bluuebunny/crossref_metadata_2025 huggingface dataset:
Orographic precipitation and the relief of mountain ranges
Authors: Roe Gerard H. , Montgomery David R. , Hallet Bernard
Published: June 2003

The influence of climate on the relief of mountain ranges has long been supposed but has received little quantitative investigation. The simplified system of a longitudinal river profile in a bedrock channel coupled to a physically based model of orographic precipitation is used to explore how orographically influenced patterns of precipitation affect the relief of fluvially sculpted mountain ranges. It is shown that the impact on the orography depends on the nature of the precipitation regime. Significant changes in relief also occur for imposed temperature changes of realistic magnitude, although the ability of the relief to respond to any given change depends sensitively on its response time and the timescale of the forcing.
Effects of surface temperature contrast on land‐atmosphere exchange: A case study from Monsoon 90
Authors: Kustas William P. , Albertson John D.
Published: June 2003

Atmospheric boundary layer (ABL) simulations over remotely sensed boundary conditions using a large eddy simulation (LES) code are employed here to explore the dynamical coupling of heterogeneous land surfaces and the ABL. The LES was recently extended to incorporate remotely observed surface states, and the ability to account for the soil and vegetation (i.e., two sources) contributions to the mass and energy exchanges [Albertson et al., 2001]. In this effort we explore the impacts of changes in the magnitude of surface variability (i.e., spatial contrasts). We focus our simulations and analysis with rescaled surface temperature fields to explore a wider range of contrasts (i.e., spatial variance). We demonstrate that the increase in temperature contrast has negligible effect on regionally averaged fluxes. However, the strength of coupling (or feedback) between spatial fields of land surface and surface layer temperature (z ∼ 10 m) increases with increasing temperature contrast. This dampens increases in the spatial variance in the sensible heat flux relative to increases in the spatial variance in surface temperature, suggesting the feedbacks act to limit the spatial variability in the flux. We also use the LES to explore the errors induced in spatially distributed heat flux predictions from using spatially uniform atmospheric variables in a related two‐source energy‐balance radiometric surface temperature scheme. The use of spatially uniform atmospheric variables is commonly employed when computing surface fluxes from remotely sensed land surface data. This leads to significant differences in the spatial distribution of land surface fluxes when compared to LES derived fluxes. This was particularly evident in the overestimated Bowen ratio (β), primarily for locations with relatively low vegetation cover.
Evidence for chorus‐driven electron acceleration to relativistic energies from a survey of geomagnetically disturbed periods
Authors: Meredith Nigel P. , Cain Michelle , Horne Richard B. , Thorne Richard M. , Summers Danny , Anderson Roger R.
Published: June 2003

We perform a survey of the plasma wave and particle data from the CRRES satellite during 26 geomagnetically disturbed periods to investigate the viability of a local stochastic electron acceleration mechanism to relativistic energies driven by Doppler‐shifted cyclotron resonant interactions with whistler mode chorus. Relativistic electron flux enhancements associated with moderate or strong storms may be seen over the whole outer zone (3 < L < 7), typically peaking in the range 4 < L < 5, whereas those associated with weak storms and intervals of prolonged substorm activity lacking a magnetic storm signature (PSALMSS) are typically observed further out in the regions 4 < L < 7 and 4.5 < L < 7, respectively. The most significant relativistic electron flux enhancements are seen outside of the plasmapause and are associated with periods of prolonged substorm activity with AE greater than 100 nT for a total integrated time greater than 2 days or greater than 300 nT for a total integrated time greater than 0.7 days. These events are also associated with enhanced fluxes of seed electrons and enhanced lower‐band chorus wave power with integrated lower‐band chorus wave intensities of greater than 500 pT2 day. No significant flux enhancements are seen unless the level of substorm activity is sufficiently high. These results are consistent with a local, stochastic, chorus‐driven electron acceleration mechanism involving the energization of a seed population of electrons with energies of a few hundred keV to relativistic energies operating on a timescale of the order of days.
Heat flow, heat generation, and crustal temperatures in the northern Canadian Cordillera: Thermal control of tectonics
Authors: Lewis T. J. , Hyndman R. D. , Flück P.
Published: June 2003

The heat flow in the northern Canadian Cordillera between 59 and 64 N is very high, 105 ± 22 mW/m2. The average upper crust heat generation is 4.6 ± 2.4 microW/m3, giving a reduced deep heat flow of 59 mW/m2, similar to the southern Canadian Cordillera, 49–53 N. Estimated Moho temperatures of 800–1000°C and lithosphere only 50–60 km thick are substantiated by slow upper mantle seismic velocities and by high elevations associated with crust only 32–35 km thick. The new data support the conclusion that all of the North and South America Cordilleras are hot. The Paleoproterozoic Wopmay orogen to the east has a remarkably high heat flow of 90 ± 15 mW/m2 for such an old and stable region. However, basement samples indicate high heat generation and estimated deep temperatures are intermediate between the Cordillera and the Slave Craton further to the east. Heat flow from the Yellowknife area of the Slave Craton, 53 mW/m2, implies low lithosphere temperatures in agreement with kimberlite xenolith P‐T data. The high temperatures in the Cordillera result in a very thin and weak lithosphere and may allow a lower crust detachment. The north and central Cordillera have been inland of the coastal Queen Charlotte transform fault since subduction stopped in the Eocene. Thus some process has maintained high temperatures in the former back arc for more than 40 Ma.
Can we improve the representation of modeled ocean mixed layer by assimilating surface‐only satellite‐derived data? A case study for the tropical Pacific during the 1997–1998 El Niño
Authors: Durand Fabien , Gourdeau Lionel , Delcroix Thierry , Verron Jacques
Published: June 2003

