bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissimilarity in the evolution of solar EUV and solar radio emission (2800 MHz) during 1999–2002
Authors: Kane R. P.
Published: December 2003

For solar UV and EUV the F10 (2800 MHZ solar radio emission), Lyman alpha, and Mg II are used as proxies. During 1999–2002, many solar indices showed two maxima, one near July 2000 and another near January 2002. For F10 and Lyman alpha, the second maximum was higher than the first maximum by ∼10%, but for Rz, the second maximum was lower than the first maximum by ∼4%. The observed EUV (26–34 nm from SEM‐SOHO) had the second maximum higher than the first maximum, but only by ∼3.5%. The model values given in SOLAR2000 [Tobiska et al., 2000] show patterns of 26–34 nm qualitatively similar to F10, with second maximum larger than the first maximum, but the magnitude is much larger, ∼20%. Thus there is a discrepancy of ∼15% between observed EUV and SOLAR2000 model EUV during 2001–2002. The model values are overestimates and do not seem to have taken into account the observed EUV values.
Comparison of the He+ layer observed over Arecibo during solar maximum and solar minimum with CTIP model results
Authors: Wilford C. R. , Moffett R. J. , Rees J. M. , Bailey G. J. , Gonzalez S. A.
Published: December 2003

Light ion concentration observations from the Arecibo incoherent scatter radar have shown regions of He+ layering in the topside ionosphere in the postmidnight hours. The He+ layering phenomenon has been observed during both solar maximum and solar minimum conditions. During solar maximum the layer is well defined, giving maximum relative abundances of over 50%. The observational results also show regions of He+ dominance in the topside ionosphere during solar maximum in the height range 750–1200 km. During solar minimum the magnitude of the layer is less, giving a maximum relative abundance of only ∼20%; however, the layer is still a well‐defined feature. The coupled thermosphere‐ionosphere‐plasmasphere (CTIP) model is shown to model accurately the He+ layer and the regions of He+ dominance, provided that the modeled temperature profiles are normalized to the observed values. This study serves to further highlight the importance of helium ions in the topside ionosphere, particularly during solar maximum nighttime conditions.
Role of unstable sporadic‐E layers in the generation of midlatitude spread F
Authors: Haldoupis Christos , Kelley Michael C. , Hussey Glenn C. , Shalimov Sergei
Published: December 2003

There is growing experimental evidence to suggest that mesoscale spread F is linked to the occurrence of midlatitude coherent backscatter from patchy sporadic‐E layers, which are unstable to the gradient‐drift and Farley‐Buneman plasma instabilities. To validate this suggestion, we have compared E‐region backscatter and spread‐F ionosonde recordings from about 100 days of joint operation during summer and found a one‐to‐one relation in the occurrence of both phenomena. Also, midlatitude backscatter studies over the last few years have shown the existence of enhanced electric fields inside patchy sporadic E. These are believed to be polarization fields set up locally by neutral winds that transport the plasma patches horizontally, and by the relatively large Hall‐to‐Pedersen conductivity ratios at E‐region altitudes. Moreover, midlatitude echoes were found to be associated with mostly westward drifting sporadic‐E patches with typical scale lengths from 10 to more than 100 km and perturbed eastward electric fields from a few to maybe more than 10 to 15 mV/m. We propose that the enhanced polarization fields set up inside unstable sporadic‐E patches can easily map up the magnetic field lines to the F region and thus contribute to the formation of midlatitude spread F. This new mechanism for spread‐F generation is basically an image process that can account for key observational properties of the phenomenon. These include the rapid plasma upwelling and the abrupt changes in height (uplifts) of the F layer, as well as the scale sizes involved and morphological characteristics.
Sudden commencements related plasma waves observed by the Akebono satellite in the polar region and inside the plasmasphere region
Authors: Shinbori A. , Ono T. , Iizima M. , Kumamoto A. , Oya H.
Published: December 2003

Plasma wave phenomena associated with sudden commencements (SC) are analyzed using the database of the Akebono satellite observations that have been carried out for more than 13 years since March 1989. All the 719 data sets simultaneously observed in the periods of SC events show that plasma waves are enhanced with one‐to‐one correspondence to SCs in entire regions of the polar cap, auroral zone, and plasmasphere within a response time of ±90 s. In the middle latitude and equatorial regions of the plasmasphere, intensification and frequency shift of electromagnetic whistler mode, LHR waves, and ion cyclotron harmonic waves are found. The electric field variations in this region also show clear response to the onset of SCs with the amplitude of 0.2–30 mV/m. The variations are observed in the nightside as well as dayside sectors, and no clear dependence of magnetic latitude, local time, and L shell is found. On the other hand, electrostatic whistler mode waves and electromagnetic ion cyclotron waves which show broadband spectra are generated in the high‐latitude region. Spectra of low‐energy particles observed simultaneously with the enhancement of these plasma waves show that electron fluxes are enhanced in all of pitch angle bins of the low‐energy particle detector onboard the Akebono satellite. Near the cusp region, the ion fluxes are more enhanced in the upward direction than in the downward direction along the magnetic field lines. In about half of the cases of the high‐latitude events, sudden appearance and intensification of AKR are also found after the onsets of SC. The delay time between the onsets of SC and AKR enhancement shows several minutes with the average time of 5.7 min. Time differences between the onsets of SC measured at Kakioka Magnetic Observatory and plasma wave enhancements observed by the Akebono satellite show positive correlation with possible delay time according to the propagation route of SC disturbances. Propagation character of SC disturbances shows two group signatures: one group takes a route which crosses the geomagnetic equator region with an average speed of 389.5 km/s. The speed is almost consistent with plasmaspheric fast‐mode MHD wave velocity. The other group takes a route which starts from the dayside cusp region. In the second case, the SC disturbances propagate through the polar ionosphere region from the dayside to the nightside sectors with an average speed of 47 km/s in the XGSM coordinate corresponding to the ionospheric fast‐mode MHD wave velocity.
Steady reconnection during intervals of northward IMF: Implications for magnetosheath properties
Authors: Petrinec S. M. , Trattner K. J. , Fuselier S. A.
Published: December 2003

