bluuebunny/crossref_metadata_2025 huggingface dataset:
German–English-speaking children's mixed NPs with ‘correct’ agreement
Authors: JORSCHICK LIANE , ENDESFELDER QUICK ANTJE , GLÄSSER DANA , LIEVEN ELENA , TOMASELLO MICHAEL
Published: August 2010

Previous research has reported that bilingual children sometimes produce mixed noun phrases with ‘correct’ gender agreement – as inder dog(derbeing a masculine determiner in German and the German word for “dog”,hund, being masculine as well). However, these could obviously be due to chance or to the indiscriminate use of a default determiner. In the current study, we established with high statistical reliability that each of three German–English bilingual children, of 2–4 years of age, produced such mixed NPs with ‘correct’ agreement at significantly greater than chance levels. Also noteworthy was the fact that all three children produced such NPs with German determiners and English nouns much more frequently than the reverse. These findings provide a solid statistical foundation for further studies into the phenomenon of mixed noun phrases with ‘correct’ gender agreement.
Determining habitability: which exoEarths should we search for life?
Authors: Horner J. , Jones B.W.
Published: August 2010

Within the next few years, the first Earth-mass planets will be discovered around other stars. Some of those worlds will certainly lie within the classical ‘habitable zone’ of their parent stars, and we will quickly move from knowing of no exoEarths to knowing many. For the first time, we will be in a position to carry out a detailed search for the first evidence of life beyond our Solar System. However, such observations will be hugely taxing and time consuming to perform, and it is almost certain that far more potentially habitable worlds will be known than it is possible to study. It is therefore important to catalogue and consider the various effects that make a promising planet more or less suitable for the development of life. In this work, we review the various planetary, dynamical and stellar influences that could influence the habitability of exoEarths. The various influences must be taken in concert when we attempt to decide where to focus our first detailed search for life. While there is no guarantee that any given planet will be inhabited, it is vitally important to ensure that we focus our time and effort on those planets most likely to yield a positive result.
Magnetic reconnection at the dayside magnetopause in global Lyon‐Fedder‐Mobarry simulations
Authors: Ouellette J. E. , Rogers B. N. , Wiltberger M. , Lyon J. G.
Published: August 2010

We present a survey of magnetic reconnection at the dayside magnetopause using the Lyon‐Fedder‐Mobarry global magnetospheric simulation code. We explore simulations of the magnetospheric response under solar wind conditions with interplanetary magnetic field (IMF) clock angles of 0, 45, 90, 135, and 180 degrees. Defining the dayside reconnection rate as the total amount of magnetic flux per unit time that changes magnetic topology, we find the reconnection rate increases linearly from 45 to 135 degrees with more modest increases from 0 to 45 degrees and 135 to 180 degrees. Similar results are obtained using two other related definitions of the reconnection rate. We show the increase in the reconnection rate with greater IMF clock angles follows a trend in the orientation of the separator line relative to the solar wind magnetic field, a quantity that scales approximately as sin(θIMF/2), as noted by Kan and Lee (1979). For northward IMF conditions, we apply a similar argument based on the width of weak ∣B∣ regions at the magnetopause. We find the simulations exhibit two qualitatively different reconnection processes. The first process we identify as three‐dimensional topology merging along a separator line, in which solar wind and dipolar field lines reconnect, creating field lines with one foot point on the Earth and the other in the solar wind. For IMF angles of 45 and 90 degrees this topology merging is a predominantly antiparallel reconnection process concentrated near nulls in the magnetic cusps, while for larger IMF clock angles of 135 or 180 degrees the reconnection extends across belt‐like regions spanning the subsolar point. For clock angles of 45 and 90 degrees we also identify a second type of reconnection process that is a three‐dimensional form of guide field reconnection and typically occurs in regions along the separator line closer to the subsolar point. This process can mediate the reconnection of solar wind field lines with each other or can couple to the topology merging, leading to a subset of field lines that exhibit reconnection in multiple locations at the same moment of time.
Modeling Earth deformation from monsoonal flooding in Bangladesh using hydrographic, GPS, and Gravity Recovery and Climate Experiment (GRACE) data
Authors: Steckler Michael S. , Nooner Scott L. , Akhter S. Humayun , Chowdhury Sazedul K. , Bettadpur Srinivas , Seeber Leonardo , Kogan Mikhail G.
Published: August 2010

The Ganges, Brahmaputra, and Meghna rivers converge in Bangladesh with an annual discharge second to the Amazon. Most of the flow occurs during the summer monsoon causing widespread flooding. The impounded water represents a large surface load whose effects can be observed in Gravity Recovery and Climate Experiment (GRACE) and GPS data. Bangladesh is at the center of the second largest seasonal anomaly in the GRACE gravity field, reflecting water storage in Southeast Asia. Eighteen continuous GPS stations in Bangladesh record seasonal vertical motions up to 6 cm that inversely correlate to river level. We use 304 river gages to compute water height surfaces with a digital elevation model to separate surface water from groundwater. Porosity of 20% was used to estimate groundwater mass and calculate the water load. Results show ∼100 GT of water are stored in Bangladesh (7.5% of annual discharge) but can reach 150 GT during extreme events. The calculated water mass agrees with monthly GRACE water mass equivalents from Bangladesh within statistical limits. We compute the deformation due to this water load on an elastic half‐space, and we vary Young's modulus to fit GPS data from our two most continuous records. The water loading can account for >50% of the variance in the GPS data. The best fitting Young's modulus is 117–124 GPa for DHAK and 133–135 GPa for SUST, although the upper bound is not well constrained. These estimates lie between sediment (30–75 GPa) and mantle (190 GPa) values, indicating that response to loading is sensitive to structure throughout the lithosphere and is not absorbed by the weak sediments.
Simultaneous observations of lower tropospheric continental aerosols with a ground‐based, an airborne, and the spaceborne CALIOP lidar system
Authors: Chazette P. , Raut J.‐C. , Dulac F. , Berthier S. , Kim S.‐W. , Royer P. , Sanak J. , Loaëc S. , Grigaut‐Desbrosses H.
Published: August 2010