In the tropical oceans the density mixed layer does influence the ocean‐atmosphere interactions, a feature that is fundamental to the development of energetic climatic events such as the El Niño‐Southern Oscillation (ENSO) phenomenon. The aim of this work is to take advantage of existing sea surface temperature (SST) and velocity together with future sea surface salinity (SSS) satellite‐derived data by assimilating these data in a primitive equation model in order to improve the modeled mixed layer. As satellite SSS data are not yet available, and to better analyze how assimilation works, we performed twin experiments in a context that renders assimilation conclusive with regard to real experiment. Two simulations using different forcing were used for the experiments. They have errors that are comparable to the ones between any simulation and real observations. The assimilation scheme is an adaptive version of the SEEK filter [Pham et al., 1998] readily usable for assimilating real data. An assimilation experiment was conducted covering the 1997–1998 ENSO event to analyze the main characteristics of the actual mixed layer. Looking in particular at the relevance of SSS, SST, mixed layer depth, and barrier layer thickness, satellite‐derived data prove to be useful to better simulate the oceanic mixed layer. Velocity data are specially needed to control the zonal equatorial current. Interestingly, assimilation of surface‐only data still worked well below the mixed layer, and some improvements were detectable in terms of barrier layer thickness, even though the limit of the assimilation scheme was reached.
Magnitude of isotope/temperature scaling for interpretation of central Antarctic ice cores
Authors: Jouzel J. , Vimeux F. , Caillon N. , Delaygue G. , Hoffmann G. , Masson‐Delmotte V. , Parrenin F.
Published: June 2003

The conventional interpretation of ice core deuterium and oxygen 18 isotope profiles based on the use of present‐day observations (spatial slope) underestimates glacial‐interglacial surface temperature changes in Central Greenland by up to a factor of two. This likely results from changes in the seasonality of the precipitation due to the particular location of the Greenland ice sheet next to the highly variable northern polar front. In this regard the situation is much simpler for central Antarctica and this should be reflected in the temperature interpretation of ice core isotopic records. With this in mind, we closely examine all relevant information, focusing on the East Antarctic Plateau where both model and empirical isotope‐temperature estimates are available. We point to the fact that correctly accounting for the influence of ocean isotopic change is important when interpreting deuterium profiles from ice cores in this region. The evidence presently available indicates that, unlike for Greenland, the present‐day spatial‐slope can probably be taken as a surrogate of the temporal slope to interpret glacial‐interglacial isotopic changes at sites such as Vostok and EPICA Dome C. Corresponding temperature changes are within −10% to +30% of those obtained from the conventional interpretation based on the use of the spatial slope.
Cloud model–based Bayesian technique for precipitation profile retrieval from the Tropical Rainfall Measuring Mission Microwave Imager
Authors: Tassa Alessandra , Di Michele Sabatino , Mugnai Alberto , Marzano Frank S. , Poiares Baptista José Pedro V.
Published: June 2003

A cloud model–based statistical retrieval technique for estimating surface precipitation and cloud profiles over ocean, called Bayesian Algorithm for Microwave Precipitation Retrieval (BAMPR), is described. The inversion scheme, based on the Bayesian estimation theory, is trained by a CRD obtained by inputting the numerical outputs of a mesoscale microphysical model into a three‐dimensional radiative transfer model. Since the performances of the retrieval are strictly dependent on the a priori information given by the CRD, the generation of the database itself, and the coupling between the forward and the inverse problem are carefully discussed. Particular emphasis is given to the database representativeness of the meteorological event under investigation and to the quantification of modeling errors. The retrieval uncertainties are provided with the estimates themselves by choosing the Minimum Mean Square technique as a Bayesian inversion method. As an example, the algorithm is applied to some case studies in the Tropics using the Tropical Rainfall Measuring Mission (TRMM) Microwave Imager data. The analysis is focused on the evaluation of the CRD performances with respect to the various events (i.e., a tropical cyclone, a tropical storm, a summer front, and some isolated convective cells in the Atolls region) and different CRDs (i.e., two hurricanes from the University of Wisconsin Nonhydrostatic Modeling System and a tropical squall line from the Goddard Cumulus Ensemble model). A detailed examination is carried out on the case of the hurricane Bonnie on 25 August 1998, which is discussed by using TRMM official products as a comparison.
Microwave remote sensing of soil moisture in southern Ontario: Aircraft and satellite measurements at 19 and 37 GHz
Authors: Morland June , Metcalfe John , Walker Anne
Published: June 2003

Aircraft microwave radiometer measurements at 19 and 37 GHz were made over a 40 km2 agricultural area in southern Ontario on 16 and 23 May 2001 when the average soil moisture in the area was 28 and 40%, respectively. SSM/I satellite data and ground‐based measurements of soil moisture were collected over the period 2 May to 25 July 2001. The emissivity of a water body (Lake Huron) calculated from the aircraft and satellite microwave radiometer measurements agreed with model calculations to within 0.02, except for the aircraft 37 GHz V channel. The 19 GHz emissivity measured by the SSM/I was higher than coincident aircraft measurements by 0.02 in moister soil conditions and 0.04 in drier conditions. Vegetation height increased from a maximum of 40 cm in hay fields in May to up to 200 cm in corn fields in July. There was a statistically significant relationship between soil moisture and 19 GHz H data for aircraft and SSM/I measurements in May. However, the standard error in the soil moisture estimate was 7%. Soil moisture seemed to have very little influence on 19 and 37 GHz emission during June and July. When the mean monthly emissivity for the May to July period was calculated from the SSM/I data, there was found to be no significant variation from month to month.
Frontal belt curvature and oblique ramp development at an obliquely collided irregular margin: Geometry and kinematics of the NW Taiwan fold‐thrust belt
Authors: Lacombe Olivier , Mouthereau Frédéric , Angelier Jacques , Chu Hao‐Tsu , Lee Jian‐Cheng
Published: June 2003