This study examines the location of the reconnection site on the magnetopause for conditions of northward interplanetary magnetic field (IMF) and its implications for properties of the magnetosheath. Ion distribution functions from the Toroidal Imaging Mass Angle Spectrometer (TIMAS) instrument on board the Polar spacecraft during passes through the dayside cusp region when the IMF was steady and northward are used. Cutoff velocities are determined from these distributions and the distance from the Polar spacecraft to the site of reconnection is estimated. A magnetospheric magnetic field model is used to map these determined distances to a location on the magnetopause where reconnection is believed to have occurred. Nearly all of these reconnection sites lie in places where the magnetosheath flow is estimated to be super‐Alfvénic (using hydrodynamic theory and an analytic magnetosheath magnetic field model). However, there exist strict constraints on the speed of the ambient magnetosheath flow at the reconnection site, in order for this particular type of particle distribution to have been observed by TIMAS. Different physical models are discussed, including the possibility of nonstationary reconnection sites and the existence of a plasma depletion layer which significantly increases the magnetosheath Alfvén speed close to the magnetopause. From the observations and mapped reconnection locations, we estimate statistically how much the average ion density must decrease (and the magnetic field must increase) in the plasma depletion layer to be consistent with the cusp region observations. The resulting range of values is consistent with the theoretical estimates of Zwan and Wolf [1976] (k ≥ 2).
On the global distribution of neutral gases in Titan's upper atmosphere and its effect on the thermal structure
Authors: Müller‐Wodarg I. C. F. , Yelle R. V. , Mendillo M. J. , Aylward A. D.
Published: December 2003

Using a time‐dependent general circulation model of Titan's thermosphere, we calculate the global distribution of neutral gases by winds and diffusion. Our calculations suggest that solar driven dynamics effectively redistribute constituents, causing considerable diurnal and seasonal changes in gas abundances. Subsidence causes an accumulation of lighter gases on the nightside, with nighttime CH4 mole fractions at equinox near 1400 km reaching up to 50%. The reverse happens on the dayside, where lighter gases are depleted, giving minimum CH4 mole fractions near 1400 km of around 12%. The vertical transport time scales are around 5–10% of a Titan day, so these extrema in gas abundances are shifted with respect to local noon and midnight by up to 4 hours Local Solar Time (LST). The strong horizontal variations in gas abundances, combined with the local time shifts of their extrema, have an important impact on the thermal structure and lead to a shift of the nighttime minimum from local midnight towards early morning hours (0330 LST). This coupling between gas distribution and thermal structure on the nightside occurs via dynamical processes, primarily through changes in adiabatic heating. The redistribution of gases effectively controls, through changes in mean molecular weight, the pressure gradients, which in turn control the horizontal and vertical winds, and thereby adiabatic heating and cooling. On the dayside, changes in solar EUV absorption due to the redistributed gases occur but are comparatively small. Although it is possible with our calculations to identify important processes, Voyager and ground based observations of Titan are currently not sufficient to constrain the dynamics of Titan's upper atmosphere, but comparisons with forthcoming Cassini observations are highly anticipated.
Modified two‐stream instability in the foot of high Mach number quasi‐perpendicular shocks
Authors: Matsukiyo Shuichi , Scholer Manfred
Published: December 2003

The modified two‐stream instability in the foot of supercritical quasi‐perpendicular shock wave is investigated. A linear analysis shows that the instability can sufficiently grow during the shock reformation cycle for the case of a realistic ion to electron mass ratio. The wave‐particle interactions of the Landau type of both the electrons and ions are essential in a finite beta plasma and lead to a reduction of the growth rate with increasing beta. The magnetic polarization in terms of wavevector is also analyzed. Additional one‐dimensional full‐particle electromagnetic simulations in a periodic system reveal some important nonlinear wave properties. The wave spectra indicate a lower cascade due to wave‐wave interactions. The parallel phase space distribution of electrons correlates well with the wave profile of the magnetic field component perpendicular to both the ambient magnetic field and the wavevector. The nonlinearly generated waves lead to electron heating parallel to the magnetic field.
A 550‐year‐old Plinian eruption at El Chichón Volcano, Chiapas, Mexico: Explosive volcanism linked to reheating of the magma reservoir
Authors: Macías J. L. , Arce J. L. , Mora J. C. , Espíndola J. M. , Saucedo R. , Manetti P.
Published: December 2003