We present an original experiment with multiple lidar systems operated simultaneously to study the capability of the Cloud‐Aerosol LIdar with Orthogonal Polarization (CALIOP), on board the Cloud‐Aerosol Lidar Pathfinder Satellite Observation (CALIPSO), to infer aerosol optical properties in the lower troposphere over a midlatitude continental site where the aerosol load is low to moderate. The experiment took place from 20 June to 10 July 2007 in southern France. The results are based on three case studies with measurements coincident to CALIOP observations: the first case study illustrates a large‐scale pollution event with an aerosol optical thickness at 532 nm (τa532) of ∼0.25, and the two other case studies are devoted to background conditions due to aerosol scavenging by storms with τa532 <0.1. Our experimental approach involved ground‐based and airborne lidar systems as well as Sun photometer measurements when the conditions of observation were favorable. Passive spaceborne instruments, namely the Spinning Enhanced Visible and Infrared Imager (SEVERI) and the Moderate‐resolution Imaging Spectroradiometer (MODIS), are used to characterize the large‐scale aerosol conditions. We show that complex topographical structures increase the complexity of the aerosol analysis in the planetary boundary layer by CALIOP when τa532 is lower than 0.1 because the number of available representative profiles is low to build a mean CALIOP profile with a good signal‐to‐noise ratio. In a comparison, the aerosol optical properties inferred from CALIOP and those deduced from the other active and passive remote sensing observations in the pollution plume are found to be in reasonable agreement. Level‐2 aerosol products of CALIOP are consistent with our retrievals.
Effect of local and regional sources on the isotopic composition of nitrous oxide in the tropical free troposphere and tropopause layer
Authors: Croteau Philip , Atlas Elliot L. , Schauffler Sue M. , Blake Donald R. , Diskin Glenn S. , Boering Kristie A.
Published: August 2010

Measurements and models of the spatiotemporal variability of surface N2O mixing ratios and isotopic compositions are increasingly used to constrain the global N2O budget. However, large variability observed on the small spatial scales of soil chambers and shipboard sampling, which appears to be very sensitive to local environmental conditions, has made extrapolation to the global scale difficult. In this study, we present measurements of the isotopic composition of N2O (δ15Nbulk, δ15Nα, δ15Nβ, and δ18O) from whole‐air samples collected at altitudes of 0.5 to 19km by the NASA DC‐8 and WB‐57 aircraft during the Costa Rica‐Aura Validation Experiment (CR‐AVE) and the Tropical Composition, Cloud and Climate Coupling Experiment (TC4) campaigns in January–February 2006 and July–August 2007, respectively. The vertical profiles of isotopic composition showed predictable, repeating patterns consistent with the influence of a surface source at lower altitudes and the influence of stratospheric photochemistry in the lower stratosphere. Their correlations with marine tracers at lower altitudes are consistent with a predominantly oceanic source, although a soil source cannot be ruled out. Measurements in a combustion plume revealed a strong depletion in 15N at the central nitrogen atom (i.e., low δ15Nα values), providing new information on N2O isotopic compositions from combustion. This new data set demonstrates that a coherent picture of the isotopic composition of tropospheric N2O is possible at currently attainable precisions and that its variations from 0.5 km to the lower stratosphere are a useful tool in investigating the sources and distributions of this important greenhouse gas.
Light absorbing material (soot) in rainwater and in aerosol particles in the Maldives
Authors: Granat L. , Engström J. E. , Praveen S. , Rodhe H.
Published: August 2010

Simultaneous measurements of soot (absorbing material at 528 nm) and inorganic ions in aerosol and precipitation at the Maldives Climate Observatory Hanimaadhoo during the period May 2005 to February 2007 have made it possible to calculate the washout ratio (WR) of these components as a measure of how efficiently they are scavenged by precipitation. On the basis of air trajectories the data have been separated into days with polluted air arriving from the Indian subcontinent in a northeasterly sector during winter and clean monsoon days with southerly flow from the Indian Ocean. The average soot concentration was a factor of 10 higher in the former situations. Despite considerable scatter for individual days, a systematic pattern emerged when the WR for the different components were compared with each other. During the monsoon season the WR for soot was similar to that of sulfate and other fine mode aerosol components, indicating that soot containing particles in these situations were efficient as cloud condensation nuclei. The origin of the light absorbing material during the monsoon season is unclear. During the polluted winter days, on the other hand, the WR for soot was three times smaller than that of sulfate. This indicates that, even after a travel time of several days, the soot containing particles from India have retained much of their hydrophobic property. The low WR and the infrequent rain during this season probably contribute to extending the atmospheric lifetime of soot well beyond several days. Surprisingly high concentrations of non‐sea‐salt calcium were measured during the monsoon season, substantially higher than during the winter season. The origin of these high values could be long‐range transport from the Australian or African continents. Another possibility might be exopolymer gels derived from the ocean surface microlayer.
Regional distribution of forest height and biomass from multisensor data fusion
Authors: Yu Yifan , Saatchi Sassan , Heath Linda S. , LaPoint Elizabeth , Myneni Ranga , Knyazikhin Yuri
Published: August 2010