Combined structural and tectonic analyses demonstrate that the NW Foothills of the Taiwan collision belt constitute mainly an asymmetric “primary arc” type fold‐thrust belt. The arcuate belt developed as a basin‐controlled salient in the portion of the foreland basin that was initially thicker, due to the presence of a precollisional depocenter (the Taihsi basin). Additional but limited buttress effects at end points related to interaction with foreland basement highs (Kuanyin and Peikang highs) may have also slightly enhanced curvature. The complex structural pattern results from the interaction between low‐angle thrusting related to shallow decollement tectonics and oblique inversion of extensional structures of the margin on the southern edge of the Kuanyin basement high. The tectonic regimes and mechanisms revealed by the pattern of paleostress indicators such as striated outcrop‐scale faults are combined with the orientation and geometry of offshore and onshore regional faults in order to accurately define the Quaternary kinematics of the propagating units. The kinematics of this curved range is mainly controlled by distributed transpressional wrenching along the southern edge of the Kuanyin high, leading to the development of a regional‐scale oblique ramp, the Kuanyin transfer fault zone, which is conjugate of the NW trending Pakua transfer fault zone north of the Peikang basement high. The divergence between the N120° regional transport direction and the maximum compressive trend that evolved from N120° to N150° (and even to N–S) in the northern part of the arc effectively supports distributed wrench deformation along its northern limb during the Pleistocene. The geometry and kinematics of the western Taiwan Foothills therefore appear to be highly influenced by both the preorogenic structural pattern of the irregularly shaped Chinese passive margin and the obliquity of its Plio‐Quaternary collision with the Philippine Sea plate.
Factors affecting the performance of conventional seepage meters
Authors: Murdoch Lawrence C. , Kelly Susan E.
Published: June 2003

The simplicity of a pan‐and‐bag seepage meter makes it an attractive tool for a variety of hydrologic investigations, but the performance of this device is far from simple. Laboratory experiments show that the hydraulic head required to fill collection bags can range from 0.5 mm to several millimeters at flow rates typical of seepage meters, and this additional head will divert water away from the pan. A theoretical analysis gives a semianalytical expression for the flux captured by a seepage meter using a collection bag. The analysis shows that bag conductance, radius of the pan, and hydraulic conductivity of the stream bed can be combined to give a dimensionless term that characterizes seepage meter performance. Field experiments in a sandy streambed show that conventional seepage meters can resolve spatial differences in ground water flux but only when using a highly conductive collection system that is isolated from the current.
Surface energy fluxes over El Reno, Oklahoma, using high‐resolution remotely sensed data
Authors: French Andrew N. , Schmugge Thomas J. , Kustas William P. , Brubaker Kaye L. , Prueger John
Published: June 2003

Accurate estimation of spatial distributions of evapotranspiration (ET) is a goal sought by hydrologists, agronomists, and meteorologists but is difficult to achieve. The usual approaches to estimating ET employ remote sensing observations and a surface energy flux model. However, resolution of remote sensing data, needed to observe patterns of biophysical variables, is commonly too coarse (>1 km) to distinguish between land cover types that constrain ET. Accuracy of ET estimates can be improved by using higher‐resolution (<100 m) remote sensing data since they can distinguish clusters of vegetation from bare soil fields and water bodies. A demonstration of this potential is shown using aircraft‐based remote sensing observations over a study site at El Reno, Oklahoma. Five midday surveys, conducted from 29 June to 2 July 1997, as part of the Southern Great Plains 1997 Experiment (SGP97), collected 12 m resolution images in the visible, near infrared, and thermal infrared. Surface temperature and vegetation density maps, created from these surveys, were combined with surface micrometeorological observations and with a two source energy balance model. Results from El Reno show that flux estimates with respect to ground‐based eddy covariance observations can be accurate to within 40–80 W m−2. This means that the high spatial resolution observations can potentially produce ET estimates similar in quality to ground‐based point measurements. Additional work, needed to show how high‐resolution remote sensing estimates can be related to coarser resolution observations, is underway using the satellite sensors ASTER (15–90 m resolution) and MODIS (250 m to 1 km resolution).
Nitrate and colloid transport through coarse Hanford sediments under steady state, variably saturated flow
Authors: Cherrey Kelly D. , Flury Markus , Harsh James B.
Published: June 2003