Some 550 years ago (1320–1433 A.D.), a powerful Plinian eruption at El Chichón Volcano in southern Mexico produced a widespread pumice fall deposit. We subdivided the deposit into three parts on the basis of structural and textural characteristics, pumice lithology and density, granulometry, and petrologic‐geochemical attributes. The deposit covers an area of 1500 km2 within the 1‐cm isopach and has a minimum estimated bulk volume of 2.8 km3 (1.1 km3 dense rock equivalent (DRE)); its eruptive column reached an altitude of ∼31 km. Consideration of field evidence, the presence and nature of mafic enclaves, and chemical data strongly suggest that the 550 year B.P. eruption is linked with the intrusion of a high‐temperature basaltic magma into preexisting but stagnated trachyandesitic magma beneath El Chichón. Thorough mixing of the two magmas produced a compositionally uniform hybrid trachyandesite magma (average SiO2 55.3 wt %), which subsequently underwent crystal growth and gas exsolution, ultimately overpressurizing the zoned magmatic system to erupt explosively. On the basis of El Chichón's known eruptive history, the intrusion‐mixing event occurred sometime after the 900 year B.P. eruption. The hybrid magma had a preeruption temperature of 820–830°C and was water undersaturated (5–6 wt % H2O) at pressures of ∼2–2.5 kbar.
Infrared stealthy surfaces: Why TES and THEMIS may miss some substantial mineral deposits on Mars and implications for remote sensing of planetary surfaces
Authors: Kirkland Laurel E. , Herr Kenneth C. , Adams Paul M.
Published: December 2003

Infrared spectral observations have yielded many important insights into the nature of Mars. However, spectral effects tied to surface roughness and particle size can make mineral deposits substantially more difficult to detect and identify than is generally known, including for current investigations. The effects hold for Mars and other planets, but here we focus on the impact on the exploration of Mars. Laboratory spectra of pure, smooth‐surfaced minerals have previously been used to conclude that the 1996 Global Surveyor Thermal Emission Spectrometer (TES) and the 2001 Mars Odyssey Thermal Emission Imaging System (THEMIS) will detect a mineral deposit that covers ∼10% of a pixel. Those laboratory spectra have formed the foundation for modeling and interpretations of TES/THEMIS data and for development of the 2003 Mars rover MiniTES. Here, for the first time, we compare TES/THEMIS foundation data to laboratory, field, and unique airborne spectra of rough surfaces. We demonstrate that substantial, well‐crystalline, regional mineral deposits, including rock outcrops, can be 100% exposed and remain undetected at the sensitivity of TES/THEMIS. We then detail the physics, which apply to all geologic materials. Previous studies have demonstrated the complicating physical effects for solids versus particulates for a range of minerals, including oxides, sulfates, carbonates, and each of the seven silicate classes. We identify three cases of spectral behavior that can impact interpretations: In Case 1, physical effects cause a target to be undetectable by a given infrared instrument (“infrared stealthy”). In Case 2, variations in spectral contrast mimic abundance variations, which confounds abundance mapping. In Case 3, alteration of the spectral band shape impacts compositional interpretations. Optically smooth materials will be well represented in TES/THEMIS/MiniTES identifications. Conversely, if a material forms an optically rough surface or sufficiently small particles on Mars, then it will be comparatively underrepresented or missed. Surface roughness occurs on three broad scales, and roughness at the grain scale can be a primary variable in whether a mineral is detectable. Nondetection of certain key minerals (e.g., carbonates) can significantly impact geologic and climatic interpretations and landing site selection. The TES/THEMIS detection threshold may be 10% coverage on the basis of specific laboratory samples, but for field measurements, that prediction represents an idealized lower bound. Interpretations built on nondetection should be revisited after defining the uncertainties in detection capabilities for specific instruments as applied to expected mineral surface textures on Mars, including at the grain scale. The impact on future measurement strategies (including MiniTES) should also be assessed.
Analysis of MOLA data for the Mars Exploration Rover landing sites
Authors: Anderson F. Scott , Haldemann Albert F. C. , Bridges Nathan T. , Golombek Matthew P. , Parker Timothy J. , Neumann Gregory
Published: December 2003

We have used Mars Orbiter Laser Altimeter (MOLA) data to demonstrate that selected landing sites meet the Mars Exploration Rover (MER) landing system topography and slope requirements at hectometer and kilometer scales. To provide a comprehensive analysis, we constrained slopes within each landing ellipse using four approaches: (1) measurements of local slopes at 1.2 km length scales using both an adirectional maximum gradient method and a higher‐resolution bidirectional, along‐track method, (2) predictions of 100 m slopes using self‐affine statistics in conjunction with (3) calculations of both pulse width and slope corrected pulse width to constrain slopes at scales smaller than the MOLA spot size (<180 m), and (4) comparisons of simultaneously acquired MOLA data with Mars Orbiter Camera data to identify the geomorphologic features associated with variations in observed slopes, pulse width, and, for this analysis only, reflectivity. The results of the analysis indicate that the selected landing sites are consistent with the MER topography requirement of being below −1.3 km, as well as having slopes less than 5° at length scales of 100 m and <2° at length scales of 1.2 km.
A description of water and sediment flow in the presence of obstacles with a two‐dimensional, lattice BGK‐cellular automata model
Authors: Jiménez‐Hornero F. J. , Giráldez J. V. , Laguna A.
Published: December 2003