Elevation data acquired from radar interferometry at C‐band from SRTM are used in data fusion techniques to estimate regional scale forest height and aboveground live biomass (AGLB) over the state of Maine. Two fusion techniques have been developed to perform post‐processing and parameter estimations from four data sets: 1 arc sec National Elevation Data (NED), SRTM derived elevation (30 m), Landsat Enhanced Thematic Mapper (ETM) bands (30 m), derived vegetation index (VI) and NLCD2001 land cover map. The first fusion algorithm corrects for missing or erroneous NED data using an iterative interpolation approach and produces distribution of scattering phase centers from SRTM‐NED in three dominant forest types of evergreen conifers, deciduous, and mixed stands. The second fusion technique integrates the USDA Forest Service, Forest Inventory and Analysis (FIA) ground‐based plot data to develop an algorithm to transform the scattering phase centers into mean forest height and aboveground biomass. Height estimates over evergreen (R2 = 0.86, P < 0.001; RMSE = 1.1 m) and mixed forests (R2 = 0.93, P < 0.001, RMSE = 0.8 m) produced the best results. Estimates over deciduous forests were less accurate because of the winter acquisition of SRTM data and loss of scattering phase center from tree‐surface interaction. We used two methods to estimate AGLB; algorithms based on direct estimation from the scattering phase center produced higher precision (R2 = 0.79, RMSE = 25 Mg/ha) than those estimated from forest height (R2 = 0.25, RMSE = 66 Mg/ha). We discuss sources of uncertainty and implications of the results in the context of mapping regional and continental scale forest biomass distribution.
Ranking climate models by performance using actual values and anomalies: Implications for climate change impact assessments
Authors: Macadam I. , Pitman A. J. , Whetton P. H. , Abramowitz G.
Published: August 2010

Reducing uncertainty in climate projections can involve giving less credence to Atmosphere‐Ocean General Circulation Models (AOGCMs) for which the simulated future climate is judged to be unreliable. Reliability is commonly assessed by comparing AOGCM output with observations. A desirable property of any AOGCM skill score is that resulting AOGCM‐performance rankings should show some consistency when derived using observations from different time periods. Notably, earlier work has demonstrated inconsistency between rankings obtained for 20‐year periods in the 20th century based on global and regional comparisons of simulated and observed near‐surface temperature anomalies. Here, we demonstrate that AOGCM‐performance rankings derived from actual temperatures, which incorporate AOGCM biases in climatological means, can be used to identify AOGCMs that perform consistently well or poorly across multiple 20‐year periods in the 20th century. This result supports the use of comparisons of simulated and observed actual values of climate variables when assessing the reliability of AOGCMs.
Non‐stormtime injection of energetic particles into the slot‐region between Earth's inner and outer electron radiation belts as observed by STSAT‐1 and NOAA‐POES
Authors: Park J. , Min K. W. , Summers D. , Hwang J. , Kim H. J. , Horne R. B. , Kirsch P. , Yumoto K. , Uozumi T. , Lühr H. , Green J.
Published: August 2010

The slot‐region between Earth's inner and outer electron radiation belts was observed on 24 February 2004 by the satellite STSAT‐1 to be populated by quasi‐trapped electrons of energy 100‐400 keV. This injection lasted for several hours and took place during a non‐stormtime substorm. This appears to be the first observation of a slot‐region electron injection that did not occur during a geomagnetic storm. We also report multi‐instrument observations of this event from NOAA‐POES and CPMN magnetic observatories, and we consider physical mechanisms that may account for the phenomenon.
Latitudinal dependence of Atlantic meridional overturning circulation (AMOC) variations
Authors: Zhang Rong
Published: August 2010

AMOC variations are often thought to propagate with the Kelvin wave speed, resulting in a short time lead between high and low latitudes AMOC variations. However as shown in this paper using a coupled climate model (GFDL CM2.1), with the existence of interior pathways of North Atlantic Deep Water (NADW) from Flemish Cap to Cape Hatteras as that observed recently, AMOC variations estimated in density space propagate with the advection speed in this region, resulting in a much longer time lead (several years) between subpolar and subtropical AMOC variations and providing a more useful predictability. The results suggest that AMOC variations have significant meridional coherence in density space, and monitoring AMOC variations in density space at higher latitudes might reveal a stronger signal with a several‐year time lead.
“Island surfing” mechanism of electron acceleration during magnetic reconnection
Authors: Oka M. , Fujimoto M. , Shinohara I. , Phan T. D.
Published: August 2010

One of the key unresolved problems in the study of space plasmas is to explain the production of energetic electrons as magnetic field lines “reconnect” and release energy in an explosive manner. Recent observations suggest possible roles played by small‐scale magnetic islands in the reconnection region, but their precise roles and the exact mechanism of electron energization have remained unclear. Here we show from two‐dimensional particle‐in‐cell simulations that secondary islands generated in the reconnection region indeed produce energetic electrons. We found that when electrons are trapped inside the islands, they are energized continuously by the reconnection electric field prevalent in the reconnection diffusion region. Applications to observations in the Earth's magnetotail are briefly discussed.
Effect of Nitric Oxide Synthase Inhibitors on Lipid Peroxide Formation in Liver Caused by Endotoxin Challenge
Authors: Sakaguchi Shuhei , Furusawa Shinobu , Yokota Katsushi , Sasaki Ken‐ichi , Takayanagi Motoaki , Takayanagi Yoshio
Published: August 2010