At the U.S. Department of Energy's Hanford Reservation, colloid‐facilitated transport is a potential mechanism for accelerated movement of radionuclides like Cs‐137. Here we investigate the transport of colloids through Hanford sediments under steady state, unsaturated flow conditions. We isolated colloids from Hanford sediments by dispersion and sedimentation and determined colloid breakthrough curves in packed sediment columns. A column system was developed with which we could control volumetric water contents with accuracy better than 0.01 effective saturation and the water potentials to better than 0.06 cm‐H2O. Inflow and outflow boundary conditions had to be meticulously controlled to ensure uniformity of water contents and water potentials inside the column. Colloid breakthrough curves were determined under a series of water contents ranging from 0.2 to 1.0 effective saturation. Colloids were mobile under all water saturations, but the total amount of colloids transported decreased with decreasing water saturation. Colloid behavior was described with the mobile‐immobile model concept, including first‐order deposition from the mobile phase only.
Probability of regional climate change based on the Reliability Ensemble Averaging (REA) method
Authors: Giorgi F. , Mearns L. O.
Published: June 2003

We present an extension of the Reliability Ensemble Averaging, or REA, method [Giorgi and Mearns, 2002] to calculate the probability of regional climate change exceeding given thresholds based on ensembles of different model simulations. The method is applied to a recent set of transient experiments for the A2 and B2 IPCC emission scenarios with 9 different atmosphere‐ocean General Circulation Models (AOGCMs). Probabilities of surface air temperature and precipitation change are calculated for 10 regions of subcontinental scale spanning a range of latitudes and climatic settings. The results obtained from the REA method are compared with those obtained with a simpler but conceptually similar approach [Räisänen and Palmer, 2001]. It is shown that the REA method can provide a simple and flexible tool to estimate probabilities of regional climate change from ensembles of model simulations for use in risk and cost assessment studies.
SAGE III aerosol extinction measurements: Initial results
Authors: Thomason Larry W. , Taha Ghassan
Published: June 2003

Beginning in February 2002, the Stratospheric Aerosol and Gas Experiment III (SAGE III) has been producing aerosol extinction profiles in the upper troposphere and stratosphere at nine wavelengths between 384 and 1545 nm. An initial examination of the data quality has found that the data agree well with coincident measurements by SAGE II and the shape of the aerosol spectra suggests that the measurement ensemble is consistent across most wavelengths. A problem, probably associated with ozone cross sections, creates small bias at 755 nm and possibly 869 nm. The channel at 601 nm is noisy due to strong ozone absorption and is produced mostly as a tool for tracking ozone data quality.
A modified zonal index and its physical sense
Authors: Li Jianping , Wang Julian X. L.
Published: June 2003

A modified zonal index (ZI) for the Northern Hemisphere (NH) general circulation is defined as the normalized difference in zonal‐averaged sea level pressure anomalies between 35°N and 65°N. The ZI is a measure of hemispheric‐wide fluctuations in air mass between two annular belts of action (ABAs) over middle and high latitudes, centered near 35°N and 65°N, respectively. The spatial structure of the NH general circulation represented by the ZI is a zonally symmetric pattern, similar to the NH annular mode. Some physical features associated with the ZI are discussed and summarized as a concept model, and the analysis indicates that the Ferrel cell stands out as a dominant signal in the zonal‐mean circulation anomalies related to the ZI, implying a strong dynamical property of the general circulation in the mid‐high latitudes.
Testing the stochastic mechanism for low‐frequency variations in ENSO predictability
Authors: Zhang Li , Flügel Moritz , Chang Ping
Published: June 2003

The Hypothesis that low‐frequency variation of ENSO predictability may be caused by stochastic processes is tested using an Intermediate Coupled Model (ICM). Three “perfect model scenario” prediction experiments were carried out, each of which consists of large ensemble predictions. In the first case (reference case), the model is solely forced by stochastic forcing without any explicit decadal‐varying background. In the other two experiments, decadal‐varying backgrounds with different amplitudes were introduced into the ICM in addition to the stochastic forcing. By comparing the low‐frequency variations of ENSO predictability in these experiments, it is found that only when the amplitude of the decadal‐varying background is unrealistically strong, the effect of decadal‐varying background on ENSO predictability is comparable to or larger than the stochastically induced low‐frequency ENSO variation. Therefore, to the extent that the simple coupled system can represent reality, it seems that one can not simply reject the null hypothesis that the decadal variation of ENSO predictability may be stochastically induced.
Regulation of Rat Organic Anion Transporters in Bile Salt–Induced Cholestatic Hepatitis: Effect of Ursodeoxycholate
Authors: Rost Daniel , Herrmann Thomas , Sauer Peter , Schmidts Hans-Ludwig , Stieger Bruno , Meier Peter J. , Stremmel Wolfgang , Stiehl Adolf
Published: June 2003

Hepatic uptake of organic anions, including bile salts, is mediated by members of the organic anion–transporting polypeptide (Oatp) family. In rat liver, Oatp1 (Slc21a1), Oatp2 (Slc21a5), and Oatp4 (Slca10) are expressed at the basolateral membrane of hepatocytes and may be differentially regulated under pathophysiologic conditions such as cholestasis. The aim of this study was to determine the effects of cholic acid (CA) and ursodeoxycholic acid (UDCA) on the expression of Oatp4 compared with Ntcp, Oatp1, and Oatp2. Wistar rats were fed with CA (0.5%) or both CA (0.5%) and UDCA (0.25%) for 3 weeks. Oatp expression was studied by Northern and Western blot analysis as well as immunofluorescence analysis. Transport function was compared measuring biliary secretion of 14C–CA and 14C–taurocholic acid (TCA). In CA–fed animals, biliary secretion of 14C–CA and 14C–TCA was markedly delayed over 40 minutes compared with controls. Accordingly, Oatp4 protein was significantly down–regulated in CA–fed animals together with Oatp1 and Ntcp. Cofeeding of CA plus UDCA prevented the impairment of 14C–CA and 14C–TCA secretion and the down–regulation of Oatp4. Oatp4 messenger RNA (mRNA) levels did not differ significantly between bile salt–fed groups, suggesting a posttranscriptional effect of CA on Oatp4 expression. In contrast to Oatp1 and Oatp4, Oatp2 protein expression was increased by CA feeding, indicating a differential regulation of Oatp transporters. In conclusion, we show that CA feeding may cause cholestasis associated with a posttranscriptional down–regulation of Oatp4. UDCA may prevent impairment of hepatic function by restoring hepatic transporter expression.
Translational Regulation by P38 Mitogen–Activated Protein Kinase Signaling During Human Cholangiocarcinoma Growth
Authors: Yamagiwa Yoko , Marienfeld Carla , Tadlock Laura , Patel Tushar
Published: June 2003

