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We report results on the ROSAT-discovered noneclipsing short-period polars RX J0154.0-5947, RX J0600.5-2709, RX J0859.1+0537, RX J0953.1+1458, and RX J1002.2-1925 collected over 30 years. We present accurate linear orbital ephemerides that allow a correct phasing of data taken decades apart. Three of the systems show cyclotron and Zeeman lines that yield magnetic field strengths of 36 MG, 19 MG, and 33 MG for the last three targets, respectively. RX J0154.0-5947, RX J0859.1+0537, and RX J1002.2-1925 show evidence for part-time accretion at both magnetic poles, while RX J0953.1+1458 is a polar with a stable one-pole geometry. RX J1002.2-1925 shows large variations in the shapes of its light curves that we associate with an unstable accretion geometry. Nevertheless, it appears to be synchronized. We determined the bolometric soft and hard X-ray fluxes and the luminosities at the Gaia distances of the five stars. Combined with estimates of the cyclotron luminosities, we derived high-state accretion rates that range from $\dot M = 2.9 \times 10^{-11}$ $M_{\odot}$yr$^{-1}$ to $9.7 \times 10^{-11}$ $M_{\odot}$yr$^{-1}$ for white dwarf masses between 0.61 and 0.82 $M_\odot$, in agreement with predictions based on the observed effective temperatures of white dwarfs in polars and the theory of compressional heating. Our analysis lends support to the hypothesis that different mean accretion rates appply for the subgroups of short-period polars and nonmagnetic cataclysmic variables., Comment: 24 pages, 11 figures, and 13 tables, accepted for publication in A&A

— Six patients with chronic hepatitis B virus (HBV)-induced liver disease were treated with human lymphoblastoid interferon. Daily, alternate day or thrice weekly regimens were employed in two, one and three patients respectively. Thrice weekly intra-muscular injections of 7.5 to 10 megaunits of interferon/m2 appeared to be as effective as daily injections in producing inhibition of HBV replication, were associated with fewer side effects and could be continued for up to 3 months. The effectiveness of this regimen in producing long-term inhibition of viral replication must now be determined.

The radial distribution of dust and gas in 38 nearby galaxies is investigated, using a sample of galaxies for which matched resolution (25 arcsec) neutral hydrogen (H i) and 850-μm images are available. Most of these radial profiles are fitted well by an exponential model, and the derived 850-μm scalelengths are proportional to the H i scalelengths. From this relation, it is found that the metallicity gradients of these galaxies are much shallower than previous studies, unless the dust temperature is constant within the disc, or a significant component of molecular gas exists at large radii that is not traced by CO observations.

We present Very Large Array (VLA) C-array 21-cm H i images of galaxies from the SCUBA Local Universe Galaxy Survey which have been observed at 850 μm with the James Clerk Maxwell Telescope. Matched-resolution (∼ 25 arcsec) H i images of 17 galaxies are presented and compared with 850-μm images. H i or 850-μm images of an additional six galaxies which were detected at only one wavelength are presented. Additionally, lower resolution H i observations of nine galaxies are presented. The observations of these galaxies, along with results previously presented, do not show any obvious trends in the H i/dust or H2/dust mass ratios with morphological type.

We present the results of a combined analysis of low-resolution spectroscopy and high-speed optical photometry of the bright eclipsing polar HU Aqr, obtained in its high accretion state. Cyclotron harmonic emission in a field of $B\simeq 34$ MG became evident and could be traced through the whole optical bright phase. The cyclotron harmonics display an asymmetric motion as a function of phase which requires a certain forward tilt of the magnetic field lines in the emission region. The optical bright phase is more extended than the bright phase in soft X-rays suggesting a more extended emission region. Also, ingress into and egress from the optical eclipse last much longer in the optical than at X-ray wavelengths. These observations require the existence of an accretion arc with total extent of about 20°. The soft X-ray accretion spot is located at the far end of the arc, where the bulk of matter is accreted. The arc is likely to be more extended than the foot-line of field lines connecting to the ballistic accretion stream in a dipolar geometry. This together with the required tilt of the accreting field lines suggest a more complex magnetic geometry than a simple dipole.

We present matched-resolution VLA H i and SCUBA 850-μm maps of 20 IRAS-bright galaxies. Of the galaxies observed, two were not detected in H i and two were detected in absorption. The H i distributions of the galaxies have a range of morphologies. Some of the systems appear H i deficient in the central regions which could be due to a high conversion rate of H i into molecules or H i absorption. In contrast to the H i, the 850-μm emission has a smooth distribution which is concentrated towards the optical centre of each galaxy. We also find evidence for 850-μm emission extending to the periphery of the optical disc in some of the galaxies. Finally, we note that the relative lack of 850-μm emission when compared with H i does not necessarily mean that the atomic gas and dust do not have similar mass distributions.