This study investigated the effect of nitric oxide on lipid peroxide formation during endotoxaemia. Nitric oxide synthase inhibitors NG‐monomethyl‐L‐arginine acetate (L‐NMMA, 20 mg/kg, intravenously), NG‐nitro‐L‐arginine‐methyl ester (L‐NAME, 10 mg/kg, intravenously), and NG‐nitro‐L‐arginine (L‐NA, 10 mg/kg, intravenously), and a relatively selective inducible nitric oxide synthase inhibitor aminoguanidine (10 mg/kg, intravenously), did not protect against endotoxin‐induced death of mice. Superoxide dismutase activity in liver 18 hr after administration of endotoxin (6 mg/kg, intraperitoneally) to L‐arginine analogues (L‐NMMA, L‐NAME, L‐NA)‐treated mice was lower than in mice treated with endotoxin alone, whereas the administration of L‐arginine analogues increased xanthine oxidase activity in the livers of endotoxin‐injected mice compared with mice treated with endotoxin alone. In mice treated with L‐arginine analogues and aminoguanidine, the levels of non‐protein sulfhydryl and lipid peroxide in liver 18 hr after endotoxin injection did not show significant differences from mice treated with endotoxin alone. L‐Arginine analogues and aminoguanidine had little effect on lipid peroxide formation in liver caused by endotoxin. Treatment with aminoguanidine (300 μM) significantly inhibited endotoxin‐induced intracellular peroxide in J774A.1 cells, however, aminoguanidine did not affect endotoxin‐induced cytotoxicity in J774A.1 cells. Our results clearly demonstrate that treatment with catalase (10 μg/ml), D‐mannitol (10 mM), or superoxide dismutase (100 U/ml), has little or no effect on nitric oxide production by endotoxin (1 μg/ml)‐activated J774A.1 cells. These findings suggest that nitric oxide is not crucial for lipid peroxide formation during endotoxaemia. Therefore, it is unlikely that nitric oxide plays a significant role in liver injury caused by free radical generation in endotoxaemia.
The Effect of Aminophylline on Right Heart Function in Young Pigs after Ligation of the Right Coronary Artery
Authors: Spalding Michael B. , Ala‐Kokko Tero I. , Kiviluoma Kai , Ruskoaho Heikki , Alahuhta Seppo
Published: August 2010

An experimental model of right heart failure was developed to determine the effects of fluid loading and aminophylline on right heart function. We hypothesised that aminophylline would specifically improve right heart function through a decrease in pulmonary vascular resistance and, possibly, an increase in cardiac contractility. Right heart infarct was induced in ten experimental pigs and seven control pigs by ligating branches of the right coronary artery. The effect of fluid loading with a colloid solution and subsequent bolus doses of aminophylline on haemodynamics was observed. Fluid loading improved haemodynamics as expected. Aminophylline transiently improved cardiac index and pulmonary vascular resistance, but simultaneously caused an increase in heart rate and a decrease in stroke volume. Although aminophylline may reduce right heart afterload, it did not improve overall cardiac function in this experimental model of right heart infarction.
Peptide Nucleic Acids: On the Road to New Gene Therapeutic Drugs
Authors: Nielsen Peter E.
Published: August 2010

Abstract: Peptide nucleic acid (PNA) is a DNA mimic based on a pseudopeptide (polyamide) backbone. PNA oligomers bind strongly and with high sequence specificity to complementary targets in RNA (or DNA), and they show very high biological stability. Furthermore, studies in cell free systems have demonstrated potent antisense (inhibition of translation) and antigene (inhibition of transcription) activity of PNA. Recently, several studies reporting methods for cellular delivery of PNA as well as antisense effects of PNA in cells ex vivo and in rats have appeared. The potential of developing PNA derived gene therapeutic drugs is discussed.
Modulation of Capsaicin‐Sensitive Nerve Activation by Low pH Solutions in Guinea‐Pig Lung
Authors: Auberson Serge , Lacroix Jean S. , Lundberg Jan M.
Published: August 2010

Abstract: We have studied the stimulation of airways sensory nerves by low pH solutions and concomitantly induced bronchoconstriction. The effect of low pH buffer and lactic acid solutions at the same pH (5 and 6) were compared and the influence of low pH on the capsaicin effect was recorded. We have used the isolated guinea‐pig perfused lung model taking the insufflation pressure as an indicator of bronchial smooth muscle tone while the calcitonin gene‐related peptide‐like immunoreactivity measured in the lung perfusate represented sensory nerves activation. Low pH buffer and lactic acid solution (3 and 4.1 mM) at the same pH of 5 and 6 induced pH‐dependent bronchoconstriction and peptides release which were completely abolished after systemic pretreatment with capsaicin. Both responses were significantly inhibited after Ca2+‐free infusion. Capsazepine (10−6 M), a selective capsaicin antagonist, significantly reduced the calcitonin gene‐related peptide‐like immunoreactivity overflow evoked by all the solutions studied. Diclofenac (10−5 M), a cyclooxygenase blocker, inhibited pH 5, pH 6 and lactic acid 3 mM (pH 6)‐evoked peptide release, but not lactic acid 4.1 mM (pH 5). The functional response was not significantly modified after diclofenac while only the lactic acid 3 mM response was significantly reduced by capsazepine. There was a synergistic interaction between capsaicin and low pH buffer on calcitonin gene‐related peptide‐like immunoreactivity release and an additive effect on bronchoconstriction. It is concluded that in the isolated perfused guinea‐pig lung, lactic acid and low pH buffer induced calcitonin gene‐related peptide‐like immunoreactivity release and bronchoconstriction by stimulation of capsaicin‐sensitive C fibres via a pathway partly dependent of extracellular Ca2+. The mechanism of calcitonin gene‐related peptide‐like immunoreactivity release seems to be the same at pH 6, while differences are evident at pH 5 between low pH buffer and lactic acid. Our results also suggest that proton activity could exert a modulatory role on the capsaicin‐sensitive sensory nerves by a mechanism which remains to be clarified.
Pharmacological Characterisation of the Enantiomers of BM‐5, a Muscarinic Partial Agonist with Opposed Enantioselectivity between Affinity and Efficacy*
Authors: Sundquist Staffan , Modiri Ali‐Reza , Nilsson Björn M. , Hacksell Uli , Gillberg Per‐Göran , Nilvebrant Lisbeth
Published: August 2010