The spatial distribution of water and sediment flow in the presence of obstacles on the soil surface is described with a coupled two‐dimensional, lattice BGK (the Bhatnagar, Groos, and Krook version of the lattice Boltzmann equation) cellular automata model. The model reproduces the main water flow characteristics of the Bunte and Poesen [1993] experiment well, as well as the mean runoff velocity. The model also approximates the main features of local scouring and sediment yield of the experiment. Although the results obtained in two dimensions are encouraging, the consideration of the erosive action of the vortexes on a plane perpendicular to the bed would improve the characterization of the scouring patterns in the stagnation points developed upstream from the obstacles.
A comparison of stochastic models for spatial rainfall downscaling
Authors: Ferraris Luca , Gabellani Simone , Rebora Nicola , Provenzale Antonello
Published: December 2003

We explore the performance of three types of stochastic models used for spatial rainfall downscaling and assess their ability to reproduce the statistics of precipitation fields observed during the GATE radar experiment. We consider a bounded multifractal cascade, an autoregressive linear process passed through a nonlinear static filter (sometimes called a meta‐Gaussian model), and a model based on the presence of individual rainfall cells with power law profile. As test statistics we use the low‐order moments of the amplitude distribution, the distribution of generalized fractal dimensions, the generalized scaling exponents, the slope of the power spectrum, and the properties of the spatial autocorrelation. The results of the analysis indicate that all models provide, on average, a satisfactory representation of the statistical properties of the GATE rainfall fields (including the anomalous scaling behavior), with a slightly better performance of the model based on individual rainfall cells. All models, however, display large scatter in the field‐to‐field comparison with the data. These results indicate that data analysis alone does not allow, at the moment, for preferring one downscaling approach over another.
Effect of cardiac vagal outflow on complexity and fractal correlation properties of heart rate dynamics
Authors: Penttilä J. , Helminen A. , Jartti T. , Kuusela T. , Huikuri H. V. , Tulppo M. P. , Scheinin H.
Published: December 2003

1 Cardiac vagal outflow is the major factor determining the magnitude of heart rate (HR) variability analysed by traditional time and frequency domain methods. New analysis techniques, such as fractal and complexity methods, have been developed to probe non‐linear features in HR behaviour that may not be detectable by traditional methods.

2 We investigated the effects of vagal blockade (glycopyrrolate i.v. 5 μg kg−1 h−1 for 2 h, n = 8 vs. unmedicated control group, n = 8) and various breathing patterns (n = 12) on two non‐linear measures of HR variability – detrended fluctuation analysis (DFA) and approximate entropy (ApEn) – in healthy male volunteers.

3 Glycopyrrolate decreased the mean (±SD) ApEn from 1.46 ± 0.18 to 0.85 ± 0.24 (P = 0.001 in comparison with the control group), and increased the short‐term (α1) and intermediate‐term (α2) fractal scaling exponents of DFA, α1 from 0.96 ± 0.19 to 1.43 ± 0.29 (P = 0.003) and α2 from 1.13 ± 0.10 to 1.34 ± 0.14 (P < 0.001).

4 Decrease in fixed respiration rate from 15 to 6 breaths min−1 increased α1 from 0.83 ± 0.25 to 1.18 ± 0.27 (P < 0.001), but decreased α2 from 0.88 ± 0.09 to 0.45 ± 0.17 (P < 0.001) and ApEn from 1.26 ± 0.12 to 1.10 ± 0.14 (P = 0.028). Rapid breathing (24 min−1) had no influence on these non‐linear measures of HR variability. Hyperventilation (15 min−1, tidal volume increased voluntarily by 0.5 l) decreased α1 from 0.83 ± 0.25 to 0.66 ± 0.28 (P = 0.002) but did not affect α2 or ApEn.

5 To conclude, vagal blockade alters the fractal scaling properties of R‐R intervals (α1, α2) and reduces the complexity (ApEn) of HR behaviour. Both the fractal and complexity measures of HR variability can also be influenced by changes in the breathing pattern.
Demonstration of functional receptors for noradrenaline and adenosine‐5′‐triphosphate, but not for prostaglandin E2, in HT‐29 human colon cancer cell line
Authors: Nylund G. , Nordgren S. , Delbro D. S.
Published: December 2003

1 The aim of the current study was to investigate in HT‐29 human colon cancer cell line, the existence of functional receptors for the signalling molecules, noradrenaline (NA), prostaglandin E2 (PGE2), and adenosine‐5′‐triphosphate (ATP).

2 We utilized microphysiometry, which monitors on‐line extracellular acidification rate (ECAR) as a measure of cellular metabolic activity, and how this variable is altered by signalling molecules.

3 Challenge with NA (5.9 μm) resulted in an increase in ECAR by approximately 24% of basal.

4 PGE2 (0.0284, 0.284 and 2.84 μm) hardly affected ECAR.

5 ATP (100 μm) elicited a biphasic effect on ECAR (increase and decrease in ECAR by about 58 and 10% of basal, respectively).

