bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnetic flux tube evolution in solar wind anisotropic magnetic turbulence
Authors: Zimbardo G. , Pommois P. , Veltri P.
Published: February 2004

The magnetic turbulence in the solar wind causes a magnetic field line transport that is reflected in the propagation in space of charged particles. Assuming a small localized source, the distribution in space of energetic particles is determined, in part, by the shape of the magnetic flux tube. The spatial evolution of a magnetic flux tube is studied here by means of a numerical realization of three‐dimensional magnetic turbulence that takes into account the anisotropy of the solar wind turbulence and is quantified by correlation lengths in the three spatial directions. Several diagnostics of flux tube evolution are shown, such as patterns of the flux tube cross sections and histograms representing possible energetic particle intensity profiles. We show that flux tube evolution can be assessed by the Kubo number R = (δB/B0)(lz/lx), where δB/B0 is the turbulence level and lz (lx) is the correlation length parallel (transversal) to the background magnetic field B0. We find that when lz/lx (i.e., R) is large, the flux tube evolves very quickly, forming very fine, diffusive structures. These diffusive structures would correspond to a nearly Gaussian envelope for the energetic particle time profile detected by a spacecraft. On the other hand, when lz/lx is small, the flux tube evolves slowly, executing large coherent transverse displacements, and thereby forms well resolved (i.e., detached) intermittent high particle fluxes in observed energetic particle profiles. Hence an accurate study of the morphology of impulsive energetic particle events, when compared with our simulation results, can give information on the microphysical evolution of flux tubes in the solar wind and on the turbulence anisotropy. A first comparison indicates that lx ≃ 3–10lz is appropriate for the solar wind. Our study also allows us to reconcile fast field line transport with the observation of sharp composition or energetic particle gradients in the solar wind, since lx ≫ lz implies considerable transverse elongation of the flux tube cross section, with the possibility of non‐Gaussian, superdiffusive transport regimes.
Homologous large‐scale activity in solar eruptive events of 24–26 November 2000
Authors: Chertok I. M. , Grechnev V. V. , Hudson H. S. , Nitta N. V.
Published: February 2004

We study large‐scale activity on the solar disk associated with a 24–26 November 2000 series of six recurrent major flares and “halo” coronal mass ejections (CMEs). The analysis is based mainly on the SOHO/EIT data, particularly by using properly rotated difference full‐disk images with 12‐min intervals at 195 Å as well as with 6‐hour intervals at 171, 195, 284, and 304 Å. We demonstrate that these eruptive events were homologous not only by their flare and CME characteristics, as Nitta and Hudson [2001] showed, but also in terms of their large‐scale CME‐associated manifestations in the EUV corona. These include long and narrow channeled dimmings, some transequatorial; anisotropic coronal waves, propagating in a restricted angular sector; and additional quasi‐stationary emitting fronts. As a whole, in all of these six events, the homologous CME‐associated disturbances covered a considerable portion of the solar disk. The homology tendency appears to be due to significant disturbance, partial eruption, and relatively fast restoration of the same large‐scale structures involved in the repeating CME events. We briefly discuss the implications of the analysis in connection with the nature of coronal equilibrium.
Ice shelf water overflow and bottom water formation in the southern Weddell Sea
Authors: Foldvik A. , Gammelsrød T. , Østerhus S. , Fahrbach E. , Rohardt G. , Schröder M. , Nicholls K. W. , Padman L. , Woodgate R. A.
Published: February 2004

Cold shelf waters flowing out of the Filchner Depression in the southern Weddell Sea make a significant contribution to the production of Weddell Sea Bottom Water (WSBW), a precursor to Antarctic Bottom Water (AABW). We use all available current meter records from the region to calculate the flux of cold water (<−1.9°C) over the sill at the northern end of the Filchner Depression (1.6 ± 0.5 Sv), and to determine its fate. The estimated fluxes and mixing rates imply a rate of WSBW formation (referenced to −0.8°C) of 4.3 ± 1.4 Sv. We identify three pathways for the cold shelf waters to enter the deep Weddell Sea circulation. One path involves flow constrained to follow the shelf break. The other two paths are down the continental slope, resulting from the cold dense water being steered northward by prominent ridges that cross the continental slope near 36°W and 37°W. Mooring data indicate that the deep plumes can retain their core characteristics to depths greater than 2000 m. Probably aided by thermobaricity, the plume water at this depth can flow at a speed approaching 1 m s−1, implying that the flow is occasionally supercritical. We postulate that such supercriticality acts to limit mixing between the plume and its environment. The transition from supercritical to slower, more uniform flow is associated with very efficient mixing, probably as a result of hydraulic jumps.
Synthetic aperture radar observation of the sea surface imprints of upstream atmospheric solitons generated by flow impeded by an island
Authors: Li Xiaofeng , Dong Changming , Clemente‐Colón Pablo , Pichel William G. , Friedman Karen S.
Published: February 2004

