testosterone to castrated mice significantly reduced the incidence of seizures induced by pentylenetetrazol. These results confirm the modulatory influence of reproductive steroids on the excitability of the central nervous system and the possible clinical importance of progesterone and testosterone in the management of partial epilepsy.
Doses and Time‐Dependent Effects of 3′‐Azido‐3′‐deoxythymidine on T47D Human Breast Cancer Cells in vitro
Authors: Mediavilla María D. , Sánchez‐Barceló Emilio J.
Published: August 2010

The objective of the present work was to study the effects of 3′‐azido‐3′‐deoxythymidine (azidothymidine, Zidovudine®) on human breast cancer cells by using, as a model, the T47D cell line (typified as oestrogen‐dependent and p53‐mutated). Low azidothymidine doses (3.125 μM) increase the percentage of cells in S‐phase, with the effect reversing after 24 hr of incubation; as azidothymidine doses increase, the magnitude and duration of its effect increase proportionally, although, even with the highest concentrations (50–100 μM) the effects decline after 48 hr of incubation. If media (containing azidothymidine or vehicle) are daily renewed, the azidothymidine effects (accumulation of cells in S‐phase) are higher and decline later than when media and drug are not changed during the whole culture period, thereby suggesting that the reversion of azidothymidine effects could be related with a degradation of the drug or accumulation in media of substances which counteract its effects. Azidothymidine inhibits T47D cell proliferation at concentrations higher than 50 μM. The exposure to 50 or 100 μM azidothymidine induced cell apoptosis after 48 hr or more of incubation. We conclude that: a) azidothymidine, with appropriate doses and duration of treatment, synchronizes cells in S‐phase, inhibits proliferation, and induces apoptosis, b) the discontinuous application of the drug rather than continuous exposure to it increases its efficiency to synchronize the T47D cell cycle. This in vitro anti‐breast cancer activity suggests that a possible clinical usefulness of azidothymidine, either alone or associated with other drugs with cycle‐specific antitumoural activity circumscribed to the S‐phase of cell cycle, is worthy of investigation.
Increase in Blood Pressure with Enhanced Na+, K+‐ATPase Activity in Stroke‐Prone Spontaneously Hypertensive Rats after 4‐Weeks Intake of Rapeseed Oil as the Sole Dietary Fat
Authors: Naito Yukiko , Konishi Chika , Katsumura Hideo , Ohara Naoki
Published: August 2010

Twenty stroke‐prone spontaneously hypertensive rats were divided into 2 groups of 10 animals each, and fed a defatted diet and orally administered rapeseed (canola) oil or soybean oil at 10 (w/w)% of the consumed diet once a day for 4 weeks. At the 4th week of administration, the systolic blood pressure in the canola oil group was higher (235±2 mmHg, mean±S.E.M., N=10) than that in the soybean oil group (225±4 mmHg, N=10, P<0.05). In isolated, perfused mesenteric bed from these rats, the increase in perfusion pressure by norepinephrine, ATP, arachidonic acid, endothelin‐1, angiotensin II or serotonin showed no between‐group differences. There were also no between‐group differences in the production of thromboxane A2 and prostaglandin I2 in the outflow by arachidonic acid injection. On the other hand, in the isolated aortic ring from the canola oil group, developed tension in potassium‐free solution was enhanced with activation of Na+, K+‐ATPase. These results suggest that canola oil intake as the sole dietary fat increases systolic blood pressure of stroke‐prone spontaneously hypertensive rats. The changes in vascular responsiveness to vasoconstrictors and production of prostanoids are unlikely to have relevance to the elevation of blood pressure. However, altered Na+, K+‐ATPase activity may play a role in the promotion of blood pressure elevation.
Mobilisation of Cadmium by meso‐ and racemic‐2,3‐Dimercaptosuccinic Acid (DMSA) in Rats
Authors: Blanuša Maja , Kostial Krista , Restek‐Samaržija Nada , Piasek Martina , Jones Mark M. , Singh Pramod K.
Published: August 2010