6 HT‐29 cells were shown to express COX‐2 by immunocytochemistry.

7 These data suggest the presence of functional receptors for NA and ATP, but not for PGE2 in HT‐29 human colon cancer cell line.
Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea
Authors: Song Byung-Cheol , Suh Dong Jin , Lee Han Chu , Chung Young-Hwa , Lee Yung Sang
Published: December 2003

It has been suggested that hepatitis B e antigen (HBeAg) seroconversion after lamivudine therapy is durable in Caucasians with chronic hepatitis B (CHB). However, little is known whether it is also durable in endemic areas of hepatitis B virus (HBV) infection. We evaluated the posttreatment durability of lamivudine-induced HBeAg seroconversion and the predictive factors for relapse in Korean patients with CHB. We retrospectively analyzed 98 HBeAg-positive patients with CHB who were treated with lamivudine between August 1996 and December 1997. Lamivudine was given at a dose of 150 mg per day. After HBeAg seroconversion, lamivudine was continued for an additional 2 to 4 months, and posttreatment monitoring continued for up to 24 months. HBeAg seroconversion was achieved in 34 of the 98 patients (34.7%). The mean duration of treatment in these seroconverters was 9.3 ± 3.0 months. During the follow-up period, the cumulative relapse rates at 1 year and 2 years posttreatment were 37.5% and 49.2%, respectively. Most relapses were accompanied by elevation of serum alanine transaminase (94%) and reappearance of HBeAg (81%). Pretreatment serum HBV DNA levels and the duration of additional lamivudine therapy after HBeAg seroconversion were 2 independent predictive factors for posttreatment relapse. In conclusion, lamivudine-induced HBeAg seroconversion was not durable in this endemic area. And the duration of additional lamivudine therapy after HBeAg seroconversion significantly affected the posttreatment relapse. Further studies are needed to determine the duration of lamivudine and to elucidate the cause of high relapse after HBeAg seroconversion in endemic areas of HBV.
Liver transplantation for autoimmune hepatitis
Authors: Reich David J. , Fiel Isabel , Guarrera James V. , Emre Sukru , Guy Stephen R. , Schwartz Myron E. , Miller Charles M. , Sheiner Patricia A.
Published: December 2003

Publications about liver transplantation (LTX) for autoimmune hepatitis (AIH) have started to emerge, but many issues remain unresolved. We reviewed data on 32 patients transplanted for AIH to determine how pretransplantation and posttransplantation characteristics correlate with recipient outcome, including disease recurrence. Recipients were 37± 14 years old; 30 of 32 were women. Most had chronic disease (8 ± 6 years); 25% had fulminant failure. The majority had ascites (91%), jaundice (88%), elevated prothrombin time (18 ± 3 seconds), and hypoalbuminemia (2.7 ± 0.6 g/dL). All had hypergammaglobulinemia (3.0 ± 1.0 g/dL) and autoantibodies (72% antinuclear, 74% smooth muscle). Only one was HLA A1-B8-DR3 positive. Other autoimmune disorders affected 25% of patients; half improved after transplantation. Actuarial survival was 81% at 1 and 2 years posttransplantation. There was a high frequency of rejection (75% of recipients had 1.7 ± 0.8 episodes), and 39% of rejections required OKT3. Among 24 recipients with long-term follow-up (27 ± 14 months), histologically proven recurrent AIH occurred in 25%, 15 ± 2 months posttransplantation; half (3 patients) required retransplantation 11 ± 3 months after diagnosis. After retransplantation 2 of 3 patients had re-recurrence within 3 months; 1 received a third LTx. Recurrence occurred in 6 of 18 patients transplanted for chronic disease vs. 0 of 6 transplanted as fulminants (P = not significant [NS]). Patients with and without recurrence had similar rejection profiles. In summary, results of LTx for AIH are excellent. However, AIH patients have a high frequency of rejection and often require OKT3. Furthermore, severe recurrent AIH sometimes develops, particularly in chronic versus fulminant AIH patients and in those already retransplanted for recurrence. Multicenter studies could elucidate the best posttransplantation immunosuppressive regimens for AIH patients.
Temporal pathogenesis of experimental neonatal woodchuck hepatitis virus infection: Increased initial viral load and decreased severity of acute hepatitis during the development of chronic viral infection
Authors: Cote Paul J. , Toshkov Ilia , Bellezza Christine , Ascenzi Mary , Roneker Carol , Graham Lou Ann , Baldwin Betty H. , Gaye Karen , Nakamura Ikuo , Korba Brent E. , Tennant Bud C. , Gerin John L.
Published: December 2003

Acute hepatitis B virus (HBV) infections either resolve or progress to chronicity. Identification of early deviations in host-virus responses associated with these outcomes can further differentiate cause-effect mechanisms that initiate and maintain chronicity. Neonatal woodchucks were infected experimentally with the woodchuck hepatitis virus (WHV) at 3 days of age. At 8 or 14 weeks of age (i.e., the early- or mid-acute stage of infection), whole blood and large surgical biopsies of the liver were obtained from infected animals and uninfected controls. These were stored for later correlating histopathologic responses and viral load with the subsequently determined outcome of infection. As of 1 year postinfection, half of the surgically treated infected woodchucks had developed self-limited infections, while the other half developed chronic infections. The self-limited outcome was characterized by decreased viral load in acute-phase liver and plasma and a generally robust acute hepatic inflammatory response. Comparisons at the same early time points revealed that the chronic outcome was characterized by increasing initial viral load in liver and plasma, and a detectable, but diminished, acute hepatic inflammation. These cotemporal comparisons indicate that there is an early host-response deviation during the acute phase of a developing chronic infection. Continued analysis of the tissues banked from this study will facilitate further temporal characterization of acute-phase mechanisms that determine resolution versus chronicity in WHV infection. Understanding such mechanisms may be useful in the rational design of therapy for established chronic HBV infection.
Murine concanavalin A-induced hepatitis is prevented by interleukin 12 (IL-12) antibody and exacerbated by exogenous IL-12 through an interferon-γ-dependent mechanism
Authors: Nicoletti Ferdinando , Di Marco Roberto , Zaccone Paola , Salvaggio Antonio , Magro Gaetano , Bendtzen Klaus , Meroni PierLuigi
Published: December 2003