Two cases of upstream propagation of atmospheric solitons generated by atmospheric flow over topography were identified on two RADARSAT‐1 synthetic aperture radar (SAR) images acquired near St. Lawrence Island in the Bering Sea on 7 September 1997 and 6 June 2001, respectively. In both cases, a group of solitons was shown as three dark‐bright linear features on the SAR images. The soliton width and peak‐to‐peak distance measured from the two SAR images are about 3 km and 4.5 km, respectively. Simultaneous radiosonde measurements, a surface weather map and operational weather model results confirm that these waves did not propagate on the lee side of the island as is commonly observed with island lee waves, but indeed propagated against the flow in the upstream direction. In the second case, the same group of solitons was also identified as a wave‐like cloud pattern on a MODIS image taken about 4.5 hours later. In this MODIS image, the soliton train propagated further upstream with the leading crest reaching about 30 km north of the island, and the number of crest‐trough features increased from three to seven. In this study, we describe the generation and evolution of upstream atmospheric solitons using the Force KdV (fKdV) model with radiosonde and island topography data. The numerical solution of the fKdV exhibits a sequence of solitons propagating upstream of the island. Both temporal and spatial scales of the solitons are in good agreement with that estimated from the successive SAR and MODIS satellite images.
Satellite estimation of photosynthetically active radiation in Southeast Asia: Impacts of smoke and cloud cover
Authors: Kobayashi Hideki , Matsunaga Tsuneo , Hoyano Akira , Aoki Masatoshi , Komori Daisuke , Boonyawat Samakkee
Published: February 2004

Since large‐scale variations in photosynthetically active radiation (PAR) influence the terrestrial carbon sources and sinks through the plant photosynthesis variations, large‐scale evaluation of PAR is required. In the present study a simple PAR estimation model was developed for Southeast Asia, where large‐scale forest fires occurred during El Niño years. The model considered the smoke aerosol released by forest fires using satellite‐based smoke detection methods. A comparison study with ground‐based solar radiation data for Malaysia and Thailand indicated that the current model could estimate monthly PAR with 10% (root‐mean‐square) accuracy and would successfully trace the seasonal and year‐to‐year variations in PAR, including the forest fire periods. During the peak‐smoke month in Indonesia, September 1997, the reduction of PAR by smoke reached 63–75% in the center of the Kalimantan and Sumatra Islands. From the analyses of the smoke and cloud cover impacts on PAR in 1997–1999, annual PAR variations were found to be mostly regulated by smoke variations on the Malay Peninsula, Sumatra, and Kalimantan Islands and cloud cover variations on the Indo‐China Peninsula. Thus annual variations in PAR changed with location. These variations did not simply correlate with year‐to‐year variations in cloud cover associated with the El Niño and La Niña cycle, but exhibited more complicated spatial variations due to the existence of smoke in Southeast Asia.
A Vertical Diffusion Scheme to estimate the atmospheric rectifier effect
Authors: Chen Baozhang , Chen Jing M. , Liu Jane , Chan Douglas , Higuchi Kaz , Shashkov Alexander
Published: February 2004

The magnitude and spatial distribution of the carbon sink in the extratropical Northern Hemisphere remain uncertain in spite of much progress made in recent decades. Vertical CO2 diffusion in the planetary boundary layer (PBL) is an integral part of atmospheric CO2 transport and is important in understanding the global CO2 distribution pattern, in particular, the rectifier effect on the distribution [Keeling et al., 1989; Denning et al., 1995]. Attempts to constrain carbon fluxes using surface measurements and inversion models are limited by large uncertainties in this effect governed by different processes. In this study, we developed a Vertical Diffusion Scheme (VDS) to investigate the vertical CO2 transport in the PBL and to evaluate CO2 vertical rectification. The VDS was driven by the net ecosystem carbon flux and the surface sensible heat flux, simulated using the Boreal Ecosystem Productivity Simulator (BEPS) and a land surface scheme. The VDS model was validated against half‐hourly CO2 concentration measurements at 20 m and 40 m heights above a boreal forest, at Fraserdale (49°52′29.9″N, 81°34′12.3″W), Ontario, Canada. The amplitude and phase of the diurnal/seasonal cycles of simulated CO2 concentration during the growing season agreed closely with the measurements (linear correlation coefficient (R) equals 0.81). Simulated vertical and temporal distribution patterns of CO2 concentration were comparable to those measured at the North Carolina tower. The rectifier effect, in terms of an annual‐mean vertical gradient of CO2 concentration in the atmosphere that decreases from the surface to the top of PBL, was found at Fraserdale to be about 3.56 ppmv. Positive covariance between the seasonal cycles of plant growth and PBL vertical diffusion was responsible for about 75% of the effect, and the rest was caused by covariance between their diurnal cycles. The rectifier effect exhibited strong seasonal variations, and the contribution from the diurnal cycle was mostly confined to the surface layer (less than 300 m).
A study of the mixing state of black carbon in urban zone
Authors: Mallet M. , Roger J. C. , Despiau S. , Putaud J. P. , Dubovik O.
Published: February 2004

The knowledge of the mixing state of black carbon particle with other aerosol species is critical for adequate simulations of the direct radiative effect of black carbon particles and its effect on climate. This paper reports the investigation of the mixing state of black carbon aerosol in the urban zone. The study uses a combination of in situ and ground‐based remote sensing observations conducted during the ESCOMPTE experiment, which took place in industrialized region in France in summer of 2001. The criteria we used for identifying mixing state relies on the known enhancement of absorption for aerosol composed by internal versus external mixtures of black carbon with weakly absorbing aerosol components. First, using in situ aerosol data, we performed Mie computations and reconstructed the single scattering albedo of aerosol for the two different mixing assumptions: black carbon mixed externally or internally with other aerosol species. Then, we compared the obtained values ωo,int and ωo,ext with the retrievals of ωo from independent AERONET Sun‐photometric measurements. The aerosol single scattering albedo (ωo,aer.) derived from the AERONET photometer observations (with the mean value equal to 0.84 ± 0.04) was found to be close to ωo,ext reconstructed from in situ observation under assumptions of external mixture. This similarity between AERONET values and external mixture simulations was observed during all the days studied. Our conclusion on external mixture of black carbon aerosol with other particles in urban zone during ESCOMPTE (close to the pollution source) is coherent with observations made during other independent studies reported in a number of recent publications.
African easterly waves and their association with precipitation
Authors: Gu Guojun , Adler Robert F. , Huffman George J. , Curtis Scott
Published: February 2004