The p38 mitogen–activated protein kinase (MAPK) signaling pathway is aberrantly expressed and maintains transformed cell growth in malignant human cholangiocytes. Because cell growth requires and is intimately related to protein synthesis, our aims were to assess the effect of p38 MAPK signaling on protein synthesis during growth of malignant human cholangiocytes. Inhibition of p38 MAPK activity during mitogenic stimulation decreased protein synthesis rates and tumor cell xenograft growth in nude mice. Altered protein synthesis resulted from decreased translational efficiency with impaired initiation of translation. Mitogenic stimulation resulted in phosphorylation of the eukaryotic initiation factor (eIF)–4E. Inhibition of p38 MAPK signaling or functional dysregulation of translation by small interfering double–stranded RNA (siRNA) to eIF–4E decreased anchorage–independent growth of malignant cholangiocytes. In conclusion, these studies identify a relationship between p38 MAPK activity and the regulation of protein synthesis during human cholangiocarcinoma growth. As protein synthesis is intimately linked to cell growth, dysregulation of translation initiation is a mechanism by which cellular p38 MAPK signaling participates in growth regulation of malignant cholangiocytes.
Maintenance Therapy With Ribavirin in Patients With Chronic Hepatitis C Who Fail to Respond to Combination Therapy With Interferon Alfa and Ribavirin
Authors: Hoofnagle Jay H. , Ghany Marc G. , Kleiner David E. , Doo Edward , Heller Theo , Promrat Kittichai , Ong Janus , Khokhar Farooq , Soza Alejandro , Herion David , Park Yoon , Everhart James E. , Liang Jake T.
Published: June 2003

To assess the efficacy and safety of maintenance therapy with ribavirin alone in chronic hepatitis C, 108 patients were treated with the combination of interferon alfa and ribavirin for 24 weeks; those who failed to have a virologic response were offered enrollment in a randomized, double–blind, controlled trial of ribavirin (1,000–1,200 mg daily) versus placebo for the subsequent 48 weeks. Patients were monitored at regular intervals with symptom questionnaires, serum aminotransferase levels, hepatitis C virus (HCV) RNA levels, and complete blood counts and underwent liver biopsy at the completion of therapy. Among 108 patients, 50 were still HCV RNA positive after 24 weeks of treatment, of whom 34 agreed to be randomized to continue either ribavirin monotherapy or placebo. Among 17 patients who received placebo, there was no overall improvement in symptoms, serum alanine aminotransferase (ALT) levels, HCV RNA levels, or hepatic histology. Among the 17 patients who received ribavirin, serum ALT levels and necroinflammatory features of liver histology were improved, whereas symptoms, HCV RNA levels, and hepatic fibrosis scores were not changed significantly from baseline. Responses to ribavirin seemed to be categorical, such that 8 patients (47%) had definite improvement in liver histology. Patients with improved histology had improvements in serum ALT levels both on combination therapy and after switching to ribavirin monotherapy. In conclusion, continuation of ribavirin monotherapy may maintain serum biochemical improvements that occur during interferon–ribavirin combination therapy in some patients and that these improvements are often associated with decreases in necroinflammatory changes in the liver. Whether these improvements will ultimately result in prevention of progression of hepatitis C requires further study.
Liver Transplantation With Hepatitis C Virus–Infected Graft: Interaction Between Donor and Recipient Viral Strains
Authors: Fan Xiaofeng , Lang Dorothy M. , Xu Yanjuan , Lyra Andre C. , Yusim Karina , Everhart James E. , Korber Bette T.M. , Perelson Alan S. , Di Bisceglie Adrian M.
Published: June 2003

Superinfection of different viral strains within a single host provides an opportunity for studying host–virus and virus–virus interactions, including viral interference and genetic recombination, which cannot be studied in infections with single viral strains. Hepatitis C virus (HCV) is a positive single–strand RNA virus that establishes persistent infection in as many as 85% of infected individuals. However, there are few reports regarding coinfection or superinfection of HCV. Because of the lack of tissue culture systems and small animal models supporting efficient HCV replication, we explored these issues in the setting of liver transplantation where both recipient and donor were infected with different HCV strains and therefore represent a distinct model for HCV superinfection. Serial serum samples collected at multiple time points were obtained from 6 HCV–positive liver donor/recipient pairs from the National Institute of Diabetes and Digestive and Kidney Diseases liver transplantation database. At each time point, HCV genotype was determined by both restriction fragment length polymorphism analysis and phylogenetic analysis. Furthermore, we selectively sequenced 3 full–length HCV isolates at the earliest time points after liver transplantation, including both 5′ and 3′ ends. Detailed genetic analyses showed that only one strain of HCV could be identified at each time point in all 6 cases. Recipient HCV strains took over in 3 cases, whereas donor HCV strains dominated after liver transplantation in the remaining 3 cases. In conclusion, in all 6 cases studied, there was no genetic recombination detected among HCV quasispecies or between donor and recipient HCV strains.
Pharmacokinetics and Pharmacodynamic Action of Budesonide in Early– and Late–Stage Primary Biliary Cirrhosis
Authors: Hempfling Wolfgang , Grunhage Frank , Dilger Karin , Reichel Christoph , Beuers Ulrich , Sauerbruch Tilman
Published: June 2003