We present ROSAT All-Sky Survey and ROSAT pointed observations (PSPC and HRI) of a complete sample of 113 bright soft X-ray AGN selected from the ROSAT Bright Source Catalog. We compare these observations in order to search for extreme cases of flux and spectral X-ray variability - X-ray transient AGN. Three definite transients and one transient candidate are found. The other sources show amplitude variations typically by factors of 2-3 on timescales of years. We found that the variability strength on timescales of days is a function of the steepness of the X-ray spectrum: steeper X-ray objects show stronger variability than flat X-ray spectrum sources. We also present new HRI measurements of our extreme X-ray transients IC 3599 and WPVS007. We discuss possible models to explain the X-ray transience and the variabilities observed in the non-transient sources., Comment: 17 pages (including 7 Figures), accepted for in A&A (main journal), also available at http://www.xray.mpe.mpg.de/~dgrupe/research/refereed.html

In the monocrotaline (MCT) model of pulmonary hypertension, the pulmonary vascular endothelium is the likely early target of the reactive metabolite monocrotaline pyrrole (MCTP). Incubation of cultured bovine pulmonary arterial endothelial cells (BPAEC) with MCTP results in covalent binding to DNA, cell cycle arrest, and delayed but progressive cell death. The mode of cell death in MCTP-induced endothelial damage has not been addressed previously. Since DNA damage is frequently associated with apoptosis, the presence or absence of apoptosis in adherent BPAEC was determined by several techniques, including morphologic and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling. Two concentrations of MCTP (5 and 34.5 microgram/ml) along with a vehicle control were examined with each assay. Both concentrations of MCTP induced increasing numbers of cells to undergo apoptosis over time beginning as early as 6 h after exposure to MCTP in the high concentration group. Control and vehicle control cells exhibited small amounts of apoptosis (1-2%), which did not change over the duration of the experiment. Additionally, cell membrane integrity was assessed over time by either exposure to membrane-impermeant dyes or measuring LDH release. By either method, BPAEC had increased membrane permeability after about 48 h of either low or high concentration MCTP exposure. We conclude that both a low or high concentration of MCTP causes cell death in BPAEC by inducing apoptosis.

The southern dwarf nova EK TrA has been suggested to show the spectrum of its white dwarf primary in the single available International Ultraviolet Explorer (IUE) post-outburst spectrum. We demonstrate that this spectrum is still disc-dominated. However, a careful analysis reveals a white dwarf contribution of -25 per cent of the SWP flux and a white dwarf temperature of T wd = 18 000 K. Our optical spectroscopy of the system deep in quiescence confirms the flux level of the white dwarf derived from the IUE data. Additional optical emission arises from a cool (T = 6500 K) accretion disc, possibly extending over the whole Roche lobe radius of the primary. Both optical and UV data yield a distance of d = 180pc.

The ROSAT All Sky Survey (RASS) was the first one performed with an imaging telescope in the soft X-ray regime and has led to the discovery of numerous new objects whose emission is dominated by soft X-rays. Among these are white dwarfs and a subclass of the cataclysmic variables (CVs), the Polars or AM Herculis binaries. From a pre-ROSAT census of only 17, the number of known sources of this class has increased to some 55 (Beuermann and Thomas 1993, Beuermann 1997). Distances or lower limits to the distance are available for some 35 of these, based on the detection or non-detection of the TiO-Features in their optical red spectra. The derived distances range from below 100 pc up to ~ 600 pc, implying that many of these objects are located within the “Local Bubble” of low gas density in interstellar space. As the soft X-ray emission can be reasonably well represented by blackbody emission with a typical temperature of kTbb ≃ 25 eV, spectral fits to the ROSAT PSPC spectra from either the All-Sky-Survey (RASS) or from subsequent pointed ROSAT observations allow to determine the foreground absorption column density in the direction of the polars.

Hepatitis B virus (HBV) replicates via an intermediate RNA step. High frequency of polymerase errors with additional selection pressure leads to mutations in the HBV genome. We investigated the number, type, and antigenic effects of mutations in the coding region of the HBV surface antigen in eight patients who underwent orthotopic liver transplantation (OLT) for HBV-related end-stage liver disease and were experiencing infection of the graft and who received hepatitis B surface antigen antibody (anti-HBs) prophylaxis (hepatitis B immune globulin [HBIG]) after OLT. Controls were chronic HBV patients who underwent kidney transplantation and received the same immunosuppressive regime but no HBIG. The S-gene was amplified from serum before and after transplantation, sequenced, and changes in the genome were analyzed. In the five patients who experienced reinfection while receiving anti-HBs, clear mutations occurred in the S-gene. In the patient who did not receive HBIG and those who experienced reinfection only after termination of HBIG, no mutations were found in the S-gene. In the kidney recipients, mutations in the S-gene occurred in only one of eight patients. Because the a determinant contains neutralizing epitopes, this region was chosen for antibody binding to quantify antigenic effects of the mutations. The two patients who selected mutations in the a determinant and became reinfected while receiving HBIG had reduced antibody binding after OLT. Our results suggest that HBIG after OLT imposes a selection pressure on the S-gene, and that mutations are one mechanism for reinfection while receiving HBIG.