Summer tropical synoptic‐scale waves over West Africa are quantified by the 850 mb meridional wind component from the National Centers for Environmental Prediction/National Center for Atmospheric Research reanalysis project. Their relationships with surface precipitation patterns are explored by applying the data from the Tropical Rainfall Measuring Mission satellite in combination with other satellite observations during 1998–2002. Evident wavelet spectral power peaks are seen within a period of 2.5–6 days in both meridional wind and precipitation. The most intense wave signals in meridional wind are concentrated along 15°N–25°N. Wave signals in precipitation and corresponding wavelet cross‐spectral signals between these two variables, however, are primarily located at 5°N–15°N, the latitudes of major summer rain events. Southerly wind perturbations tend to lag (lead) precipitation signals south (north) of 15°N. In some cases either an in‐phase or out‐of‐phase relationship can even be found, suggesting two distinct relationships between the waves and convection. Moreover, the lagging relationship (and/or the out‐of‐phase tendency) is only observed south of 15°N during July–September, indicating a strong seasonal preference. This phase relationship is generally consistent with the horizontal wave structures from a composite analysis.
Thermodynamic phase of maritime Antarctic clouds from FTIR and supplementary radiometric data
Authors: Lubin Dan
Published: February 2004

A Fourier Transform Infrared (FTIR) spectroradiometer was deployed at Palmer Station, Antarctica, from 1 September to 17 November 1991. This instrument is similar to the Atmospheric Emitted Radiance Interferometer (AERI) deployed with the U.S. Department of Energy Atmospheric Radiation Measurement (ARM) program. The instrument measured downwelling zenith radiance in the spectral interval 400–2000 cm−1, at a resolution of 1 cm−1. The spectral radiance measurements, which can be expressed as spectral brightness temperature Tb(ν), contain information about cloud optical properties in the middle infrared window (800–1200 cm−1, 8.3–12.5 μm). In this study, this information is exploited to (1) provide additional characterization of Antarctic cloud radiative properties, and (2) demonstrate how multisensor analysis of ARM data can potentially retrieve cloud thermodynamic phase. Radiative transfer simulations demonstrate how Tb(ν) is a function of cloud optical depth τ, effective particle radius re, and thermodynamic phase. For typical values of τ and re, the effect of increasing the ice fraction of the total optical depth is to flatten the slope of Tb(ν) between 800–1000 cm−1. For optically thin clouds (τ ∼ 3) and larger ice particles (re (ice) > 50 μm) the behavior of Tb(ν) in this interval switches from a decrease with increasing wavenumber ν to an increase with ν, once the ice fraction of the total optical depth exceeds ∼0.7. The FTIR spectra alone cannot be interpreted to obtain thermodynamic phase, because a relatively small slope in Tb(ν) between 800–1000 cm−1 could represent either an optically thin cloud in the ice or mixed phase, or an optically thick cloud radiating as a blackbody. Sky observations and ancillary radiometric data are needed to sort the FTIR spectra into categories of small cloud optical depth, where the mid‐IR window data can be interpreted; and larger cloud optical depth, where the FTIR data contain information only about cloud base temperature. Spectral solar ultraviolet (UV) irradiance measurements from the U.S. National Science Foundation's UV Monitor at Palmer Station are used to estimate area‐averaged effective cloud optical depth τsw, and these estimates are used to sort the FTIR data. FTIR measurements with colocated τsw < 16 are interpreted to estimate cloud thermodynamic phase. Precipitating cloud decks generally show flatter slopes in Tb(ν), consistent with the ice or mixed phase. Altostratus decks show a larger range in Tb(ν) slope than low cloud decks, including increasing slopes with ν, suggesting a more likely occurrence of the ice phase. This study illustrates how cloud thermodynamic phase can be defensibly retrieved from FTIR data if high quality shortwave radiometric data are also available to sort the FTIR measurements by cloud opacity, and both data types are available at the ARM sites.
Surface radiative forcing by soil dust aerosols and the hydrologic cycle
Authors: Miller R. L. , Tegen I. , Perlwitz Jan
Published: February 2004

For absorbing aerosols like soil (or “mineral”) dust, radiative forcing at the surface differs substantially from the value at the top of the atmosphere (TOA). The climate response depends not only upon the TOA forcing, but its difference with respect to the surface value, which represents radiative heating within the atmosphere. Surface forcing alters evaporation and the hydrologic cycle, which feeds back upon the aerosol burden through the efficiency of wet deposition. We calculate the surface forcing by soil dust aerosols and its global sensitivity by varying aspects of the dust distribution that are poorly constrained by observations. Ignorance of the global dust burden corresponds to a forcing uncertainty of over a factor of two, with smaller uncertainties due to imprecise knowledge of particle optical properties and the particle size distribution. While global evaporation and precipitation are reduced in response to surface radiative forcing by dust, precipitation increases locally over desert regions, so that dust emission can act as a negative feedback to desertification. The effect of the global reduction in precipitation is to lengthen the particle lifetime by reducing the efficiency of wet deposition, representing a positive feedback upon the global dust burden. For the current climate, we calculate the reduction in wet deposition by dust radiative forcing and find that the aerosol burden is increased only modestly. However, the global dust burden and associated radiative forcing are substantially higher during glacial climates, so that the amplification of the dust load by this feedback is larger. By extrapolating from its radiative forcing in the current climate, we estimate that dust reduces precipitation during glacial times by as much as half the reduction due to the colder climate alone.
SO42− minimum in summer snow layer at Dome Fuji, Antarctica, and the probable mechanism
Authors: Iizuka Yoshinori , Fujii Yoshiyuki , Hirasawa Naohiko , Suzuki Toshitaka , Motoyama Hideaki , Furukawa Teruo , Hondoh Takeo
Published: February 2004