Budesonide has been discussed as a potential treatment option in primary biliary cirrhosis (PBC). Therefore, we studied the pharmacokinetics and pharmacodynamics of budesonide in patients with PBC stage I/II and stage IV. Twelve patients with early PBC stage I/II and 7 patients with PBC stage IV under continuous treatment with ursodeoxycholic acid (UDCA) were enrolled in an exploratory trial. Each patient received oral budesonide for 3 weeks at weekly increasing dosages of 3 mg once to thrice per day. Budesonide and cortisol plasma levels, urinary cortisol excretion, serum liver tests, and immunoglobulins were determined on days 1, 7, and 21 of the study. Patients with PBC stage IV showed significantly higher peak plasma concentrations (4.9 ± 3.5 vs. 1.5 ± 0.4 ng/mL; P < .05) and areas under the plasma concentration–time curves (AUC) (23.2 ± 16.8 vs. 5.1 ± 1.4 hours · ng/mL, P < .01, total AUC extrapolated to infinity [AUC0–∞]) after a single dose of 3 mg budesonide when compared with patients with PBC stage I/II. Equally, AUC of budesonide were significantly increased under a multiple dose regimen on day 21 (14.0 ± 11.6 vs. 5.0 ± 1.9 hours · ng/mL, P < .01, AUC at steady state from dosing time to 8 hours [AUCss,0–8 h]). Higher levels of budesonide were related to a significant decrease in plasma cortisol and reduction of urinary cortisol excretion in patients with stage IV disease. Two patients with stage IV disease developed portal vein thrombosis (PVT). In conclusion, administration of budesonide leads to markedly elevated plasma levels in cirrhotic patients with PBC associated with serious adverse drug reactions. Thus, further evaluation of combined treatment with UDCA may be considered in early–stage PBC but not in cirrhotic patients with PBC.
Effect of Treatment With Peginterferon or Interferon Alfa–2B and Ribavirin on Steatosis in Patients Infected With Hepatitis C
Authors: Poynard Thierry , Ratziu Vlad , McHutchison John , Manns Michael , Goodman Zachary , Zeuzem Stefan , Younossi Zobair , Albrecht Janice
Published: June 2003

It has been suggested that hepatitis C virus (HCV) and especially genotype 3 is associated with steatosis. We assess the effect of treatment with peginterferon or interferon alfa–2b and ribavirin on steatosis. We analyzed 1,428 naïve patients included in a randomized trial. A single pathologist scored steatosis at baseline and 24 weeks after the treatment. At baseline, steatosis was present in 935 of 1,428 patients (65%), including 175 (83%) of 210 patients with genotype 3 versus 760 (62%) of 1,218 with other genotypes (P < .001). The variables associated with steatosis in logistic regression were genotype 3 (P < .001), triglycerides greater than 1.7 mmol/L (P < .001), body mass index greater than 27 (P < .04), age greater than 40 years (P < .001), and septal fibrosis (P = .007). In genotype 3–infected patients, steatosis was associated with high viral load and with lower serum cholesterol. Steatosis was associated with lower sustained response rate, even after taking into account other factors (P < .001). Among virologic responders, steatosis was much improved in genotype 3, improvement of at least 1 grade in 77%, and disappearance in 46% compared with other genotypes, 46% and 29%, respectively (P < .001 both comparisons). In genotype 3 responders, the baseline low serum cholesterol was corrected by treatment (P < .001). Steatosis was associated with HCV genotype 3, triglycerides, high body mass index, age, fibrosis stage, and lower virologic response to treatment. In conclusion, sustained disappearance of the virus is associated with reduction of steatosis in genotype 3 as well as a correction of baseline low serum cholesterol.
Expression of Wilms' Tumor Suppressor in the Liver With Cirrhosis: Relation to Hepatocyte Nuclear Factor 4 and Hepatocellular Function
Authors: Berasain Carmen , Herrero José-Ignacio , García-Trevijano Elena R. , Avila Matías A. , Esteban Juan Ignacio , Mato José M. , Prieto Jesús
Published: June 2003