Concanavalin A (ConA)-induced hepatitis is a cell-mediated immunoinflammatory condition similar to human autoimmune hepatitis. We investigated the role of interleukin 12 (IL-12) in hepatitis induced in NMRI and C57/BL6 mice by a single injection of ConA. Recombinant murine IL-12 administered 24 hours and 1 hour prior to ConA exacerbated both transaminase activities in plasma and histologic signs of hepatitis. These markers of liver injury were significantly reduced by prophylactic, but not therapeutic treatment with anti-IL-12 monoclonal antibody (mAb). The disease-modulatory effects of IL-12 and anti-IL-12 mAb were associated with profound and reverse modifications of a ConA-induced increase in the circulating levels of IL-4, IL-6, interferon gamma (IFN-γ) and tumor necrosis factor (TNF). Relative to control animals receiving ConA alone, the plasma levels of these cytokines were all augmented in IL-12/ConA-treated mice and diminished in anti-IL-12 mAb/ConA-treated mice. Anti-IFN-γ mAb also impeded the appearance of IL-12/ConA-induced hepatitis. Thus, IL-12-induced production of IFN-γ might play a role in mediating the hepatitis-inducing effect of ConA. However, IL-12p40-deficient C57/BL6 mice were as susceptible as wild-type controls to the hepatitis-inducing effect of ConA.
Hepatocellular carcinoma cell cycle: Study of Long-Evans Cinnamon rats
Authors: Masaki Tsutomu , Shiratori Yasushi , Rengifo William , Igarashi Kouichi , Matsumoto Kouzou , Nishioka Mikio , Hatanaka Yoshio , Omata Masao
Published: December 2003

Amplification found in a number of cyclin genes, especially in cyclin D and E, is an important event process that takes place in cancers, including hepatocellular carcinoma (HCC). The activities of a wide range of cell cycle-related kinases remain obscure in HCC. The purpose of the present study is to determine the cyclins and kinase activities of HCC in Long-Evans Cinnamon (LEC) rats. Cyclin D1, E, A, H, Cdk1(cyclin-dependent kinase; Cdc2), Cdk4, and Cdk6 protein levels were determined by Western blot analysis at different pathologic stages of liver tissues exhibiting HCC. Enzymatic activities of cyclin D1, E, A, Cdk4, Cdk6, Cdc2, Cdk7, and Wee1 kinase were measured by in-gel kinase assay. Protein levels and kinase activities of cyclin D1, E, Cdk4, cyclin A, and Wee1 increased proportionally with the development of HCC, especially in the transition process from chronic hepatitis to HCC. Although Cdc2 kinase activity was found to increase slightly from normal liver to chronic hepatitis, its activity remained unchanged in the process from chronic hepatitis to HCC. Cdk6 and Cdk7 activities remained unchanged in the process from normal liver to HCC. These data suggest that the increase in Cdc2 kinase may play a role in the process from normal liver to chronic hepatitis, whereas the predominant increase in cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 suggests involvement not only in the process from normal liver to chronic hepatitis, but also during transition into HCC.
Detection of residual hepatitis C virus RNA by transcription-mediated amplification in patients with complete virologic response according to polymerase chain reaction-based assays
Authors: Sarrazin Christoph , Teuber Gerlinde , Kokka Robert , Rabenau Holger , Zeuzem Stefan
Published: December 2003

A considerable proportion of patients with chronic hepatitis C who achieve a virologic end-of-treatment response relapse after discontinuation of therapy. It is conceivable that polymerase chain reaction (PCR)-based assays with a lower detection limit of 100 to 1,000 hepatitic C virus (HCV) RNA copies/mL are still too insensitive to detect residual viremia. End-of-treatment serum samples of 47 patients with a virologic relapse according to results of qualitative PCR assays (Amplicor HCV; Roche Molecular Systems, Mannheim, Germany) were tested by transcription-mediated amplification (TMA), an isothermal, autocatalytic target amplification method that has the potential to detect less than 50 HCV RNA copies/mL. Virologic sustained responders (n = 59) and nonresponders (n = 49) served as controls. In end-of-treatment serum samples of virologic sustained responders and nonresponders an almost complete concordance between PCR and TMA results was observed (98%). However, HCV RNA was detectable by TMA in end-of-treatment serum samples from 16 of 25 relapse patients (64%) who were HCV-RNA-negative according to Amplicor HCV version 1.0 (lower detection limit 1,000 copies/mL) and in 8 of 22 patients (36%) who were HCV-RNA-negative according to Amplicor HCV version 2.0 (lower detection limit 100 copies/mL). End-of-treatment alanine transaminase (ALT) levels of sustained virologic responders and TMA-negative relapsers were similar, whereas a trend toward higher ALT values was observed in TMA-positive relapsers compared with sustained virologic responders (P = 0.09). In conclusion, HCV RNA can be detected at the end of treatment by TMA in a considerable proportion of patients who were classified as virologic end-of-treatment responders with a subsequent virologic relapse according to PCR-based methods.
Randomized, double-blind, placebo-controlled trial of interferon Alfa2a with and without amantadine as initial treatment for chronic hepatitis C
Authors: Zeuzem Stefan , Teuber Gerlinde , Naumann Uta , Berg Thomas , Raedle Jochen , Hartmann Susanne , Hopf Uwe
Published: December 2003