By chemically analyzing snow samples at Dome Fuji, Antarctica, we found that the snowdrift deposited just after snowfall and the snow layer down to 3.4 m have summer minima in the non‐sea‐salt (nss)‐SO42− and Na+ concentrations and summer maxima of Cl−/Na+. Such a summer nss‐SO42− minimum in either snowdrift or the snow layer has not been reported at any other site in Antarctica and arises in spite of the known maximum in the nss‐SO42− concentration in aerosol at Dome Fuji in summer. We then did laboratory experiments to better understand the phenomenon. The results supported the following mechanism for the summer nss‐SO42− minimum in the snowdrift and snow layer. In summer, water vapor sublimates from within the snow in the daytime and condenses on the surface as frost in the nighttime, resulting in a dilution of the nss‐SO42− concentration. This sublimation‐condensation process likely occurs at other cold inland regions. In addition, the results might be useful for obtaining a high‐resolution dating method for Dome Fuji deep ice cores by counting the number of layers with low nss‐SO42− concentration.
A simple two‐dimensional inversion technique for imaging homogeneous targets in stratified media
Authors: Catapano Ilaria , Crocco Lorenzo , Isernia Tommaso
Published: February 2004

The problem of reconstructing in a quantitative fashion dielectric objects embedded in a layered medium with possibly (unknown) rough interfaces is dealt with. In particular, a nonlinear inverse scattering technique is proposed as a suitable tool for giving an accurate imaging of homogenous targets. The proposed approach, which exploits multifrequency data, is not limited to the weak scattering case. Moreover, a simple method is proposed so that simultaneous reconstruction of both unknown permittivity and roughness profile can be performed. In order to assess effectiveness and accuracy of the proposed approach under actual field conditions, a small number of antennas placed on a short measurement line is considered. A large number of numerical simulations confirm the effectiveness of the inversion approach, as well as its robustness with respect to noise on data and approximate knowledge of background parameters.
Effects of Space Weather on Technology Infrastructure
Authors: Baker D. N. , Daly Eamonn , Daglis Ioannis , Kappenman John G. , Panasyuk Mikhail
Published: February 2004

An interdisciplinary NATO Advanced Research Workshop on Effects of Space Weather on Technology Infrastructure (ESPRIT) was held in Rhodes, Greece, on 25‐29 March 2003, bringing together internationally renowned experts from the physics, engineering, and application/user communities to review and assess the current knowledge on space weather dynamics and its technological and societal consequences.
Large‐eddy simulation of neutral atmospheric boundary layer flow over heterogeneous surfaces: Blending height and effective surface roughness
Authors: Bou‐Zeid Elie , Meneveau Charles , Parlange Marc B.
Published: February 2004

A new generation large‐eddy simulation (LES), based on a Lagrangian scale‐dependent dynamic subgrid model, is applied to neutral atmospheric flow over heterogeneous land surfaces. This LES is faithful to the physics of the interaction of the lower atmosphere and the land surface based on classical validation tests of the simulated mean wind profile and the atmospheric turbulence. Simulations of the atmospheric boundary layer (ABL) over heterogeneous land surfaces with a range of characteristic lengths and surface roughness values are performed, each simulated surface consisting of equal‐size stripes of different roughness. The simulated mean wind profiles are analyzed to identify the height of the blending layer and used to develop a relationship between blending layer height and characteristic surface length scales. For hydrologic and atmospheric applications where the regional‐scale surface roughness needs to be known, the analysis is extended to derive an effective surface roughness knowing local surface patch roughness values.
Space‐time scaling in high‐intensity Tropical Ocean Global Atmosphere Coupled Ocean‐Atmosphere Response Experiment (TOGA‐COARE) storms
Authors: Deidda Roberto , Badas Maria Grazia , Piga Enrico
Published: February 2004

A scale‐invariance analysis of rainfall retrieved during the Tropical Ocean Global Atmosphere Coupled Ocean‐Atmosphere Response Experiment (TOGA‐COARE) campaign is discussed. As already found in the previous Global Atmospheric Research Program (GARP) Atlantic Tropical Experiment (GATE) rainfall data set, these new analyses of high‐intensity storms confirm the evidence of scale invariance under self‐similar space‐time transformations. A simple interpretation of this space‐time self‐similarity accounting for the hierarchical organization of precipitation patterns is proposed. Finally, a downscaling model based on a log‐Poisson generator is calibrated on the results of the multifractal analysis and applied to the generation of synthetic fields, reproducing observed statistical properties over a wide range of space scales and timescales.
Conserved selenoprotein synthesis is not critical for oxidative stress defence and the lifespan of Drosophila
Authors: Hirosawa‐Takamori Mitsuko , Chung Ho‐Ryun , Jäckle Herbert
Published: February 2004