The presence of unique hepatitis B virus (HBV) variants has been investigated in two Chinese patients with chronic liver disease, whose sera were positive for HBV-DNA by dot blot hybridization or polymerase chain reaction (PCR) but hepatitis B surface antigen (HBsAg)-negative by conventional polyclonal antibody based immunoassays. PCR amplification of HBV-DNA followed by direct sequencing showed an insertion of six nucleotides, which introduced two additional amino acids between codons 122 and 123 in one patient (Isolate 1), whereas a nine nucleotide insertion in the other patient (Isolate 2) gave rise to three amino-acids between codons 123 and 124 immediately upstream from the 'a' determinant in the S gene. These insertions have not been described previously in any published sequences of the known subtypes and were absent from sequences of 30 HBsAg-positive Chinese patients from the same region. In the cases under study, the insertion is associated with four consecutive adenine molecules from nucleotides 516 to 519. It seems likely that this area is a hot spot for insertions in HBV. We found none of the previously described amino-acid deletions or substitutions in the pre-S1, pre-S2 and S genes, which are involved in unusual antigenic profiles. This finding suggests that genetic mutations in the S gene outside the 'a' determinant may be responsible for failure to detect HBsAg in some Chinese patients with chronic hepatitis caused by HBV infection.

We report optical and X-ray observations of the high-field polar RXJ1007.5-2017 performed between 1990 and 2012. It has an orbital period of 208.60 min determined from the ellipsoidal modulation of the secondary star in an extended low state. The spectral flux of the dM3- secondary star yields a distance of 790+-105 pc. At low accretion levels, \RX{} exhibits pronounced cyclotron emission lines. The second and third harmonic fall in the optical regime and yield a field strength in the accretion spot of 94 MG. The source is highly variable on a year-to-year basis and was encountered at visual magnitudes between V \sim 20 and V \sim 16. In the intermediate state of 1992 and 2000, the soft X-ray luminosity exceeds the sum of the luminosities of the cyclotron source, the hard X-ray source, and the accretion stream by an order of magnitude. An X-ray high state, corresponding to the brightest optical level, has apparently not been observed so far., To be published in A&A

Patients with chronic hepatitis C infection may exhibit neuropsychological symptoms and cognitive impairment. Post-mortem studies of hepatitis C virus HCV quasispecies and replicative intermediates indicate that the brain might act as a separate compartment for viral replication and microglia may be the locus for infection and subsequent neuroinflammatory activity. We sought to use two independent in vivo imaging techniques to determine evidence of neuroinflammation in patients with histologically mild chronic hepatitis C. Using positron emission tomography (PET) with a ligand for microglial/brain macrophage activation, (11)C-(R)-PK11195 (PK11195) and cerebral proton magnetic resonance spectroscopy, we determined whether there was evidence of neuroinflammation in a pilot study of 11 patients with biopsy-proven mild chronic hepatitis C, compared to healthy volunteers. Patients were characterized by cognitive testing and the fatigue impact scale to assess for CNS impairment. PK11195 binding potential was significantly increased in the caudate nucleus of patients, compared to normal controls (P = 0.03). The caudate and thalamic binding potential were more significantly increased in six patients with genotype 1 infection (P = 0.007) and positively correlated with viraemia (r = 0.77, P = 0.005). Basal ganglia myo-inositol/creatine and choline/creatine ratios were also significantly elevated in patients with chronic hepatitis C compared to normal controls (P = 0.0004 and P = 0.01, respectively). Using PET, we demonstrated evidence of microglial activation, which positively correlated with HCV viraemia and altered cerebral metabolism in the brains of patients with mild hepatitis C. This provides further in vivo evidence for a neurotropic role for HCV.

In zahlreichen Anwendungen von Computern spielen Texte eine dominierende Rolle. Man denke etwa an Texteditoren, Literaturdatenbanken, Bibliothekssysteme und Systeme zur Symbolmanipulation. Der Begriff Text wird hier meistens in einem sehr allgemeinen Sinne benutzt. Texte sind nicht weiter strukturierte Folgen beliebiger Lange von Zeichen aus einem endlichen Alphabet. Das Alphabet kann Buchstaben, Ziffern und zahlreiche Sonderzeichen enthalten.