Abstract: The interaction of (R) and (S) enantiomers of the chiral oxotremorine analogue BM‐5 with muscarinic acetylcholine receptors was studied in vitro using radioligand binding and isolated tissue preparations. The in vivo effects of (R)‐BM‐5 were also studied in anaesthetised cat. No receptor or tissue selectivity was found for either enantiomer in radioligand binding studies in cells expressing human muscarinic receptors (M1‐M5) or in guinea pig tissues. The affinity of (R)‐BM‐5 was about 40 times, or 15–60 times higher than that of (S)‐BM‐5 in recombinant cells or in guinea pig tissues, respectively. Both enantiomers induced contraction of the guinea pig isolated urinary bladder and ileum. (R)‐BM‐5 was more potent than (S)‐BM‐5 in bladder (EC50 590 and 3500 nM, respectively) and in ileum (EC50 39 and 2600 nM, respectively). The maximal agonist effect was lower for (R)‐BM‐5 than for (S)‐BM‐5 in bladder (2.7% and 6.6%, respectively) and in ileum (32% and 48%, respectively). Contractions were completely inhibited by atropine (1 μM). In vivo, (R)‐BM‐5 induced bladder contraction and salivation after intravenous administration in the anaesthetised cat (ED50 4.1 and 6.2 μg kg−1, respectively). In conclusion, (R)‐ and (S)‐BM‐5 act as partial muscarinic agonists in the isolated bladder and ileum. (R)‐BM‐5 was the more potent enantiomer but had a lower maximal agonist effect giving an opposed enantioselectivity for affinity and efficacy. (R)‐BM‐5 showed agonist activity in vivo, confirming in vitro findings. From affinity and efficacy data it can be concluded that the effects of racemic BM‐5 are mediated by the (R)‐enantiomer.
Effects of Anticonvulsants on Local Anaesthetic‐Induced Neurotoxicity in Rats
Authors: Sawaki Kohei , Ohno Katsumi , Miyamoto Kazuhiko , Hirai Shigenori , Yazaki Kinya , Kawaguchi Mitsuru
Published: August 2010

Abstract: The effects of various anticonvulsants on local anaesthetics procaine‐ and lidocaine‐induced convulsions were investigated in rats. Pretreatment with diazepam (2.5–5 mg/kg, intraperitoneally) and clonazepam (5–10 mg/kg, intraperitoneally) completely protected the rats against both local anaesthetic‐induced convulsions. Phenobarbital (12.5–50 mg/kg, subcutaneously) also significantly decreased the incidence of both convulsions and prolonged their latencies. Carbabazepine (10–40 mg/kg, intraperitoneally) did not completely repress both convulsions, but it prolonged their latencies. Phenytoin (5–20 mg/kg, intraperitoneally) and primidone (30–60 mg/kg, intraperitoneally) markedly enhanced both local anaesthetic‐induced convulsions, as shown by shortening of latency and increase in mortality. Valproate (100–200 mg/kg, intraperitoneally) produced a protective effect against procaine‐induced convulsions, while it strongly enhanced lidocaine‐induced convulsions. These results suggest that the benzodiazepines are effective drugs to prevent neurotoxicity induced by local anaesthetics, while phenytoin and primidone potentiate them.
Evaluation of Flutamide Genotoxicity in Rats and in Primary Human Hepatocytes
Authors: Martelli Antonietta , Brambilla Campart Giulia , Carrozzino Roberto , Ghia Marco , Mattioli Francesca , Mereto Eugenio , Orsi Patrizia , Porta Puglia Cristina
Published: August 2010

Flutamide, an effective competitive inhibitor of the androgen receptor used orally for palliative treatment of prostatic carcinoma and regulation of prostatic hyperplasia was evaluated for its genotoxic effects in the intact rat and in primary cultures of human hepatocytes. Negative responses were obtained in all the in vivo assays as well as in the in vitro assay. In rats given a single oral dose of 500 mg/kg flutamide, fragmentation and repair of liver DNA were absent, and no increase was observed in the frequency of micronucleated hepatocytes. In the liver of rats given flutamide as initiating agent at the dose of 500 mg/kg/week for 6 successive weeks, γ‐glutamyltraspeptidase‐positive foci were detected only in 3 of 10 rats. There was no evidence of a promoting effect on the development of aberrant crypt foci in rats given 100 mg/kg flutamide on alternate days for 8 successive weeks. In primary cultures of human hepatocytes from one male and one female donor DNA fragmentation as measured by the Comet assays, and DNA repair synthesis as revealed by quantitative autoradiography, were absent after a 20 hr exposure to flutamide concentrations ranging from 18 to 56 μM. Taken as a whole, our results seem to indicate that flutamide is a non‐genotoxic drug.
Nitric Oxide Protects Murine Embryonic Liver Cells (BNL CL.2) from Cytotoxicity Induced by Glucose Deprivation
Authors: Pae Hyun‐Ock , Kim Hong‐Gone , Paik Young‐Suk , Paik Sang‐Gi , Kim Young‐Myeong , Oh Gi‐Su , Chung Hun‐Taeg
Published: August 2010