Selenoprotein synthesis is conserved from bacteria to man. It involves the differential decoding of the UGA stop codon as selenocysteine. The proteomes of both prokaryotes and eukaryotes, with the exception of yeast, contain only few selenoproteins. This low number is explained by a counterselection of readily oxidized selenocysteine after the introduction of oxygen into the atmosphere and the need to conserve selenoenzymes that control redox homeostasis of cells. Lack of selenoprotein synthesis in vertebrates impairs the oxidative stress defence and causes lethality. Here we show that Drosophila mutants that lack the translation elongation factor SelB/eEFsec fail to decode the UGA codon as selenocysteine, but they are viable and fertile. Oxidative stress responses and the lifespan of these flies are not affected. Protecting cells from oxidative stress can therefore not account for the selection pressure that conserves selenoprotein biosynthesis during the course of evolution.
A short synthetic peptide inhibits signal transduction, migration and angiogenesis mediated by Tie2 receptor
Authors: Tournaire Roselyne , Simon Marie‐Pierre , Noble Ferdinand le , Eichmann Anne , England Patrick , Pouysségur Jacques
Published: February 2004

Tie2, an endothelial cell‐specific receptor kinase, has an important role in tumour angiogenesis. In an attempt to identify peptides that specifically interact with and block the Tie2 pathway, a phage‐displayed peptide library was screened on a recombinant Tie2 receptor. One peptide, NLLMAAS, completely abolished the binding to Tie2 of both angiopoietin 2 and angiopoietin 1 (Ang1). We further show that NLLMAAS specifically suppresses both Ang1‐induced ERK activity and migration in human umbilical endothelial cells. Moreover, in vivo, this peptide inhibits angiogenesis in the chick chorioallantoic membrane assay. NLLMAAS is the first peptide described to interact with Tie2. Our results demonstrate that it is an efficient and specific antagonist of the binding of Tie2 ligands, and suggest that this peptide or its derivates may have potential applications in the treatment of angiogenesis diseases. It also represents a potent tool to dissect the molecular mechanisms involved in the Tie2 pathway.
Do Taq‐generated RT‐PCR products from RNA viruses accurately reflect viral genetic heterogeneity?
Authors: Mullan B. , Sheehy P. , Shanahan F. , Fanning L
Published: February 2004

Summary.  Since the first report of genetically heterogeneous, or quasispecies, populations of RNA viruses, the genetic heterogeneity of the RNA genomes of major viral pathogens has been extensively studied. These studies aim to provide insights into the evolutionary pressures that act upon viruses, in order to define windows where anti‐viral therapies will be most effective, to take prognostic values from viral genetic distributions at a given time, and to aid the development of novel therapeutic compounds that may tilt viral replication towards information loss.

Many methodologies are employed to analyse genetic distributions of a virus in a given sample, but all involve the generation, and subsequent analysis, of the sequence information contained in a reverse‐transcription‐polymerase chain reaction (RT‐PCR) product. Despite the fact that the aim of these RT‐PCRs is to obtain sequence information from viral genomes, their application to this task is approached without adequate consideration of this end‐goal. The establishment of an RT‐PCR for a specific viral target genome generally proceeds in the same fashion as one would apply to establishing a PCR to determine the presence or absence of a specific target sequence in a given sample. However, it is becoming increasingly apparent that RT‐PCR products generated by amplification with the ubiquitous thermostable DNA polymerase Taq, coupled with standard cloning and sequencing methodologies, has the potential to yield inaccurate and misleading data as pertains to the information content of populations of RNA viral genomes. This review discusses varying approaches employed to analyse heterogeneous populations of hepatitis C virus RNA genomes.
Secondary structure and hybridization accessibility of the hepatitis C virus negative strand RNA 5′‐terminus
Authors: Smith R. M. , Wu G. Y.
Published: February 2004

Summary.  The positive strand RNA genome of hepatitis C virus (HCV) is transcribed exclusively from a full‐length cytoplasmic replication intermediate, the negative strand RNA. Despite this essential role in hepatocellular infection, the negative strand has not yet been subjected to extensive molecular characterization, and in comparison with the HCV genome and proteome, remains relatively unexplored as a target for antiviral therapy. The highly conserved negative strand terminal sequences, complementary to the positive strand 5′‐ and 3′‐untranslated regions, are believed to contribute structural features essential for the initiation of positive strand synthesis and the maintenance of template integrity. We investigated the solution structure of the HCV negative strand 5′‐terminal region by endoribonuclease mapping and thermodynamic modelling of RNA secondary structure. The enzymatic probing data are consistent with structural models featuring a large terminal stem loop (SL), which constitutes a mirror image of the complementary 3′‐X region SL I structure. Nucleotide positions within the negative strand accessible to hybridization were mapped by RNase H digestion in the presence of combinatorial oligonucleotide libraries. The hybridization data further support the existence of a terminal SL, and reveal target sites within the negative strand 5′‐terminus which may be susceptible to antisense‐mediated inhibition.
Type I interferon receptor and response to interferon therapy in chronic hepatitis C patients: a prospective study
Authors: Fujiwara D. , Hino K. , Yamaguchi Y. , Kubo Y. , Yamashita S. , Uchida K. , Konishi T. , Nakamura H. , Korenaga M. , Okuda M. , Okita K.
Published: February 2004