Datenstrukturen zur Reprasentation einer Kollektion von Datenmengen, auf der gewisse Operationen ausgefuhrt werden sollen, wurden erstmals von Aho, Hopcroft und Ullman [3] systematisch behandelt. Die abstrakte Behandlung solcher Mengenmanipulationsprobleme erleichtert in vielen Fallen den Entwurf und die Analyse von Algorithmen aus verschiedenen Anwendungsgebieten. Man formuliert Algorithmen zunachst auf hohem Niveau unter Ruckgriff auf Strukturen und Operationen zur Manipulation von Mengen, die in herkommlichen Programmiersprachen ublicherweise nicht vorkommen. In einem zweiten Schritt uberlegt man sich dann, wie die Kollektion von Datenmengen und die benotigten Operationen implementiert, also programmtechnisch realisiert werden konnen. Besonders erfolgreich war dieser Ansatz bei der Verbesserung und Neuentwicklung von Algorithmen auf Graphen. Beispiele sind Verfahren zur Berechnung spannender Baume, kurzester Pfade und maximaler Flusse, vgl. hierzu auch das Kapitel 9 und die Monographie von Tarjan [196].

We compared in vivo hepatic (31) P magnetic resonance spectroscopy ((31) P MRS) and hepatic vein transit times (HVTT) using contrast-enhanced ultrasound with a microbubble agent to assess the severity of hepatitis C virus (HCV)-related liver disease. Forty-six patients with biopsy-proven HCV-related liver disease and nine healthy volunteers had (31) P MRS and HVTT performed on the same day. (31) P MR spectra were obtained at 1.5 T. Peak areas were calculated for metabolites, including phosphomonoesters (PME) and phosphodiesters (PDE). Patients also had the microbubble ultrasound contrast agent, Levovist (2 g), injected into an antecubital vein, and time-intensity Doppler ultrasound signals of the right and middle hepatic veins were measured. The HVTT was calculated as the time from injection to a sustained rise in Doppler signal 10% greater than baseline. The shortest times were used for analysis. Based on Ishak histological scoring, there were 15 patients with mild hepatitis, 20 with moderate/severe hepatitis and 11 with cirrhosis. With increasing severity of disease, the PME/PDE ratio was steadily elevated, while the HVTT showed a monotonic decrease. Both imaging modalities could separate patients with cirrhosis from the mild and moderate/severe hepatitis groups. No statistical difference was observed in the accuracy of each test to denote mild, moderate/severe hepatitis and cirrhosis (Fisher's exact test P =1.00). (31) P MRS and HVTT show much promise as noninvasive imaging tests for assessing the severity of chronic liver disease. Both are equally effective and highly sensitive in detecting cirrhosis.

The ROSAT All-Sky Survey has for the first time permitted a synoptic view of the soft X-ray sky with high sensitivity. In this paper, we discuss the X-ray properties of known cataclysmic variables (CVs) as observed in the Survey and present a status report on programs to identify CVs among the newly discovered ROSAT X-ray sources. Of 170 CVs with known orbital period, 92 were detected in the Survey and 22 of these fall in the bright-source category with more than 0.5 PSPC cts/s. Among the new bright sources, so far 19 have been identified as CVs and 3 as CV candidates, about doubling the census. We present spectra and light curves of known and new systems and discuss the origin of the X-ray emission in the different subclasses of CVs.

This paper, describes nitrate concentrations in a groundwater catchment currently designated as a nitrate-sensitive area. Although the scheme has been operational for two years, groundwater nitrate concentrations have regularly exceeded the EC maximum admissible concentration of 11.3 mg/1 NO3-N (50 mg/1 NO3) from sources draining both arable and grassland management regimes. Nitrate levels from arable areas tend to produce a seasonal pattern of winter leaching and summer uptake, whilst no such pattern or fluctuation is observed from grassland areas. Four processes are defined which regulate nitrate inputs to the saturated zone of the Great Oolite aquifer: (i) availability of ‘free’nitrogen, (ii) variations in nitrogen uptake, (iii) leaching of nitrates from the soil environment, and (iv) limited atttenuation within the unsaturated zone.