We investigated the protective effects of nitric oxide on cell death of murine embryonic liver cells (BNL CL.2) after glucose deprivation. Endogenous nitric oxide production by BNL CL.2 cells was induced by 6 hr pretreatment with interferon‐gamma and lipopolysaccharide. We used sodium nitroprusside and S‐nitroso‐L‐glutathione as exogenous nitric oxide‐generating compounds. All agents were used at doses that did not show direct cytotoxicity as measured by crystal violet staining assay. In the BNL CL.2 cells, the viability dropped very steeply after 24 hr incubation with glucose‐free media. Endogenous nitric oxide produced by treatment of the cells with interferon‐gamma and lipopolysaccharide protected the cells from glucose deprivation‐induced cytotoxicity, but did not protect them in the presence of the nitric oxide synthesis inhibitor, NG‐monomethyl‐L‐arginine. Exogenous nitric oxide protected the cells from glucose deprivation‐induced cytotoxicity in a concentration‐dependent manner. Cytoprotection by nitric oxide donors was abolished by the use of nitric oxide scarvenger, 2‐phenyl‐4,4,5,5,‐tetramethylimidazole, but not by the soluble guanosine cyclase inhibitor, 1H‐[1,2,4]oxadiazole[4,3‐a]quinoxalin‐1‐one. In addition, cytoprotective effects comparable to endogenous or exogenous nitric oxide were not observed when the cells were incubated with dibutyl guanosine 3′,5′‐cyclic monophosphate. Based upon these results, we suggest that nitric oxide may enhance the cell survival of BNL CL.2 cells after glucose deprivation via a guanosine 3′,5′‐cyclic monophosphate‐independent pathway.
Ultrastructural Evidence of the Protective Effect of Na+/H+ Exchange Inhibition on the in vitro Damage Induced by Ischaemia Reperfusion in the Interventricular Septum of the Rabbit Heart
Authors: Salinas Pedro , Gil‐Loyzaga Pablo , Barrigon Santos
Published: August 2010

We investigated the effects of the Na+/H+ antiporter inhibitor, dimethylamiloride, on myocardial injury after 1 h global ischaemia and 30 min. reperfusion in the isolated arterially perfused interventricular septum of the rabbit heart. After ischaemia and reperfusion challenge, dimethylamiloride significantly increased the recovery of developed tension in a dose‐dependent manner, and significantly decreased the maximal increase in resting tension. Ultrastructural analysis of myocytes submitted to the experimental in vitro model supported functional maintenance of physiologically‐like conditions. Where myocardial portions were submitted to ischaemic conditions and reperfusion, myocyte cell damage reached usual characteristics of infarct‐like induced lesions. Intracellular oedema, severe disruption of myofibrils with loss of muscle striation and both swelling and fragmentation of mitochondria were the main characteristics observed. Dimethylamiloride treatment clearly modifies ultrastructural findings towards the normalization of cell shape and structure, only a slight‐middle intracellular oedema and contraction bands were found. On the basis of the present results, we suggest that the protective effects exhibited by dimethylamiloride on the ischaemic myocardium are compatible with its Na+/H+ antiporter inhibition properties, they diminish Na+ accumulation and then either Ca2+ overload or non‐exocytotic noradrenaline release during the ischaemia and reperfusion challenge.
Dose‐Dependent Protection by Lipoic Acid against Cisplatin‐Induced Nephrotoxicity in Rats: Antioxidant Defense System
Authors: Somani Satu M. , Husain Kazim , Whitworth Craig , Trammell Gary L. , Malafa Mokenge , Rybak Leonard P.
Published: August 2010

This study was designed to investigate the role of graded doses of lipoic acid pretreatment against cisplatin‐induced nephrotoxicity. Male Wistar rats were divided into six groups and treated as follows: 1) vehicle (saline) control; 2) cisplatin (16 mg/kg, intraperitoneally); 3) lipoic acid (100 mg/kg, intraperitoneally); 4) cisplatin plus lipoic acid (25 mg/kg); 5) cisplatin plus lipoic acid (50 mg/kg) and 6) cisplatin plus lipoic acid (100 mg/kg). Rats were sacrificed three days after treatment, and plasma as well as kidneys were isolated and analyzed. Plasma creatinine increased (677% of control) following cisplatin administration alone which was decreased by lipoic acid in a dose‐dependent manner. Cisplatin‐treated rats showed a depletion of renal glutathione (GSH), increased oxidized GSH and decreased GSH/GSH oxidized ratio (62%, 166% and 62% of control), respectively which were restored with lipoic acid pretreatment. Renal superoxide dismutase, catalase, glutathione peroxidase (GSH peroxidase) and glutathione reductase activities decreased (62%, 75%, 62% and 80% of control), respectively, and malondialdehyde content increased (204% of control) following cisplatin administration, which were restored with increasing doses of lipoic acid. The renal platinum concentration increased following cisplatin administration, which was possibly decreased by chelation with lipoic acid. The data suggest that the graded doses of lipoic acid effectively prevented a decrease in renal antioxidant defense system and prevented an increase in lipid peroxidation, platinum content and plasma creatinine concentrations in a dose‐dependent manner.
Age‐Dependent Induction of Aberrant Crypt Fociin Rat Colon by 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine and Azoxymethane
Authors: Paulsen Jan Erik , Fulland Randi Cathrine , Alexander Jan
Published: August 2010