Summary.  The type I interferon (IFN) receptor consists of at least two subunits, IFNAR1 and IFNAR2. We previously found a correlation between IFNAR1 and IFNAR2 expression in liver, and a correlation in IFNAR2 expression, but not in IFNAR1, between liver and peripheral blood mononuclear cells (PBMCs). The aim of this study was to prospectively assess whether IFNAR2 expression levels in PBMCs as well as in liver act as markers for predicting response to IFN therapy in chronic hepatitis C patients. Fifty‐two Japanese patients with chronic hepatitis C, were enrolled. IFNAR2 mRNA was quantified using competitive polymerase chain reaction, in liver and PBMC specimens, and of the 52 patients assigned to receive a 6‐month course of interferon‐α therapy, 36 patients who received more than 300 million units of interferon were analysed. IFNAR2 mRNA expression levels were significantly higher in liver than in PBMCs in all 36 patients (P = 0.016). Seventeen sustained virologic responders showed lower pretreatment hepatitis C virus (HCV)‐RNA levels (P = 0.017) in serum and higher pretreatment levels of IFNAR2 mRNA in liver (P = 0.007), but not in PBMCs, compared with nonsustained virologic responders. In multivariate analysis, these factors were independently associated with a sustained virologic response (i.e. HCV‐RNA level: odds ratio 0.23, 95% CI 0.038–0.864; and IFNAR2 in liver: odds ratio 1.116, 95% CI 1.015–1.227). Hence, IFNAR2 expression levels in liver, but not in PBMCs, is predictive of response to IFN treatment in chronic hepatitis C patients.
Lamivudine prophylaxis for prevention of chemotherapy‐induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies
Authors: Idilman R. , Arat M. , Soydan E. , Törüner M. , Soykan İ. , Akbulut H. , Arslan Ö. , Özcan M. , Türkyilmaz A. R. , Bozdayı M. , Karayalçın S. , Van Thiel D. H. , Özden A. , Beksaç M. , Akan H.
Published: February 2004

Summary.  Although hepatitis B virus (HBV) reactivation in HBV carriers undergoing immunosuppressive therapy is clearly documented, the role of antiviral prophylaxis in such individuals is still controversial. The aim of this study was to determine the efficacy of lamivudine prophylaxis in HBV carriers with haemato/oncological malignancies, who receive chemotherapy. Eighteen HBV carriers with malignancy, who were candidates for chemotherapy, were enrolled. Eight subjects (three with leukaemia, four with lymphoma and one with multiple myeloma) were enrolled for prophylactic lamivudine therapy. The remaining 10 patients (six with leukaemia, three with lymphoma and one with breast cancer) were not treated with lamivudine and were used as a control. Lamivudine was administered beginning on the same day as the chemotherapy and was maintained for a year after chemotherapy was discontinued. No HBV‐related mortality was observed in either group. In the lamivudine‐treated group, none of the subjects had clinical, biochemical or serological evidence of HBV reactivation during the time they were receiving chemotherapy and after their chemotherapy was discontinued. In contrast, five of the 10 HBV carriers not receiving lamivudine therapy experienced a reactivation of HBV infection. This reactivation of HBV was observed during the chemotherapy in four with one individual experiencing a HBV activation 12 months after chemotherapy was discontinued. No lamivudine‐related major adverse effects were observed. Hence prophylactic lamivudine treatment in HBV carriers with haemato/oncological malignancy receiving chemotherapy prevents chemotherapy‐induced HBV reactivation.
Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as well as virological responses by preventing liver‐related death
Authors: Kasahara A. , Tanaka H. , Okanoue T. , Imai Y. , Tsubouchi H. , Yoshioka K. , Kawata S. , Tanaka E. , Hino K. , Hayashi K. , Tamura S. , Itoh Y. , Kiyosawa K. , Kakumu S. , Okita K. , Hayashi N.
Published: February 2004

Summary.  Interferon therapy for chronic hepatitis C reduces the risk of hepatocellular carcinoma, especially among virological and biochemical responders. However, little is known about the effect of interferon therapy on mortality. We studied the long‐term effect of interferon therapy on mortality in patients with chronic hepatitis C. For this retrospective cohort study, 2954 patients with chronic hepatitis C were recruited, of whom 2698 received interferon therapy and 256 did not. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality data for the general Japanese population and by risk ratio calculated by proportional hazard regression. Over 6.0 ± 2.2 years follow‐up, death from liver‐related diseases was observed in 69 (68%) of 101 deaths among interferon‐treated patients and in 42 (81%) of 52 deaths among untreated patients. Compared with the general population, overall mortality was high among untreated patients (SMR: 2.7; 95% CI: 2.0–3.6) but not among interferon‐treated patients (SMR: 0.9; 95% CI: 0.7–1.1). Liver‐related mortality was extremely high among untreated patients (SMR: 22.2; 95% CI: 16.0–30.0) and less among interferon‐treated patients (SMR: 5.5; 95% CI: 4.3–6.9). The risk of death from all causes was lower for interferon‐treated than untreated patients (risk ratio: 0.47; 95% CI: 0.261–0.836; P = 0.01). The risk of death from liver‐related diseases was significantly lower for sustained virological responders (risk ratio: 0.04; 95% CI: 0.005–0.301; P = 0.002) compared with untreated patients, but not for nonsustained virological responders. Sustained biochemical responders (risk ratio: 0.03; 95% CI: 0.004–0.230; P < 0.001) and transient biochemical responders (risk ratio: 0.18; 95% CI: 0.063–0.532; P = 0.002) showed a significantly reduced risk of death from liver‐related death, whereas biochemical nonresponders did not. Hence interferon treatment improved survival in chronic hepatitis C patients showing a biochemical as well as a virological response by preventing liver‐related deaths.
Comparison of quality of life, work productivity and medical resource utilization of peginterferon alpha 2a vs the combination of interferon alpha 2b plus ribavirin as initial treatment in patients with chronic hepatitis C
Authors: Perrillo R. , Rothstein K. D. , Rubin R. , Alam I. , Imperial J. , Harb G. , Hu S. , Klaskala W.
Published: February 2004