The Wilms' tumor suppressor WT1 is a transcriptional regulator present in the fetal but not in the mature liver. Its expression and functional role in liver diseases remains unexplored. In this study, we analyzed WT1 expression by reverse–transcription polymerase chain reaction (RT–PCR) and by immunohistochemistry in normal and diseased livers. In addition, we performed in vitro studies in isolated rat hepatocytes to investigate WT1 regulation and function. We detected WT1 messenger RNA (mRNA) in 18% of normal livers, 17% of chronic hepatitis with minimal fibrosis, 49% of chronic hepatitis with bridging fibrosis, and 71% of cirrhotic livers. In cirrhosis, WT1 immunoreactivity was localized to the nucleus of hepatocytes. WT1 mRNA abundance correlated inversely with prothrombin time (P = .04) and directly with serum bilirubin (P = .002) and with the MELD score (P = .001) of disease severity. In rats, WT1 expression was present in fetal hepatocytes and in the cirrhotic liver but not in normal hepatic tissue. In vitro studies showed that isolated primary hepatocytes express WT1 when stimulated with transforming growth factor β (TGF–β) or when the cells undergo dedifferentiation in culture. Moreover, we found that WT1 down–regulates hepatocyte nuclear factor 4 (HNF–4), a factor that is essential to maintain liver function and metabolic regulation in the mature organ. Hepatic expression of HNF–4 was impaired in advanced human cirrhosis and negatively correlated with WT1 mRNA levels (P = .001). In conclusion, we show that WT1 is induced by TGF–β and down–regulates HNF–4 in liver cells. WT1 is reexpressed in the cirrhotic liver in relation to disease progression and may play a role in the development of hepatic insufficiency in cirrhosis.
Moderate Alcohol Consumption Increases Oxidative Stress in Patients With Chronic Hepatitis C
Authors: Rigamonti Cristina , Mottaran Elisa , Reale Emanuela , Rolla Roberta , Cipriani Valentina , Capelli Francesca , Boldorini Renzo , Vidali Matteo , Sartori Massimo , Albano Emanuele
Published: June 2003

The mechanisms by which alcohol consumption worsens the evolution of chronic hepatitis C (CHC) are poorly understood. We have investigated the possible interaction between hepatitis C virus (HCV) and ethanol in promoting oxidative stress. Circulating IgG against human serum albumin (HSA) adducted with malondialdehyde (MDA–HSA), 4–hydroxynonenal (HNE–HSA), or arachidonic acid hydroperoxide (AAHP–HSA) and against oxidized cardiolipin (Ox–CL) were evaluated as markers of oxidative stress in 145 CHC patients with different alcohol consumption, 20 HCV–free heavy drinkers (HD) without liver disease, and 50 healthy controls. Anti–MDA IgG was increased in CHC patients irrespective of alcohol intake as well as in the HD group. CHC patients with moderate alcohol intake (<50 g ethanol/d), but not HD, also had significantly higher values of anti–AAHP–HSA, anti–HNE–HSA, and anti–Ox–CL IgG (P < .05) than controls. A further elevation (P < .001) of these antibodies was evident in CHC patients with heavy alcohol intake (>50 g ethanol/d). Anti–AAHP and anti–Ox–CL IgG above the 95th percentile in the controls were observed in 24% to 26% of moderate and 58% to 63% of heavy drinkers but only in 6% to 9% of the abstainers. The risk of developing oxidative stress during CHC was increased 3–fold by moderate and 13– to 24–fold by heavy alcohol consumption. Heavy drinking CHC patients had significantly more piecemeal necrosis and fibrosis than abstainers. Diffuse piecemeal necrosis was 4–fold more frequent among alcohol–consuming patients with lipid peroxidation–related antibodies than among those without these antibodies. In conclusion, even moderate alcohol consumption promotes oxidative stress in CHC patients, suggesting a role for oxidative injury in the worsening of CHC evolution by alcohol.
Octreotide in Hepatorenal Syndrome: A Randomized, Double–Blind, Placebo–Controlled, Crossover Study
Authors: Pomier-Layrargues Gilles , Paquin Sarto C. , Hassoun Ziad , Lafortune Michel , Tran Albert
Published: June 2003

The hepatorenal syndrome (HRS) is related to vasoconstriction of the renal cortex induced by systemic hypovolemia that follows splanchnic vasodilatation as the primary event in the cascade of hemodynamic changes associated with portal hypertension. We evaluated the effects of octreotide, a splanchnic vasoconstrictor, on HRS in cirrhotic patients. We compared the effects of octreotide infusion (50 μg/h) to placebo using a randomized, double–blind, cross–over design over 2, 4–day periods. Nineteen patients were included, and 14 patients could complete the 2 phases of the study (group 1: placebo first; n = 8 and group 2: octreotide first; n = 6) The end point of the study was to evaluate improvement in renal function as defined by a 20% decrease in serum creatinine value after a 4–day treatment as compared with baseline. In all the patients, a normal central venous pressure was maintained by daily intravenous administration of 2 units of albumin. The 2 groups were similar with regard to demographic data and liver and kidney function parameters at baseline. Improvement in renal function was observed in 2 patients after the placebo and 1 patient after octreotide infusion in group 1 and in 2 patients after octreotide infusion and 1 patient after placebo in group 2 (P = not significant). In addition, treatment with octreotide infusion did not result in significant changes in creatinine clearance, daily urinary sodium, plasma renin activity, plasma aldosterone and glucagon levels, or renal and mesenteric artery resistance indices as measured by Doppler ultrasonography. In conclusion, the present study demonstrates that, under our experimental conditions, octreotide infusion combined with albumin is not effective for the treatment of HRS in cirrhotic patients.
A Model to Predict Severe Hcv–Related Disease Following Liver Transplantation
Authors: Berenguer Marina , Crippin Jeffrey , Gish Robert , Bass Nathan , Bostrom Alan , Netto George , Alonzo Judy , Garcia-Kennedy Richard , Rayón Jose-Miguel , Wright Teresa L.
Published: June 2003

