Impact of IL28B-related single nucleotide polymorphisms on liver histopathology in chronic hepatitis C genotype 2 and 3

Background and Aims

Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of HCV infection as well as outcome following peginterferon and ribavirin therapy among HCV genotype 1 infected patients. The present study aimed to evaluate the impact of IL28B SNP variability on liver histology in the context of a phase III treatment trial (NORDynamIC) for treatment-naïve patients with chronic HCV genotype 2 or 3 infection, where pretreatment liver biopsies were mandatory.

Methods

Three hundred and thirty-nine Caucasian patients had samples available for IL28B genotyping (rs12979860) of whom 314 had pretreatment liver biopsies that were evaluated using the Ishak protocol, allowing for detailed grading and staging of liver histopathology.

Results

IL28B CC_rs12979860 genotype in HCV genotype 3 infected patients was associated with higher ALT levels (p<0.0001), higher AST to platelet ratio index (APRI; p = 0.001), and higher baseline viral load (p<0.0001) as compared to patients with the CT or TT genotypes. Additionally the CC_rs12979860 genotype entailed more pronounced portal inflammation (p = 0.02) and steatosis (p = 0.03). None of these associations were noted among HCV genotype 2 infected patients.

Conclusion

This study shows that the CC_rs12979860 SNP is associated with more pronounced liver histopathology in patients chronically infected with HCV genotype 3, which may be secondary to higher viral load. The finding that IL28B variability did not impact on liver pathology or viral load among genotype 2 infected patients implies that IL28B may differentially regulate the course of genotype 2 and 3 infection.     

A 27-year study of brown trout population dynamics and exploitation in Lake Songsjøen, central Norway

From 1968–1984 (period I), a brown trout Salmo trutta , population in a 70-ha oligotrophic lake in central Norway was exploited using larger mesh gill-nets selectively removing the larger fish. From 1985–1994 (period II), intermediate sized fish were removed using smaller-mesh sizes gill-nets. Fishing mortality and CPUE were correlated positively with effort and numbers of fish >3 years old for period II. The gill-net catchability was correlated negatively with spawner biomass and number of trout >3 years old. The significant positive correlation between natural mortality and stock biomass and spawning stock biomass indicated density-dependent mortality. The significant correlation between spawning stock and recruitment described by the Ricker model, indicated density-dependent recruitment of 1-year-old trout. The fishing regimes in the two periods affected the population dynamics and density differently. Selective removal of smaller fish permitted the larger fish to survive, and was beneficial in reducing fish density and maintaining stocks at low levels, consequently, achieving the expected increase in fish growth rates.     

Evidence that neomycin inhibits binding of herpes simplex virus type 1 to the cellular receptor.

The effect of neomycin, a phosphoinositide-binding aminoglycoside, on herpes simplex virus type 1 (HSV-1) infection of BHK cells was studied. We showed earlier that it specifically inhibits HSV-1 production but not HSV-2 production (Langeland et al., Biochem Biophys. Res. Commun. 141:198-203, 1986). We now show that neomycin had no effect on cellular protein synthesis, as judged by the appearance of 35S-labeled polypeptides separated by polyacrylamide gel electrophoresis. Virus-induced polypeptides, however, were strongly inhibited at neomycin concentrations above 2 mM. Comparison among different aminoglycosides showed a variation in inhibition of HSV-1 production that paralleled the cationic charge of the aminoglycosides. HSV-1 receptor binding at 4 degrees C was completely inhibited by neomycin. At 37 degrees C both receptor binding and internalization, as measured by an indirect assay, appeared to be inhibited by more than 90%. The effect of neomycin on the infection was almost immediate upon the addition of the drug and preceded virus internalization. Possible mechanisms of the neomycin effect are discussed.     

Interactions between zooplankton and fish in a fertilized lake

The effects of fish predation on the zooplankton community in an oligotrophic lake, Langvatn, near Trondheim in Central Norway, were investigated during a six-year period (1973–1978), together with the added effects of changes produced by adding artificial fertilizer in 1975 and 1976. The improved nutrient conditions in 1975 resulted in a rapid increase in biomass and production of the largest herbivore zooplankton species and of the fish population. A change in the behaviour and food habits of the arctic char was recorded; they became more pelagic and fed mainly on zooplankton. An increased survival rate of 0-group and biomass of planktivorous fish in 1975 enhanced the degree of fish predation on the zooplankton during subsequent years (1976–1978). As a consequence of fish predation, the composition of the zooplankton changed, from a mainly large-sized to a mainly small-sized community, dominated by Bosmina longirostris and rotifers. Since fish predation is size-selective and visibility-dependent, it induced a decrease in mean size and in body length at onset of maturity of the cladoceran populations and probably also weakened their ability to produce resting eggs.     

Herpes simplex virus-1-specific proteins are involved in alteration of polyphosphoinositide metabolism in baby-hamster kidney cells.

Herpes simplex virus type 1 (HSV-1) induces altered phosphoinositide metabolism in baby hamster kidney (BHK) cells, measured as incorporation of [3H]inositol or [32P]Pi [Langeland, Haarr & Holmsen (1986) Biochem. J. 237, 707-712]. We now report that this response in the inositol phospholipids is dependent on virus-specific proteins synthesized in the beta (early) stage of virus protein synthesis. This was demonstrated both by resistance to the inhibitory effect of cycloheximide after this stage of infection, and by the use of temperature-sensitive (ts) mutants of HSV-1; ts mutants in which protein synthesis was blocked so that only the alpha proteins were expressed showed a PIP2/PIP (phosphatidylinositol 4,5-bisphosphate/phosphatidylinositol 4-monophosphate) ratio similar to uninfected cells, while ts mutants which were defective in protein synthesis at a late beta stage or later showed increased PIP2/PIP ratios similar to cells infected by wild type HSV-1.     