Combinations of noninvasive markers may improve discrimination of chronic liver disease severity. The aims of this study were to compare four validated serum and ultrasound-based markers of hepatic disease severity head-to-head with liver biopsy and to assess optimal combinations with consideration of cost. A total of 67 patients with biopsy-proven chronic hepatitis C underwent all four techniques on the same visit [aspartate aminotransferase (AST) to platelet ratio index (APRI); Enhanced Liver Fibrosis (ELF) panel; transient elastography (TE) and ultrasound microbubble hepatic transit times (HTT)]. Markers were combined according to increasing financial cost and ordinal regression used to determine contributions. APRI, ELF, TE and HTT predicted cirrhosis with diagnostic accuracy of 86%, 91%, 90% and 83% respectively. ELF and TE were the most reliable tests with an intra-class correlation of 0.94 each. Either ELF or TE significantly enhanced the prediction of fibrosis stage when combined with APRI, but when combined together, did not improve the model further. Addition of third or fourth markers did not significantly improve prediction of fibrosis. Combination of APRI with either ELF or TE effectively predicts fibrosis stage, but combinations of three or more tests lead to redundancy of information and increased cost.

The excellence of a journal depends on the quality of peer review. The process of publishing scientific discoveries depends on considerable work by unpaid experts who volunteer time as peer reviewers. Peer reviewers are the essential gatekeepers who maintain high standards of scientific rigor. Equally important, many manuscripts are significantly improved when the authors respond to insightful suggestions from peer reviewers. Veterinary Pathology has been fortunate over the years in having a pool of highly dedicated and high-quality reviewers. Scientists are motivated to spend time reviewing manuscripts for a number of reasons. Altruism and service to the community of science, and to the discipline of veterinary pathology, motivate many to spend time reading and reviewing manuscripts, but these are not the only reasons. Curiosity and the desire to stay current are equally important. Reviewers enjoy the challenge involved in the careful analysis and assessment of a manuscript. Finally, for the success of Veterinary Pathology, manuscripts must be reviewed carefully and rapidly, and this would be impossible without the active participation of the broad scientific community. Conflict with other workloads is a major reason that potential reviewers decline invitations to review manuscripts. As discussed in the 2007 American College of Veterinary Pathologists (ACVP) Town Hall meeting, pathologists have increasing demands on their time, and the stresses of multitasking continue to increase. The problem is compounded by the retirement or death of some of the stalwart experts of veterinary pathology.

The ROSAT All Sky Survey (RASS) was the first one performed with an imaging telescope in the soft X-ray regime and has led to the discovery of numerous new objects whose emission is dominated by soft X-rays. Among these are white dwarfs and a subclass of the cataclysmic variables (CVs), the Polars or AM Herculis binaries. From a pre-ROSAT census of only 17, the number of known sources of this class has increased to some 55 (Beuermann and Thomas 1993, Beuermann 1997). Distances or lower limits to the distance are available for some 35 of these, based on the detection or non-detection of the TiO-Features in their optical red spectra. The derived distances range from below 100 pc up to ~ 600 pc, implying that many of these objects are located within the “Local Bubble” of low gas density in interstellar space. As the soft X-ray emission can be reasonably well represented by blackbody emission with a typical temperature of kT bb ≃ 25 eV, spectral fits to the ROSAT PSPC spectra from either the All-Sky-Survey (RASS) or from subsequent pointed ROSAT observations allow to determine the foreground absorption column density in the direction of the polars.

Two new BL Lacertae objects, located within the error boxes of hard X-ray sources, have been discovered during a systematic program to identify a large sample of EXOSAT serendipitous sources. Both hard X-ray sources were detected during the HEAD 1 whole sky survey and have been associated to a Seyfert galaxy and to a Be star. The EXOSAT data are consistent with the two BL Lacs being the only counterparts of the hard X-ray sources. If this is the case the space density of BL Lacs, at fluxes ≥ 3 x 10−11erg cm−2s−1 (2–10 keV), might be higher than previously thought. The implications for the shape on the X-ray LogN-LogS of BL Lac objects are briefly discussed.

Using a sample of 11 X-ray selected BL Lacertae objects extracted from the EXOSAT High Galactic Latitude Survey we derive the LogN-LogS relation of BL Lacs and we compare it with the results obtained with other X-ray surveys. All EXOSAT BL Lacs are characterized by featureless optical spectra and have been detected in the radio band. Excellent agreement is found between our results and those of the Einstein EMSS and HEAO1-A2 surveys if the energy spectral slope of BL Lacs is approximately 1.5 or greater. Evidence for a drastic difference in the number-flux relation between the population of BL Lacs and that of other types of AGN has been found. A good description of the observed LogN-LogS can be obtained under the assumption of pure luminosity evolution if the BL Lacs' luminosity function is very flat or is characterized by a break. However, in contrast to the preliminary results currently available, a large number of high redshift objects are predicted by these models. Acceptable fits can also be obtained assuming no cosmological evolution and a steep luminosity function. In this case the observed redshift distribution can easily be reproduced.