Post–transplantation recurrence is increasing in patients with HCV. Early antiviral therapy may be of benefit in this setting. Thus, accurate and early prediction of progression may help select candidates for treatment. We developed a model based on pre– and/or early post–transplantation variables, which may predict progression to severe disease. Clinical and histologic outcomes were assessed in 554 liver recipients. A total of 1,353 biopsy specimens obtained after 1 year (median of 2 biopsies per patient; range, 1–8) were scored. Two outcome measures were used: cumulative probability of developing severe disease (fibrosis 3 and 4) within 5 years and actual progression to severe disease in 2 years. We used Cox proportional hazard survival analysis for the whole cohort. Predictors analyzed included HCV genotype and recipient, donor, and transplant–related variables. The cumulative risk of progressing to fibrosis 3 and 4 was significantly greater in patients transplanted recently (P < .001) and was present in all centers. Factors increasing this risk were genotype, induction with mycophenolate, donor age, short course of azathioprine, and prednisone (<12 months). To create a model of prediction, 285 patients with 2–year follow–up were used to create a logistic regression analysis. The estimated probability of being at high risk for severe disease was calculated from a formula that included donor age and recipient therapy as critical variables. In conclusion, we have developed a model that uses early post–transplantation variables to predict severe HCV recurrence. Accuracy of the model is not perfect (c–statistic 0.80), probably reflecting the complexity of HCV in the liver transplant setting.
Week 48 Resistance Surveillance in Two Phase 3 Clinical Studies of Adefovir Dipivoxil for Chronic Hepatitis B
Authors: Westland Christopher E. , Yang Huiling , Delaney William E. , Gibbs Craig S. , Miller Michael D. , Wulfsohn Michael , Fry John , Brosgart Carol L. , Xiong Shelly
Published: June 2003

Seven hundred nucleoside treatment–naive patients were enrolled in two phase 3 trials of adefovir dipivoxil (ADV) for the treatment of chronic hepatitis B. To monitor for the emergence of potential adefovir resistance mutations over the first 48 weeks, all intent–to–treat patients (467 ADV–treated and 228 placebo patients) were included in a prospectively defined, treatment–blinded, virology substudy. The study protocol mandated genotypic analysis for all patients with detectable hepatitis B virus (HBV) DNA by Roche Amplicor polymerase chain reaction (PCR) at baseline and week 48, and in vitro phenotypic analyses for patients with conserved site substitutions in HBV polymerase or 1.0 log10 or greater increase in HBV DNA from nadir. Paired sequences of the entire HBV reverse transcriptase were obtained for 271 ADV–treated and 227 placebo patients by using a sequencing method that detects down to 30% of minor species present within mixtures. Four substitutions (rtS119A, rtH133L, rtV214A, and rtH234Q) developed once each at conserved sites in HBV polymerase in 4 ADV–treated patients. Seven conserved site substitutions developed in 6 placebo patients. HBV mutants encoding the 4 substitutions that emerged in ADV–treated patients remained fully susceptible to adefovir in vitro. Furthermore, these 4 ADV–treated patients had HBV–DNA reductions of 3.3 to 5.9 log10 copies/mL by week 48 with no rebound. All other substitutions occurred at very low frequencies (<1.6%) at polymorphic sites and were not associated with HBV–DNA increases in patients or adefovir resistance in vitro. In conclusion, no adefovir resistance mutations were identified in a large group of chronic hepatitis B patients treated with ADV for 48 weeks.
Hepatic Gene Expression in Histologically Progressive Nonalcoholic Steatohepatitis
Authors: Sreekumar Raghavakaimal , Rosado Barbara , Rasmussen Deborah , Charlton Michael
Published: June 2003

Although the molecular basis for the pathophysiology of nonalcoholic steatohepatitis (NASH) is poorly understood, insulin resistance and mitochondrial dysfunction are physiologic hallmarks of this condition. We sought evidence of a transcriptional or pretranscriptional basis for insulin resistance and mitochondrial dysfunction through measurement of hepatic gene expression (messenger RNA [mRNA]) using high–density synthetic oligonucleotide microarray analysis (Hu6800 GeneChip, Affymetrix, CA). Global hepatic gene expression was determined in snap–frozen liver biopsy specimens from 4 groups: (1) patients with cirrhotic–stage NASH (n = 6), (2) patients with cirrhosis caused by hepatitis C virus (HCV) (n = 6), (3) patients with cirrhosis secondary to primary biliary cirrhosis (PBC) (n = 6), and (4) healthy controls (n = 6). Genes were considered to be expressed differentially in NASH only if there was a greater than 2–fold difference in abundance of mRNA when compared with each of the control groups. Sixteen genes were uniquely differentially expressed (4 overexpressed and 12 underexpressed) in patients with cirrhotic–stage NASH. Genes that were significantly underexpressed included genes important for maintaining mitochondrial function (copper/zinc superoxide dismutase, aldehyde oxidase, and catalase). Glucose 6–phospatase, alcohol dehydrogenase, elongation factor–TU, methylglutaryl coenzyme A (CoA), acyl CoA synthetase, oxoacyl CoA thiolase, and ubiquitin also were underexpressed in NASH. Genes that were overexpressed in NASH included complement component C3 and hepatocyte–derived fibrinogen–related protein, potentially contributing to impaired insulin sensitivity. In conclusion, these studies provide evidence for a transcriptional or pretranscriptional basis for impaired mitochondrial function (attenuated capacity for the dismutation of reactive oxygen species) and diminished insulin sensitivity (increased acute phase reactants) in patients with histologically progressive NASH. Further studies are required to determine the mechanism and the physiologic significance of these findings.