Summary.  The on‐treatment impact of interferon‐based therapies on quality of life (QOL), work productivity, and medical resource utilization has not been systematically studied. We evaluated the effects of treatment with peginterferon alpha (pegIFNα) 2a monotherapy and the combination of interferon alpha (IFNα) 2b plus ribavirin (RBV) on health‐related QOL, work productivity and resource utilization. A total of 412 patients with hepatitis C infection were randomized to open‐label treatment with either pegIFNα 2a (n = 206) or IFNα 2b/RBV (n = 206). PegIFNα 2a was administered subcutaneously at a dose of 180 μg once weekly for 48 weeks; and IFNα 2b/RBV at doses of 3 MU thrice weekly subcutaneously and 1000–1200 mg/day orally. Outcome measures included the SF‐36 Health Survey Questionnaire and additional generic and specific scales. During treatment, for all SF‐36 summary and Hepatitis Quality of Life Questionnaire (HQLQ)‐specific scales, the pegIFNα 2a group experienced less impairment than did the IFNα 2b/RBV patients. The between‐treatment differences were significant for many of the scores particularly in the first 24 weeks of treatment. Across all measures of work functioning and productivity at each visit, patients randomized to pegIFNα 2a treatment showed less impairment relative to the group treated with IFNα 2b/RBV. Hence treatment with pegIFNα 2a relative to IFNα 2b/RBV minimizes the adverse impact of therapy on health‐related QOL. Patients randomized to pegIFNα 2a had improved work productivity, less activity impairment, decreased need for prescription drugs to treat adverse effects, and better adherence to therapy.
Improving the accuracy of long‐term prognostic estimates in hepatitis C virus infection
Authors: Yi Q. , Wang P. P. , Krahn M.
Published: February 2004

Summary.  Obtaining unbiased estimates of HCV prognosis is difficult because of potential biases associated with study design and calculation methods. We propose a new method for estimating fibrosis progression rates. A Markov model with fibrosis health states (F0–F4) was created. The maximum likelihood method was used to estimate stage‐specific progression rates. We compared the standard method to the new method using two well‐known cohort studies. The known stage distribution at the end of follow‐up was compared with stage predicted by the Markov model using both methods of calculating transition rates. We also compared rates obtained using both methods to known fibrosis rates in a series of Monte Carlo simulations. For Kenny‐Walsh's study (1999), transition rates between F0–F1, F1–F2, F2–F3, and F3–F4 were 0.042, 0.045, 0.097 and 0.070 fibrosis units/year (new method) and 0.045 units/year (standard method). The new method predicted fibrosis stage and known transition rates in Monte Carlo simulations more accurately. The standard method underestimates 30‐year cirrhosis rates by up to 40%. The new (Markov maximum likelihood or MML) method allows accurate estimation of stage‐specific transition probabilities from the many studies in which only a single biopsy is available. Application of the method supports the hypothesis that rates of fibrosis vary between stages.
Dynamic analysis of hepatitis B virus DNA and its antigens in 2.2.15 cells
Authors: Liu M.‐C. , Yu M. , Zhang N.‐L. , Gong W.‐B. , Wang Y. , Piao W.‐H. , Wang Q.‐H. , Wang G.‐Q.
Published: February 2004

The 2.2.15 cells‐derived from HepG2 cells transfected with a plasmid containing hepatitis B virus (HBV) DNA secrete surface antigen (HBsAg) particles, nucleocapsids and virions (Proc Natl Acad Sci U S A 1987; 84: 1005–1009). The latter elicit acute hepatitis in chimpanzees (Proc Natl Acad Sci U S A 1987; 84: 4641–4644). We studied the presence of intracellular and extracellular HBV covalently closed circular (ccc) DNA in this culture system by polymerase chain reaction (PCR), kinetically analysed HBsAg and hepatitis B e antigen (HBeAg) released in the culture media by quantitative enzyme‐linked immunosorbent assay and quantitated by real‐time PCR but HBV DNA from intracellular and extracellular HBV‐DNA. HBV cccDNA was found both intracellularly and extracellularly. A significant correlation was seen between the extracellular HBV DNA levels and virus antigens (r = 0.833; P = 0.01 and r = 0.939; P < 0.01 for HBsAg and HBeAg, respectively), whereas there was no statistical correlation between intracellular HBV DNA levels and virus antigen levels (r = 0.024; P = 0.955 and r = 0.177; P = 0.625 for HBsAg and HBeAg, respectively). These data would be valuable in studies of the HBV life cycle and of potential anti‐viral agents.
Expression of FasL and perforin/granzyme B mRNA in chronic hepatitis B virus infection
Authors: Lee J. Y. , Chae D. W. , Kim S. M. , Nam E. S. , Jang M. K. , Lee J. H. , Kim H. Y. , Yoo J. Y.
Published: February 2004