We report the results of near infrared observations of 19 soft X-ray selected AGN. The goal of the observations was to search for strong, narrow Paschen-alpha or Brackett-gamma emission lines, as a sign of nuclear starbursts. We found Pa-alpha emission in the spectra of 11 sources and Br-gamma in at least five. Strong NIR emission has been found in two sources, CBS 126 and Mkn 766, both objects with strong [OIII]5007 emission, weak FeII emission and wavelength dependent degree of polarization in the optical. Classical Narrow Line Seyfert 1 galaxies do not show exceptionally strong NIR emission lines. We present the results of our study and discuss how our findings fit into an evolutionary scheme of AGN., Comment: 6 pages (including 20 Figures), accepted for A&A also available at http://www.xray.mpe.mpg.de/~dgrupe/research/refereed.html

We report the discovery of a highly X-ray variable AGN, RX J2217.9-5941. This object was bright during the ROSAT All-Sky Survey (RASS), during which a decrease in the count rate by a factor of 12 was observed. It was found to be much fainter in follow-up HRI observations and is therefore an X-ray transient AGN candidate. On long time scales of years, its count rate decreased by a factor of about 30 between the RASS and the ROSAT HRI and ASCA observations in 1998. Analysis of the ASCA data, complicated by source confusion and poor statistics, tentatively indicates a steep spectrum in the faint state. There is no evidence for variability among 5 optical observations of the object obtained between 1992 and 1998. We discuss the variability of RX J2217.9-5941 and its possible X-ray transient nature., Comment: 10 pages (including 7 Figures), accepted for A&A, also available at http://www.xray.mpe.mpg.de/~dgrupe/research/refereed.html

Hepatitis C is now recognized as the most common infection causing chronic liver disease in the European population. Our aim was to assess the prevalence of the antibody to hepatitis C virus (HCV), and the incidence of HCV seroconversion in the general population and the main risk groups, namely intravenous drug users, haemodialysis and transfused patients, in seven countries of the European Union, by carrying out a critical analysis of the literature. Data sources used were the Medline database and a manual search using the key words: hepatitis C, prevalence, incidence, transmission, risk factors and epidemiology. Articles published between January 1990 and March 1997 were reviewed. Articles were reviewed according to a critical analysis method regarding title, type of article, study design, period and population, tests, results and their consistency with data. The tests performed were mainly second- or third-generation serological tests. The average prevalence rate in blood donors was 1%, with a north-south gradient ranging from 0.04% to 2%. Prevalence varied from 20% to 30% in haemodialysis patients. The incidence in transfused patients was less than 1% after 1991. The prevalence in intravenous drug users was about 80%. Multicentre studies conducted in larger samples are needed to obtain more accurate and reliable results, in particular. However, the epidemiological studies available allowed us to assess the magnitude of HCV infection in Europe.

The anti-inflammatory/antiallergic activity of a novel second-generation p38 mitogen-activated protein kinase inhibitor, SB 239063[trans-1-(4-hydroxycyclohexyl) -4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl)imidazole], was investigated in vivo and in vitro. SB 239063 had an IC(50) of 44 nM for inhibition of recombinant purified human p38alpha. In lipopolysaccharide-stimulated human peripheral blood monocytes, SB 239063 inhibited interleukin-1 and tumor necrosis factor-alpha production (IC(50) values = 0.12 and 0.35 microM, respectively). A role for p38 kinase in cytokine-associated inflammation in the mouse was shown by p38 activation in the lung and inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production by SB 239063 (ED(50) = 5.8 mg/kg p.o.). Antiallergic activity was demonstrated by essential abolition (approximately 93% inhibition) of inhaled ovalbumin (OA)-induced airway eosinophilia by SB 239063 (12 mg/kg p.o.), measured by bronchoalveolar lavage (BAL) in OA-sensitized mice. In addition, p38 kinase was found by Western analysis to be activated in guinea pig lung. Administration of SB 239063 (10 or 30 mg/kg p.o.) in conscious guinea pigs markedly reduced ( approximately 50% inhibition) OA-induced pulmonary eosinophil influx, measured by BAL 24 h after antigen. SB 239063 (10 mg/kg b.i.d. p.o.) administered after leukotriene D(4) inhalation, reduced by 60% the persistent airway eosinophilia seen at 4 days. Apoptosis of cultured eosinophils isolated from guinea pig BAL was increased by SB 239063 (1-10 microM) in the presence of interleukin-5. These results indicate that SB 239063 is a potent inhibitor of inflammatory cytokine production, inhibits eosinophil recruitment, in addition to enhancing apoptosis of these cells. Collectively, the results support the potential utility of p38 kinase inhibitors, such as SB 239063, for the treatment of asthma and other inflammatory disorders.