Evidence that neomycin inhibits HSV 1 infection of BHK cells

The effect of neomycin on the Herpes Simplex Virus (HSV) type 1 and 2 infection of baby hamster kidney cells was studied. Neomycin concentrations of 3 mM or more caused a more than 90% inhibition of HSV 1 proliferation, while it had no effect on HSV 2 proliferation, measured as plaque-forming units. Furthermore, neomycin must be present at the time of infection in order to exert full effect, addition 1 hour postinfection was comparable to untreated cells. This indicates that neomycin may specifically interfere with very early stages of HSV 1 infection.     

Activated platelet-derived growth factor autocrine pathway drives the transformed phenotype of a human glioblastoma cell line

Human glioblastoma cells (A172) were found to concomitantly express PDGF-BB and PDGF β-receptors. The receptors were constitutively autophosphorylated in the absence of exogenous ligand, suggesting the presence of an autocrine PDGF pathway. Neutralizing PDGF antibodies as well as suramin inhibited the autonomous PDGF receptor tyrosine kinase activity and resulted in up-regulation of receptor protein. The interruption of the autocrine loop by the PDGF antibodies reversed the transformed phenotype of the glioblastoma cell, as determined by (1) diminished DNA synthesis, (2) inhibition of tumor colony growth, and (3) reversion of the transformed morphology of the tumor cells. The PDGF antibodies showed no effect on the DNA synthesis of another glioblastoma cells line (U343MGa 31L) or on Ki-ras-transformed fibroblasts. The present study demonstrates an endogenously activated PDGF pathway in a spontaneous human glioblastoma cell line. Furthermore, we provide evidence that the autocrine PDGF pathway drives the transtormed phenotype of the tumor cells, a process that can be blocked by extracellular antagonists. © 1994 Wiley-Liss, Inc.     

Lamprey <Emphasis Type="Italic">snail</Emphasis> highlights conserved and novel patterning roles in vertebrate embryos

snail genes mark presumptive mesoderm across bilaterian animals. In gnathostome vertebrates, snail genes are a multimember family that are also markers of premigratory neural crest (pnc) and some postmigratory neural crest derivatives in the pharyngeal arches. Previous studies of nonvertebrate chordates indicate that they have single snail genes that retain ancestral functions in mesoderm development and perhaps in specification of a pnc-like cell population. Lampreys are the most basal extant vertebrates, with well-defined developmental morphology. Here, we identify a single snail gene from the lamprey Petromyzon marinus that is the phylogenetic outgroup of all gnathostome snail genes. This single lamprey snail gene retains ancestral snail patterning domains present in nonvertebrate chordates. Lamprey snail is also expressed in tissues that are broadly equivalent to the combined sites of expression of all three gnathostome snail paralogy groups, excepting in embryonic tissues that are unique to gnathostomes. Importantly, while snail does not appear to demarcate an early neural crest population in lampreys as it does in gnathostomes, it may be involved in later neural crest development. Together, our results indicate that significant cis-regulatory innovation occurred in a single snail gene before the vertebrate radiation, and significant subfunctionalization occurred after snail gene duplications in the gnathostome lineages.     

Escaping parasitism in the selfish herd: age, size and density-dependent warble fly infestation in reindeer

It has been suggested that animals may escape attack from mobile parasites by aggregating in selfish herds. A selfish herd disperses the risk of being attacked among its members and the per individual risk of parasite infection should therefore decrease with increasing animal density through the encounter–dilution effect. Moreover, in a selfish herd, dominant and agile animals should occupy the best positions and thereby receive fewer attacks compared to lower ranked animals at the periphery. We tested these predictions on reindeer ( Rangifer tarandus tarandus ) parasitized by warble flies ( Hypoderma tarandi ). Warble flies oviposit their eggs on reindeer during summer and induce strong anti-parasitic behavioural responses in the herds. In this period, reindeer are sexually segregated; females and calves form large and dense herds while males are more solitary. After hatching, the warble fly larvae migrate under the skin of their host where they encyst. In the present study encysted larvae were counted on newly slaughtered hides of male calves and 1.5 year old males from 18 different reindeer herds in Finnmark, northern Norway with large contrasts in reindeer density. In reindeer, body mass is correlated with fitness and social status and we hypothesized that individual carcass mass reflected the animal's ability to occupy the best positions within the herd. Larval abundance was higher among the 1.5 year old males than among the calves. For calves we found in accordance with the selfish herd hypothesis a negative relationship between larval abundance and animal density and between larval abundance and body mass. These relationships were absent for the 1.5 year old males. We suggest that these differences were due to different grouping behaviour where calves and females, but not males, aggregated in selfish herds where they escaped parasitism.     

Cryptosporidium parvum Infections in Bergen, Norway, during an Extensive Outbreak of Waterborne Giardiasis in Autumn and Winter 2004

During a large waterborne giardiasis outbreak in Norway, many diarrheic patients were found to have Cryptosporidium infections. Gene sequencing identified these infections as Cryptosporidium parvum infections, although they were not identical. Whether these infections were due to a simultaneous outbreak of waterborne cryptosporidiosis or reflected background levels not normally detected is discussed.