Pups and adult rats received seven oral exposures (three time weekly) of the food mutagen PhIP (50 mg/kg), or two subcutaneous exposures (once weekly) of the experimental carcinogen azoxymethane (3.75 mg/kg). Aberrant crypt foci (ACF) were scored 8 weeks after the first exposure. In addition, lactating dams with suckling pups were orally exposed to 50 mg/kg of PhIP, three times weekly for three weeks. Direct PhIP exposure of pups induced 2.2 times more ACF than similar exposure of adult rats (2.0±0.0 versus 0.9±0.8, P<0.05). The growth of ACF, expressed as crypt multiplicity AC/ACF, was 3.5 times larger in neonatally exposed rats than in rats exposed in adulthood (8.0±7.3 versus 2.3±1.6, P<0.05). PhIP exposure via breast milk induced ACF in 3 of 25 animals. However, the difference versus controls, which had no ACF, did not reach statistical significance. Contrary to PhIP, azoxymethane induced more ACF in adult rats than in pups (2.8±1.9 versus 4.8±1.7, P<0.05). Similarly to PhIP however, azoxymethane induced 3.2 times larger ACF (AC/ACF) in pups than in adult rats (11.9±8.4 versus 3.7±1.9, P<0.001). Whereas no PhIP‐induced ACF (0/15) were observed in the lymphoid follicles, approximately 60% of the azoxymethane‐induced ACF (32/56) were located in these structures. This difference was statistically significant (P<0.001). The density of azoxymethane‐induced ACF was 80 times larger in the lymphoid follicles than in the surrounding mucosa (P<0.01). Based on the assumption that the formation of ACF with high multiplicity is predicative for the tumour development we conclude that neonatal rats are more susceptible to PhIP and azoxymethane than adult rats.
Is the 5‐HT2C Receptor a Therapeutic Target in Cerebral Ischaemia?
Authors: Torup Lars , Diemer Nils Henrik
Published: August 2010

This study examines the effect of a 5‐HT2C agonist (RO 60–0175, (s)‐2‐(chloro‐5‐fluoro‐indol‐1‐yl)‐1‐methylethylamine) and a 5‐HT2C antagonist (RO 43–0440, benzofuran‐2‐carboxamidine) for neuroprotective activity in a rat model of global cerebral ischaemia. A mini‐osmotic pump implanted subcutaneously delivered 0.25 mg/kg/hr. Seven days after ischaemia the rats were sacrificed and the damage in the CA1 pyramidal cell layer in hippocampus was estimated and the treated groups were compared with vehicle groups. Pretreatment with the 5‐HT2C agonist RO 60–0175 significantly increased the damage, whereas the 5‐HT2C antagonist RO 43–0440 had no effect on the cell damage. Measurement of the core temperature in a RO 60–0175‐treated group of rats revealed no effect compared to a vehicle‐treated group. Thus the aggravation of damage in the RO 60–0175‐treated group cannot be explained by temperature effect. Our data do not indicate the 5‐HT2C receptor as a therapeutic target in cerebral ischaemia.
Evidence for a Trigger Function of Valproic Acid in Xenobiotic‐Induced Hepatotoxicity
Authors: Klee Sabine , Johanssen Sandra , Ungemach Fritz Rupert
Published: August 2010

The influence of the antiepileptic drug, valproic acid (2‐n‐propylpentanoic acid), on the hepatocellular capacity, to cope with an extrinsic oxidative stress was investigated. Freshly isolated rat hepatocytes exposed to therapeutic concentrations of valproic acid (0.25–1.0 mmol/l) were less resistant than controls, as evidenced by a significant cytotoxic response after challenge of the cells with a non‐toxic dose of allyl alcohol (2‐propen‐1‐ol). Valproic acid alone was not toxic to hepatocytes even at ten times higher concentrations (10 mmol/l), suggesting that cell damage was not a mere additive effect. Incubation with valproic acid plus allyl alcohol induced an irreversible depletion of hepatocellular glutathione, in contrast to allyl alcohol alone which induced a transient loss. Hepatocytes treated with valproic acid plus allyl alcohol were protected by N‐acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatocellular defence mechanisms and suggest that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid in epileptic patients.
Comparison of in vitro and in vivo Developmental Toxicity and Pharmacokinetics of Phenytoin in the Rat
Authors: Beekhuijzen Manon E. W. , Verhoef Aart , Klaassen Rob , Rompelberg Cathy J. M. , Piersma Aldert H.
Published: August 2010

The rat whole embryo culture was compared to an in vivo experiment with regard to embryotoxicity as well as exposure characteristics, using phenytoin as a model compound. Intra‐embryonic concentrations and their embryotoxic effects were determined on gestation day 11 after in vitro administration of 50–150 μg/ml or in vivo gavage of 500–1500 mg/kg body‐weight on gestation day 10. In addition, exposure kinetics were studied in vivo after a single oral dose on gestation day 10, and developmental defects on gestation day 21 were scored. The embryotoxic effects observed on gestation day 11 were more pronounced after in vitro exposure in comparison to in vivo exposure at similar intra‐embryonic concentrations. Exposure of phenytoin on gestation day 10 in vitro via the culture medium resulted in general embryotoxicity on gestation day 11, whereas in vivo effects as determined on gestation day 11 were minimal. Plasma concentrations of phenytoin increased and plateaued around 35 μg/ml during the 48 hr monitoring period. Plasma concentration curves and pharmacokinetic parameters did not show remarkable differences between the dose groups, indicating that absorption is the limiting factor at the dose range used. Although the developmental effects were minimal as observed in vivo on gestation day 11, specific malformations (defects encompassing the urogenital, craniofacial and skeletal systems) were observed on gestation day 21. These findings show that with similar intra‐embryonic concentrations of phenytoin the embryotoxicity in rat whole embryo culture was not comparable with the in vivo embryotoxicity as determined on gestation day 11. This discrepancy may at least partly be explained by differences in exposure characteristics.
Involvement of Iron (Ferric) Reduction in the Iron Absorption Mechanism of a Trivalent Iron‐Protein Complex (Iron Protein Succinylate
Authors: Raja Kishor B. , Jafri Shanaz E. , Dickson Dominic , Acebròn Alvaro , Cremonesi Piero , Fossati Gianluca , Simpson Robert J.
Published: August 2010