Although the antiviral effects of amantadine sulphate (1-aminoadamantan sulphate) have not been characterized for the hepatitis C virus (HCV), previous pilot studies have suggested promising results in patients with chronic hepatitis C. The aim of the present study was to compare the efficacy, safety, and health-related quality of life (HRQOL) of interferon alfa (IFN-α) alone or in combination with oral amantadine for treatment of chronic hepatitis C. One hundred nineteen previously untreated patients with chronic hepatitis C were randomly allocated to treatment with IFN-α2a at a dose of 6 megaunits 3 times a week subcutaneously for 24 weeks, followed by 3 megaunits thrice weekly for an additional 24 weeks plus amantadine sulphate administered orally 100 mg twice a day for 48 weeks or the same IFN regimen plus a matched placebo. The primary endpoint was undectable serum HCV RNA (<1,000 copies/mL) at week 24 after treatment. At the end of treatment and the 24-week follow-up period serum HCV RNA was undetectable in 20 (34%) and 6 (10%) of the 59 patients treated with the combination IFN-α plus amantadine and in 20 (33%) and 13 (22%) of the 60 patients treated with IFN-α alone, respectively (P = n.s.). Discontinuation of therapy for adverse events was similar in both treatment groups. Although treatment with IFN-α worsened HRQOL, combination with amantadine showed a substantial trend to improve fatigue and vigor. In conclusion, combination therapy IFN-α plus amantadine is as effective as IFN-α monotherapy in previously untreated patients with chronic hepatitis C.
γ-Glutamyltranspeptidase-deficient knockout mice as a model to study the relationship between glutathione status, mitochondrial function, and cellular function
Authors: Will Yvonne , Fischer Kay A. , Horton Robert A. , Kaetzel Rhonda S. , Brown Marda K. , Hedstrom Olaf , Lieberman Michael W. , Reed Donald J.
Published: December 2003

γ-Glutamyltranspeptidase (GGT)-deficient mice (GGT−/−) display chronic glutathione (GSH) deficiency, growth retardation, and die at a young age (<20 weeks). Using livers from these mice, we investigated the relationship between GSH content, especially mitochondrial, and mitochondrial and cellular function. We found that the GSH content of isolated liver mitochondria was diminished by ≥50% in GGT−/− mice when compared with wild-type mice. Respiratory control ratios (RCRs) of GGT−/− mice liver mitochondria were ≤60% those of wild-type mice primarily as a result of impaired state 3 respiration. Mitochondrial adenine nucleotide content was decreased by ≥40% in mitochondria obtained from GGT−/− mice. We observed a strong correlation between mitochondrial GSH content and RCRs. Even moderate decreases (<50%) correlated with adverse effects with respect to respiration. Electron microscopy revealed that livers from GGT−/− knockout mice were deprived of fat and glycogen, and swollen mitochondria were observed in animals that were severely deprived of GSH. Thus, GGT−/− mice exhibit a loss of GSH homeostasis and impaired oxidative phosphorylation, which may be related to the rate of adenosine triphosphate (ATP) formation and subsequently leads to progressive liver injury, which characterizes the diseased state. We also found that supplementation of GGT−/− mice with N-acetylcysteine (NAC) partially restored liver GSH, but fully restored mitochondrial GSH and respiratory function. Electron microscopy revealed that the livers of NAC-supplemented GGT−/− mice contained fat and glycogen; however, slightly enlarged mitochondria were found in some livers. NAC supplementation did not have any beneficial effect on the parameters examined in wild-type mice.
Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B
Authors: Hadziyannis Stephanos J. , Papatheodoridis George V. , Dimou Evangelini , Laras Andreas , Papaioannou Christos
Published: December 2003

We evaluated the safety and efficacy of long-term lamivudine monotherapy in a group of 25 patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. Lamivudine was administered in a daily dose of 150 mg for a mean of 26 ± 7 months and was well tolerated. No patient lost hepatitis B surface antigen (HBsAg). The rate of initial biochemical response increased from 88% at 6 months to 96% at 12 months of therapy, but it progressively decreased thereafter; the biochemical remission rate was 68% at 18 months, 59.5% at 24 months, and 42.5% at ≥30 months. Alanine transaminase (ALT) increased to higher than the baseline levels in 8 of the 11 patients with a biochemical breakthrough reaching acute hepatitis levels in 6 of them. Acute icteric hepatitis developed in one patient. The virologic remission rate assessed by a sensitive quantitative polymerase chain reaction (PCR) assay was 68% at both 6 and 12 months, decreasing thereafter to 52% at 18 months and to 41.6% at both 24 and ≥30 months. Virologic breakthroughs were always persistent and preceded ALT elevations by a median of 4 (3-24) months. YMDD mutants were detected in all patients with a virologic breakthrough. In conclusion, in patients with HBeAg-negative chronic hepatitis B, long-term lamivudine therapy is safe and is associated with high biochemical and virologic response rates at the end of the first year. However, response rates tend to decrease with time and breakthroughs due to YMDD mutants accumulate. ALT activity during breakthroughs often exceeds the baseline and may reach even acute hepatitis levels.
Identification of the gene for a novel liver-related putative tumor suppressor at a high-frequency loss of heterozygosity region of chromosome 8p23 in human hepatocellular carcinoma
Authors: Liao Cheng , Zhao Mujun , Song Hai , Uchida Kiyoshi , Yokoyama Kazunari K. , Li Tsaiping
Published: December 2003