A higher efficiency of cadmium binding with racemic than with meso‐2,3‐dimercaptosuccinic acid (rac‐DMSA; meso‐DMSA) was found in an in vitro speciation model by Fang et al. (1996). This finding has not yet been tested in vivo. This paper presents results on mobilisation of cadmium by meso‐ and rac‐DMSA in rats. Cadmium chloride was administered as the radioactive isotope 109Cd intraperitoneally to all animals. One group was an untreated control and two groups were treated with meso‐ and rac‐DMSA, respectively. Treatment with chelators was applied twice, immediately after 109Cd and 24 hr afterwards intraperitoneally at the dose of 1 mmol/kg, each. Six days later radioactivity was measured in the liver and kidneys. Whole‐body counting was carried out on days 1, 2, 3 and 6 of the experiment. At the end of the experiment, both treatments caused a decrease in 109Cd whole‐body retention with rac‐DMSA being more efficient (decrease from 83% in control to 74% and 64% in groups treated with meso‐ and rac‐DMSA, respectively). The same reduction of 109Cd was obtained by both chelators in the liver (from 57% to about 47%). In the kidney only rac‐DMSA produced significant reduction of 109Cd (from 5.3% to 3.5%). In conclusion, these results show modest reduction of cadmium in the body by two isoforms of DMSA with rac‐DMSA being slightly more efficient than meso‐DMSA.
Blood Concentration and Toxicity of the Antimetastasis Agent NAMI‐A Following Repeated Intravenous Treatment in Mice
Authors: Cocchietto Moreno , Sava Gianni
Published: August 2010

NAMI‐A is a new generation antitumour ruthenium‐based agent and characterised by strong efficacy against lung metastases of experimental solid tumours in mice. The effects of intravenous administration of 15, 35 and 50 mg/kg/day of NAMI‐A for 5 consecutive days on blood concentration and host toxicity were tested on Swiss CD1 male and female mice. The blood concentration of NAMI‐A, both after the first injection and at the end of the 5‐day treatment fell rapidly and 5 min. after the last injection it was always below 10% of the administered dose. Kinetic parameters, calculated at the end of the 5‐day treatment cycle according to a mono‐compartment model (fitting with R2=0.9), indicate a t1/2 of about 18 hr. Toxicity i) was observed only at the highest dose used (50 mg/kg/day), ii) was greater in females than in males, iii) in mice which survived treatment was completely reversed within 3‐weeks of the end of the treatment. Haematological examinations, clinical chemistry data and histopathologic studies were consistent in terms of the effect on host lymphoid tissues, consisting in spleen and lymph node depletion and in a general increase of circulating leukocytes. Data on ruthenium organ retention confirm lack of brain penetration and a relatively high lung concentration which might account for the remarkable effect on lung metastases.
Relaxant Effects of Hydrastis canadensis L. and its Major Alkaloids on Guinea Pig Isolated Trachea
Authors: Abdel‐Haq Hanin , Cometa Maria Francesca , Palmery Maura , Leone Maria Grazia , Silvestrini Bruno , Saso Luciano
Published: August 2010

Hydrastis or goldenseal, one of the most popular medicinal herbs in the U.S.A., is used in mild pathological conditions like cold and flu, based on the pharmacological properties of its active components, berberine (anticholinergic, antisecretory, and antimicrobial) and β‐hydrastine (astringent). We previously reported the relaxant effect of a total ethanolic extract of hydrastis on carbachol precontracted isolated guinea pig trachea, and with the present study, using the same experimental model, we aimed at evaluating the contribution of its major alkaloids, berberine, β‐hydrastine, canadine and canadaline to the total effect. Furthermore, using specific pharmacological tools, like timolol and xanthine amine congener, we attempted to elucidate its mechanism of action. The EC50 of berberine, β‐hydrastine, canadine and canadaline, were 34.2±0.6, 72.8±0.6, 11.9±1.2 and 2.4±0.8 μg/ml, respectively. Timolol effectively antagonized the effect of canadine (EC50=19.7±3.0 μg/ml) and canadaline (EC50=17.1±1.2 μg/ml) but not that of berberine and β‐hydrastine, while xanthine amine congener antagonized the effect of β‐hydrastine (EC50=149.9±35.3 μg/ml) and canadaline (EC50=26.1±3.0 μg/ml) but not that of berberine and canadine. Besides, the hydrastis extract, at concentrations between 0.01 and 0.1 μg/ml, potentiated the relaxant effect of isoprenaline on carbachol‐precontracted isolated guinea pig trachea. These data, which are insufficient to draw definite mechanistic conclusions, indicate that the aforementioned alkaloids may act by interacting with adrenergic and adenosinic receptors.
The Endothelin ETB Receptor Agonist [125I]BQ‐3020 Binds Predominantly to Nerves in the Bovine Retractor Penis Muscle and Penile Artery
Authors: Parkkisenniemi Ulla‐Mari , Palkama Arto , Virtanen Ismo , Klinge Erik
Published: August 2010