The outcome of infection with hepatitis C virus (HCV) varies substantially among individuals. Host genetic factors are likely to give rise to some of this variability. Polymorphisms in the MHC class II loci may influence the outcome of HCV infection; however, reports of MHC class II allele associations have been inconsistent. We aimed to confirm these associations in a cohort of European patients with different clinical outcomes.The distribution of MHC class II alleles was compared between patients with self-limiting infection (n=85) and matched patients with persistent infection (n=170); between patients with mild (n=321) and severe (n=321) histological injury; and between patients who responded to interferon (n=96) and those who did not (n=192). The results of these comparisons were confirmed with a second-stage study of self-limiting infection (n=52) versus persistent infection (n=152).Self-limiting HCV infection was associated with HLA-DRB1*1101 (odds ratio 2.14 [95% CI 1.11-4.12]; p=0.013) and HLA-DQB1*0301 (2.22 [1.24-3.96], p=0.004). Persistent HCV infection was associated with HLA-DRB1*0701 (2.04 [1.03-4.17], p=0.027), and HLA-DRB4*0101 (2.38 [1.29-4.35], p=0.002). These results were confirmed in the second-stage study. No significant associations (p0.05 after Bonferroni correction) were found between MHC class II alleles and severe histological injury or response to interferon therapy.Specific MHC class II alleles influence susceptibility or resistance to persistent HCV infection.

Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The present open-label, multicenter, dose-escalation phase I/II study was designed to assess tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneously administered recombinant human interleukin-12 (rHuIL-12) in the treatment of chronic hepatitis C. Sixty patients (42 men, 18 women, aged 24-60) were treated with 0.03 microgram/kg (n = 16), 0.1 microgram/kg (n = 14), 0.25 microgram/kg (n = 15), or 0.5 microgram/kg rHuIL-12 (n = 15) for 10 consecutive weeks. rHuIL-12 was generally well tolerated, with 2 patients (3.3%) being withdrawn from treatment for adverse events. Treatment was associated with temporary decreases in neutrophils and lymphocyte counts and with elevations in serum transaminases and bilirubin. Serum IL-12 levels observed were higher at 0.5 microgram/kg compared with 0.25 microgram/kg doses, suggesting a dose-related increase in systemic exposure of IL-12. Measurable levels of interferon gamma (IFN-gamma) were also observed at the highest dose of 0.5 microgram/kg. At the end of treatment hepatitis C virus (HCV) RNA was detectable in all patients. A more than 50% decrease in pretreatment HCV RNA levels was observed in 3 of 16 patients of the 0.03-microgram/kg dose group, in 3 of 14 of the 0.10-microgram/kg dose group, in 6 of 15 of the 0.25-microgram/kg dose group, and in 8 of 15 patients of the 0.5-microgram/kg dose group. Although in several cases serum alanine transaminase (ALT) levels decreased either during or after treatment, ALT normalization was observed in only 4 patients at the end of treatment and in 5 patients at the end of follow-up. Significant anti-rHuIL-12 antibody titers were not detectable in any patient. In conclusion, antiviral activity of rHuIL-12 in patients with chronic hepatitis C does not appear advantageous in comparison with other currently available treatments.

The aim of this study was to determine the prevalence of infection with the newly described hepatitis G virus (HGV) in a liver transplant cohort, and to establish the frequency and nature of hepatitis in those with and without HGV infection. A reverse transcriptase-polymerase chain reaction technique was employed to determine viraemia in the patients, and liver biopsies taken at different times after transplantation were assessed histologically. Hepatitis G virus RNA was detected in 47% of the liver transplant recipients investigated. Those positive for HGV had received significantly more blood or blood products than the HGV-negative patients. The frequency of abnormal liver function tests was similar in HGV-positive and HGV-negative recipients. Bile duct epithelial cell damage was more frequently seen in those with HGV viraemia. This study indicates that almost half of the liver transplant recipients in Northern England are positive for HGV, and that infection is associated with exposure to blood and blood products. It appears that, in the immunosuppressed patient, HGV does not cause clinically significant liver disease, at least up to 2 years after transplantation. If HGV infection is associated with hepatitis outside this clinical setting, it is likely that the liver damage is immunopathologically mediated rather than as a result of direct viral cytotoxicity.

The successful prevention of infection with hepatitis B virus (HBV) has been achieved by vaccination with purified hepatitis B surface antigen (HBsAg). The ability of a novel synthetic HBV envelope antigen vaccine (Hep B-3, Hepagene; Medeva), which contains part of the pre-S1 and the complete pre-S2 regions and the whole of the S region and was produced in a mammalian cell line, to induce antibodies required for a protective immune response is of importance. In this study, the use of a panel of monoclonal antibodies known to bind to epitopes within the common "a" determinant has demonstrated that the epitopes present on this new vaccine are comparable to those found with plasma-derived HBsAg. In addition, the epitope specificity of the antibodies induced by this vaccine was examined and shown to accord well with previous results obtained using both a plasma-derived vaccine and a recombinant vaccine prepared in yeast.