Human chromosome 8p23 is known as a region that is associated with loss of heterozygosity (LOH), which is frequently deleted in hepatocellular carcinoma (HCC) tissues. We report here the characterization of a gene for a liver-related putative tumor suppressor (LPTS) localized at 8p23, that was isolated by allelic-loss mapping and positional candidate cloning. The expression of the gene for LPTS was ubiquitous in normal human tissues, albeit at relatively low levels, whereas levels appeared to be significantly reduced, or sometimes undetectable in HCC cells and neoplastic tissues. Thus, it appeared that LPTS might be involved in the control of cell proliferation. Indeed, we observed the significant suppression of growth and growth arrest of SMMC-7721 HCC cells after introduction of the gene for LPTS. We also used antisense oligodeoxynucleotides (AS-ODNs) to suppress the expression of LPTS in normal liver cells L02. Several AS-ODNs specific for LPTS mRNA significantly enhanced cell growth, whereas control oligodeoxynucleotides (ODNs) did not. Our results suggest that LPTS might be a growth-inhibitory protein in human hepatocytes.
Up-regulation of Fas ligand at early stages and down-regulation of Fas at progressed stages of intrahepatic cholangiocarcinoma reflect evasion from immune surveillance
Authors: Shimonishi Tomonori , Isse Kumiko , Shibata Fumie , Aburatani Isao , Tsuneyama Koichi , Sabit Hemragul , Harada Kenichi , Miyazaki Kohji , Nakanuma Yasuni
Published: December 2003

We examined immunohistochemically the possible participation of the Fas/Fas ligand (FasL) system in intrahepatic cholangiocarcinoma (ICC) during the escape from immune surveillance, using 68 cases of ICC, 29 cases of normal intrahepatic large bile ducts, and 18 cases of biliary dysplasia. Apoptosis of tumor-infiltrating lymphocytes (TIL) was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Fas was weakly expressed in normal intrahepatic bile ducts. Almost all biliary dysplasia and well-differentiated ICCs showed moderate to marked expression of Fas, while Fas expression was variable in moderately and poorly differentiated ICCs. Down-regulation of Fas expression was significantly correlated with histologic de-differentiation, vascular invasion, the size of ICCs, and short survival of ICC patients. By in situ hybridization, FasL mRNA were frequently and strongly expressed in biliary dysplasia compared with non-neoplastic intrahepatic bile duct. In well-differentiated ICCs, FasL mRNA expression was frequent and intense. But, the expression gradually decreased in moderately and poorly differentiated ICCs. Down-regulation of FasL mRNA expression in ICCs was correlated with perineural invasion and tumor size (over 4 cm) (P < .05). Apoptotic TIL were more frequent in ICC foci than in non-neoplastic foci remote from ICC foci. These findings suggest that a tumor evasion mechanism involving Fas/FasL exists in ICC; frequent and intense expression of FasL mRNA in well-differentiated ICCs enable them to escape immune surveillance by counterattacking Fas-bearing TIL. This counterattack becomes insensitive in poorly differentiated ICCs, in which the down-regulation of Fas gives them a resistance against the FasL-expressing TIL. These mechanisms may be involved in the tumor progression.
Nitric oxide prevents tumor necrosis factor α-induced rat hepatocyte apoptosis by the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase-8
Authors: Kim Young-Myeong , Kim Tae-Hyoung , Chung Hun-Taeg , Talanian Robert V. , Yin Xiao-Ming , Billiar Timothy R.
Published: December 2003

Mitochondrial cytochrome c release plays a critical role in apoptotic signal cascade after the activation of cell surface death receptors. We investigated the role played by nitric oxide (NO) in mitochondrial apoptotic signaling in tumor necrosis factor α (TNF-α) plus actinomycin D (TNF-α/ActD)-induced apoptosis. NO produced either by S-nitroso-N-acetyl-DL-penicillamine (SNAP) or inducible NO synthase (iNOS) prevented TNF-α/ActD-induced apoptosis in hepatocytes and also inhibited both caspase-8-like (IETDase) and caspase-3-like protease (DEVDase) activity as well as mitochondrial cytochrome c release. Recombinant human (rh) caspase-8 induced the cleavage of the cytochrome c-effluxing factor Bid and cytochrome c release from purified mitochondria in the reconstitution system with Bid +/+ cytosol, but not with Bid −/− cytosol. The addition of SNAP and the caspase-8 inhibitor Ac-IETD-fmk inhibited caspase-8-dependent Bid cleavage and cytochrome c release. The inhibitory effect of NO on caspase-8 was reversed by dithiothreitol (DTT). Furthermore, rh-caspase-8 was found to be modified by S-nitrosylation with 1.7 moles of NO bound per mole of enzyme. Treatment of hepatocytes with interleukin 1β (IL-1β) plus interferon gamma (IFN-γ), which induced iNOS expression and NO production, suppressed TNF-α/ActD-induced Bid cleavage and mitochondrial cytochrome c release. The NOS inhibitor N G-monomethyl-L-arginine (NMA) inhibited the protective effects of IL-1β and IFN-γ. The liver-specific NO donor V-PYRRO/NO also inhibited in vivo elevation of IETDase activity, Bid cleavage, and mitochondrial cytochrome c release in the livers of rats injected with TNF-α plus D-galactosamine. Our results indicate that one mechanism by which NO protects hepatocytes from TNF-α/ActD-induced apoptosis is via the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase-8.