Summary.  Cytotoxic T lymphocytes are essential components of immune responses during chronic hepatitis B (CHB). It has been known that Fas ligand (FasL) and perforin/granzyme B‐based mechanisms account for all T cell‐mediated cytotoxicity. In the present work, we examined the correlation between injury of the hepatocytes and mRNA expression of FasL and perforin/granzyme B in liver tissue to investigate the roles of both the FasL and the perforin/granzyme B pathways in CHB. Reverse transcription‐polymerase chain reaction was used to identify intrahepatic expression of FasL and perforin/granzyme B in liver biopsy specimens from 24 patients with hepatitis B virus (HBV) infection. In addition, the transferase‐mediated deoxyuridine triphosphate nick end‐labelling (TUNEL) method was used to determine the degree of apoptosis. The degree of mRNA expression and apoptosis were compared with the histologic activity index (HAI) and serology, including alanine aminotransferase (ALT). Intrahepatic mRNA expression rates of FasL, perforin and granzyme B were seen in 79.2, 62.5 and 33.3% of patients, respectively, and correlated with ALT levels (P < 0.05). Intrahepatic expression of FasL and perforin mRNA were significantly correlated with HAI (P < 0.05). Also, apoptosis documented by the TUNEL assay was correlated with HAI and intrahepatic mRNA expression of FasL and perforin (P < 0.05). Our results show that the T‐cell mediated perforin death pathway as well as the Fas system play important roles in liver cell injury in HBV infection and that apoptosis mediated by the Fas/FasL system is closely correlated with HAI in chronic HBV infection.
Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C
Authors: Lebray P. , Zylberberg H. , Hue S. , Poulet B. , Carnot F. , Martin S. , Chretien Y. , Pol S. , Caillat‐Zuckman S. , Bréchot C. , Nalpas B.
Published: February 2004

Summary.  We analysed liver histology findings in a large cohort of patients with chronic hepatitis C and in roughly half of them their response to interferon‐α‐based on iron parameters and HFE status. Histological activity and virological response to antiviral therapy (n = 146) were analysed in 273 immunocompetent and nonalcoholic patients with chronic hepatitis C, in terms of serum iron load, intrahepatic iron load (n = 110) and HFE mutations. Patients who were heterozygous for the C282Y and H63D mutations exhibited higher iron serum parameters than subjects without these mutations. The intrahepatic iron load was higher in H63D patients only. No association was observed between HFE mutations and histological activity. Increased iron parameters were associated with liver disease severity by univariate analysis only. Genotype 1 and ferritinaemia were associated with a poor response to antiviral therapy, whereas the H63D mutation emerged as a positive predictive factor for end of treatment and sustained antiviral response. Therefore, in chronic hepatitis C patients serum and intrahepatic iron levels were weakly correlated with histological activity, while HFE mutations were not. As for the response to interferon‐α, elevated ferritinaemia constituted a negative predictive factor whereas the H63D mutation was a positive one. The H63D mutation might form part of an immunogenetic profile influencing the response to interferon therapy.
Living in towers as risk factor of pollen allergy
Authors: Armentia A. , Asensio T. , Subiza J. , Arranz M. L. , Gil F.‐J. Martín , Callejo A.
Published: February 2004

Background:  The effects of fluctuations in pollen counts have important implications for health services. Little research on the clinical implications of the vertical distribution of pollen in allergy symptoms has been carried out.

Methods:  We have investigated the allergic symptoms of a population of 17 171 patients coming from our health area (Valladolid, Spain) and living in the city and villages. We compared the prevalence of sensitization to different pollens: Graminae, trees and shrub in relation with the floor of the building where they were living.

Results:  Relative risk of pollen sensitization (confidence index, CI 95%) was higher in patients who were living at high floors than in those patients who were living in lower floors or at street level, independently of rural or urban conditions The chi‐square showed a lineal trend in this relationship in the case of sensitization to grass pollen: χ2: 1794, P > 0.00001

Conclusions:  On the basis of our local investigations, natural pollen sensitization appears to increase with height where the patient lives. This paper reports clinical results on the influence of vertical pollen distribution in pollen allergy.
Developing the BALANCE trial – the role of the pilot study and start‐up phase
Authors: Rendell Jennifer M , Juszczak Ed , Hainsworth Jane , Gucht Emma Van der , Healey Christine , Morriss Richard , Ferrier Nicol , Young Allan H , Young Heather , Goodwin Guy M , Geddes John R
Published: February 2004

Objectives:  The initial design of the BALANCE (Bipolar Affective disorder: Lithium / ANtiConvulsant Comparative Evaluation) Trial of maintenance treatment for bipolar disorder was based on the experience of previous trials in bipolar disorder and psychiatry and on the methods developed for large randomized trials in other areas of medicine. This report describes the adaptations to the initial design and trial procedures following the initial phases of the study. The rationale for the trial and full protocol have been published elsewhere.

Methods:  A pilot study and start‐up phase were used to check the tolerability of the interventions, refine the trial design and develop trial procedures that are acceptable to both clinicians and patients.

Results:  Changes to the procedures included: the dropping of masking of allocated treatment from clinicians and participants; introduction of the use of postal delivery to supply medication; and dispensing with the proposed schedule of regular follow up appointments. In addition, support was made available to participating psychiatrists who often had limited experience of participating in randomized trials.

Conclusions:  Pilot studies and start‐up phases are essential to refine clinical trial design and allow development of procedures that are both methodologically rigorous and flexible and robust enough to promote recruitment and follow up. BALANCE is now actively recruiting in the UK and USA.