Preliminary pharmacological experiments have suggested that in the bovine retractor penis muscle there are relaxation‐mediating endothelin ETB receptors, at least part of which are located on the inhibitory nitrergic nerves. The present work was undertaken to test this hypothesis by means of receptor autoradiography and additional pharmacological experiments. In the retractor penis muscle and the penile artery, specific binding of the ETB receptor‐selective agonist [125I]BQ‐3020 took place predominantly to nerve trunks and minor nerve branches. The situation was the same in the dorsal metatarsal artery, that was included as a reference because of its different innervation. Throughout the nerves the silver grains were evenly distributed over the nuclei of Schwann cells and the spaces between them. In the retractor penis there was also a small amount of specific binding to smooth muscle. No specific endothelial binding was observed in any of the tissues examined. The pharmacological studies confirmed that the relaxation of the retractor penis muscle induced by the ETB receptor‐selective agonist, sarafotoxin S6c, is susceptible to tetrodotoxin as well as to inhibition of nitric oxide synthase. The relaxation was also characterized by inconsistency, weakness and tachyphylaxis. The electrical field stimulation‐induced submaximal relaxation of the retractor penis was unaffected by stimulation or blockade of ETB receptors. The autoradiography suggests that in all the three bovine tissues studied there are ETB receptors located on nerves independently of the type of efferent nerve. The pharmacological experiments do not support the concept that in the bovine retractor penis muscle neuronal ETB receptors exert important immediate effects on the functioning of the penile erection‐mediating nitrergic nerves.
Mitochondrial shape changes: orchestrating cell pathophysiology
Authors: Campello Silvia , Scorrano Luca
Published: August 2010

Mitochondria are highly dynamic organelles, the location, size and distribution of which are controlled by a family of proteins that modulate mitochondrial fusion and fission. Recent evidence indicates that mitochondrial morphology is crucial for cell physiology, as changes in mitochondrial shape have been linked to neurodegeneration, calcium signalling, lifespan and cell death. Because immune cells contain few mitochondria, these organelles have been considered to have only a marginal role in this physiological context—which is conversely well characterized from the point of view of signalling. Nevertheless, accumulating evidence shows that mitochondrial dynamics have an impact on the migration and activation of immune cells and on the innate immune response. Here, we discuss the roles of mitochondrial dynamics in cell pathophysiology and consider how studying dynamics in the context of the immune system could increase our knowledge about the role of dynamics in key signalling cascades.
Preventing Obesity during Infancy: A Pilot Study
Authors: Paul Ian M. , Savage Jennifer S. , Anzman Stephanie L. , Beiler Jessica S. , Marini Michele E. , Stokes Jennifer L. , Birch Leann L.
Published: August 2010

More than 20% of US children between ages 2 and 5 years are overweight suggesting efforts to prevent obesity must begin earlier. This study tested the independent and combined effects of two behavioral interventions delivered to parents, designed to promote healthy infant growth in the first year. Mother‐newborn dyads intending to breastfeed were recruited from a maternity ward. With a 2 × 2 design, 160 dyads were randomized into one of four treatment cells to receive both, one, or no interventions delivered at two nurse home visits. The first intervention (“Soothe/Sleep”) instructed parents on discriminating between hunger and other sources of infant distress. Soothing strategies were taught to minimize feeding for non‐hunger‐related fussiness and to prolong sleep duration, particularly at night. The second intervention (“Introduction of Solids”) taught parents about hunger and satiety cues, the timing for the introduction of solid foods, and how to overcome infants' initial rejection of healthy foods through repeated exposure. A total of 110 mother‐infant dyads completed the year‐long study. At 1 year, infants who received both interventions had lower weight‐for‐length percentiles (P = 0.009). Participants receiving both interventions had a mean weight‐for‐length in the 33rd percentile; in contrast, those in other study groups were higher first intervention only—50th percentile; second intervention only—56th percentile; control group—50th percentile).This suggests that multicomponent behavioral interventions may have potential for long‐term obesity prevention (ClinicalTrials.gov number, NCT00359242).