BACKGROUND & AIMS: Lamivudine inhibits hepatitis B virus replication. This study investigated 6 months of lamivudine treatment at three doses. METHODS: Fifty-one patients (43% white, 49% Asian) with chronic hepatitis B were randomly assigned to receive 25, 100, or 300 mg of lamivudine orally once daily for 24 weeks with 24 weeks' follow-up. RESULTS: Serum hepatitis B DNA by liquid hybridization decreased in all patients and was undetectable at the end of the treatment in 7 of 12 (58%, 25 mg), 13 of 14 (93%, 100 mg), and 14 of 16 (88%, 300 mg) patients. Of the 36 patients with abnormal alanine aminotransferase (ALT) levels at baseline, 7 of 11 (64%, 25 mg), 5 of 11 (45%, 100 mg), and 5 of 14 (36%, 300 mg) normalized ALT at treatment completion. Quantitative decreases hepatitis Be antigen and hepatitis B surface antigen concentrations were observed at all doses. In most patients, markers of replication returned after treatment. Two patients (4%) were anti-HBe positive at the end of follow-up. Lamivudine was well tolerated. The incidence of adverse events was similar across all dose groups. However, 2 patients developed temporary hepatic decompensation after increase in transaminase levels after treatment. CONCLUSIONS: Lamivudine was well tolerated and induced sustained suppression of hepatitis B replication during treatment in all patients at all doses. These data support investigation of longer treatment durations of 100 mg once daily. (Gastroenterology 1997 Oct;113(4):1258-63)

T-cell responses to hepatitis B virus nucleocapsid antigens (HBcAg and HBeAg) play an important role in disease outcome in those infected with hepatitis B virus (HBV). The woodchuck is naturally infected in the wild with woodchuck hepatitis virus (WHV), which shows a high degree of genetic homology to HBV and produces a similar pattern of infection in its natural host. Twenty-three overlapping peptides were constructed to cover the entire WHV core region and used to identify immunodominant cellular epitopes in the nucleocapsid antigen using peripheral blood lymphocytes from 12 chronic WHV carrier and 4 uninfected control animals. A peripheral blood lymphocyte response was seen in all of the chronic WHV carrier animals to at least one peptide, and in 8 of the 12 chronic carrier animals a response was observed to 5 common peptides: peptide analogues of amino acids 16-30, 38-52, 50-69, 76-90 and 91-105. Peptide 91-105 produced maximal proliferation in 5 out of 12 infected animals. In addition, a difference in response was observed between wild and laboratory infected animals; the latter appeared to have a lower response to peptides than animals infected in the wild. This study provides evidence that the woodchuck has a population of peripheral blood cells which are sensitised to epitopes within the nucleocapsid protein and provides a basis on which to develop the use of the woodchuck as an immunological model of HBV infection for testing therapeutic means of enhancing this response.

In the monocrotaline (MCT) rat model of pulmonary hypertension, the pulmonary vascular endothelium is thought to be the early target of the bifunctionally reactive metabolite monocrotaline pyrrole (MCTP). In previous studies, bovine pulmonary arterial endothelial cells (BPAEC) exposed to MCTP exhibited inhibition of proliferation. Since other compounds that crosslink DNA lead to cell cycle alterations, we utilized BPAEC to correlate the effects of MCTP on the cell cycle with the extent of covalent binding of [14C]MCTP to BPAEC DNA. Dose response (0.0 to 50.0 micrograms MCTP/ ml) and 96-hr time course (5 micrograms MCTP/ml low dose or 34.5 micrograms MCTP/ml high dose) studies were carried out followed by flow cytometric cell cycle analysis. High concentrations of MCTP caused cell cycle arrest in S phase, beginning by 24 hr, while an S phase delay was observed at low concentrations, but progressed to a G2 + M phase arrest by 48 hr. Covalent DNA binding (34.5 micrograms/ml of [14C]MCTP incubated with BPAEC) occurred within 1 hr and progressively increased through 96 hr. In conclusion, covalent binding of MCTP to DNA is associated with cell cycle arrest; however, the position of cell cycle arrest is dependent on dose, with an S phase arrest at high concentrations and a G2 + M phase arrest at low concentrations of MCTP. The mechanism by which MCTP induces proliferative inhibition could be cell cycle arrest.

A new flavivirus, provisionally designated as hepatitis G virus, has recently been identified. Its genomic organization is similar to that of the hepatitis C virus (HCV) with which it has only 25% nucleotide homology. The virus is transmissible by blood transfusion, by exposure to blood products or by intravenous drug use. Concurrent infection with hepatitis B virus and HCV is common and persistent viraemia has been documented, in many cases in the absence of transaminase elevations.