Iron protein succinylate is a non‐toxic therapeutic iron compound. We set out to characterise the structure of this compound and investigate the importance of digestion and intestinal reduction in determining absorption of the compound. The structure of the compound was investigated by variable temperature Mössbauer spectroscopy, molecular size determinations and kinetics of iron release by chelators. Intestinal uptake was determined with radioactive compound force fed to mice. Reduction of the compound was determined by in vitro incubation with intestinal fragments. The compound was found to contain only ferric iron, present as small particles including sizes below 10 nm. The iron was released rapidly to chelators. Digestion with trypsin reduced the molecular size of the compound. Intestinal absorption of the compound was inhibited by a ferrous chelator (ferrozine), indicating that reduction to ferrous iron may be important for absorption. The native compound was a poor substrate for duodenal reduction activity, but digestion with pepsin, followed by pancreatin, released soluble iron complexes with an increased reduction rate. We conclude that iron protein succinylate is absorbed by a mechanism involving digestion to release soluble, available ferric species which may be reduced at the mucosal surface to provide ferrous iron for membrane transport into enterocytes.
Effects of Neonatal Ganglioside GM1 Administration on Memory in Adult and Old Rats
Authors: Silva Regina H. , Bergamo Marcelo , Frussa‐Filho Roberto
Published: August 2010

Numerous investigations have been reporting the involvement of GM1 ganglioside in central nervous system development and memory formation. The effects of neonatal treatment with GM1 ganglioside on the performance of adult rats in a plus‐maze discriminative avoidance task and old rats in a step‐down passive avoidance task were investigated. Rats were injected subcutaneously from day 3 to 15 after birth with 10 mg/kg GM1 or saline. GM1 treatment did not modify indicative landmarks of physical and motor development. Behavioural tasks were carried out when the animals were 4 (discriminative avoidance) or 24 (passive avoidance) months old. Discriminative avoidance conditioning was performed in a modified elevated plus‐maze. During the training session, the animals received aversive stimulation (light and hot air blow) in one of the enclosed arms. Tests were performed 7, 14 and 21 days after conditioning (tests 1, 2 and 3), in the absence of the aversive stimulation. In all tests, GM1‐treated animals spent less time in the aversive arm than in the non‐aversive enclosed arm. Control animals, however, spent a shorter time in the aversive arm only in tests 1 and 2. Passive avoidance conditioning was performed in an acrylic box with a grid floor, that was partially covered by an inclined platform. Animals were placed on the platform and received a 0,5 mA foot shock when stepped down. A test was performed 48 hr later. Latency to step down presented by GM1‐treated animals was significantly higher in the test session, whereas no significant increase in latency to step down was found for control animals. The results suggest a possible action of GM1 on the maturation of the central nervous system that persists during adulthood and ageing.
2‐Phenylmelatonin: A Partial Agonist at Enteric Melatonin Receptors
Authors: Santagostino‐Barbone Maria Grazia , Masoero Elisabetta , Spelta Valeria , Lucchelli Adele
Published: August 2010

The effect of the melatonin receptor ligand, 2‐phenylmelatonin, has been assessed in isolated strips of the guinea‐pig proximal colon. 2‐Phenylmelatonin (0.01 nM‐1 μM) caused a concentration‐dependent contractile response. The potency value (−log EC50) was 9.3±1.0. The maximum effect was 25±4% of that elicited by the maximally effective concentration (0.3 μM) of 5‐HT and 43±3% of that by the maximally effective concentration (10 μM) of melatonin. When used as an antagonist, 2‐phenylmelatonin (0.01 nM and 0.1 nM) concentration‐dependently inhibited melatonin‐induced contractions with depression of the maximum response by 25% and 54%, respectively. Higher (1 nM) 2‐phenylmelatonin concentrations failed to antagonize melatonin‐induced response. Prazosin (0.3 μM), a selective antagonist of melatonin MT3 sites, antagonized melatonin‐induced contractions to an extent similar to that induced by 0.01 nM 2‐phenylmelatonin (with 30% reduction of the maximum effect to melatonin). The combination of 0.3 μM prazosin and 0.01 nM 2‐phenylmelatonin caused antagonism similar in extent to that caused by each individual antagonist. 2‐Phenylmelatonin at subnanomolar concentrations behaves as an antagonist of melatonin‐induced contractile responses while at nanomolar/micromolar concentrations it behaves as a weak contractile agonist.
Antinociceptive Effect of Intracerebroventricular Administration of Cholecystokinin Receptor Agonist and Antagonist in Nerve‐Ligated Mice
Authors: Zarrindast Mohammad‐Reza , Samiee Farzaneh , Rezayat Mehdi
Published: August 2010

In the present study we investigated the effects of intracerebroventricular injection of caerulein, the cholecystokinin receptor agonist and proglumide, the receptor antagonist on morphine response in the sciatic nerve ligation in mice. Subcutaneous administration of morphine induced antinociception in the both intact and ligated mice, however, the response of the opioid was lower in the ligated mice as compared with the intact animals. Caerulein induced antinociception in the non‐ligated but not in the nerve‐ligated animals. Combination of caerulein with morphine elicited higher response in ligated animals, however, the response induced in ligated animals was much more prominent. Proglumide alone did not elicit any response in both animal groups. The antagonist decreased the response of caerulein in the non‐ligated mice. Low doses of proglumide in the combination with caerulein induced antinociception in the ligated mice. We conclude that cholecystokinin receptor mechanism(s) may alter morphine resistance induced by nerve ligation.