Suppressor of cytokine signal 3 and IL28 genetic variation predict the viral response to peginterferon and ribavirin

Aim: The aim of this study was to investigate the relationship among the expression of suppressor of cytokine signaling 3 (SOCS 3) in the liver, the SNPs in the IL28B locus, and the outcome of interferon therapy. Methods: Prior to interferon treatment, we immunostained 67 liver specimens from chronic hepatitis C (CHC) patients who were receiving peginterferon alpha‐2b/ribavirin therapy for suppressor of cytokine signaling 3 (SOCS3), and compared the expression of SOCS3, IL28 polymorphisms and other clinical factors between the patients and compared their eventual outcomes. Results: Significant differences between the low SOCS3 group and high SOCS3 group were found in age, as well as in the platelet, transaminase, gamma‐glutamyl transpeptidase levels. The incidence of high SOCS3 was not significantly different between subjects with the TT genotype and the TG genotype (TT : TG = 71%:29%, P = 0.250). In a multivariate analysis, age (≥65 years old) (odds ratio 0.221 [0.120–0.966], P = 0.045), IL28B gene (genotype TT) (odds ratio 5.422 [1.254–23.617], P = 0.024) and SOCS3 (high) (odds ratio 0.308 [0.104–0.948], P = 0.040) were significant predictors of the interferon response. In patients with the TT genotype, those with low SOCS3 immunostaining showed a high sustained virological response (69%), while the sustained virological rate was low (27%) in the patients with high SOCS3 immunostaining. Conclusions: Using a combination of the SOCS3 immunostained area in the liver and the expression of IL28B single nucleotide polymorphisms might be a useful predictor of hepatitis C virus clearance by interferon therapy.     

Global water resources affected by human interventions and climate change

Humans directly change the dynamics of the water cycle through dams constructed for water storage, and through water withdrawals for industrial, agricultural, or domestic purposes. Climate change is expected to additionally affect water supply and demand. Here, analyses of climate change and direct human impacts on the terrestrial water cycle are presented and compared using a multimodel approach. Seven global hydrological models have been forced with multiple climate projections, and with and without taking into account impacts of human interventions such as dams and water withdrawals on the hydrological cycle. Model results are analyzed for different levels of global warming, allowing for analyses in line with temperature targets for climate change mitigation. The results indicate that direct human impacts on the water cycle in some regions, e.g., parts of Asia and in the western United States, are of the same order of magnitude, or even exceed impacts to be expected for moderate levels of global warming (+2 K). Despite some spread in model projections, irrigation water consumption is generally projected to increase with higher global mean temperatures. Irrigation water scarcity is particularly large in parts of southern and eastern Asia, and is expected to become even larger in the future.Terrestrial water fluxes are affected by both climate and direct human interventions, e.g., dam operations and water withdrawals. Climate change is expected to alter the water cycle and will subsequently impact water availability and demand. Several hydrologic modeling studies have focused on climate change impacts on discharge in large river basins or global terrestrial areas under naturalized conditions using a single hydrologic model forced with multiple climate projections (1, 2). Recently, hydrological projections from eight global hydrological models (GHMs) were compared (3). In many areas, there was a large spread in projected runoff changes within the climate–hydrology modeling chain. However, at high latitudes there was a clear increase in runoff, whereas some midlatitude regions showed a robust signal of reduced runoff. The study also concluded that the choice of GHM adds to the uncertainty for hydrological change caused by the choice of atmosphere–ocean general circulation models (hereafter called GCMs) (3). Expected runoff increases in the north and decreases in parts of the middle latitudes have been found also when analyzing runoff from 23 GCMs (4).These studies focused on the naturalized hydrological cycle, i.e., the effects of direct human interventions were not taken into account. However, in many river basins humans substantially alter the hydrological cycle by constructing dams and through water withdrawals. Reservoir operations alter the timing of discharge, although mean annual discharge does not necessarily change much. A study with the water balance model (WBM) showed that the impact of human disturbances, i.e., dams and water consumption, in some river basins is equal to or greater than the impact of expected climate changes on annual runoff over the next 40 y (5). Also, rising water demands are found to outweigh global warming in defining the state of global water systems in the near future (6). Water for irrigation is the largest water use sector, currently accounting for about 70% of global water withdrawals and nearly 90% of consumptive water use (7). A recent synthesis of simulations from seven GHMs found that irrigation water consumption currently amounts to 1,250 km³⋅y⁻¹ (±25%) and that considerable differences among models appear in the spatiotemporal patterns of water consumption (8).Direct comparisons of the climate impact and human intervention modeling studies can be difficult given that the setups are not identical, i.e., the input forcing data and climate models vary. Also, because of the uncertainty of model-specific results, a multimodel approach is preferable in impact modeling studies (3, 9). This approach is similar to assessments performed within the climate community. Here, multimodel results on current and future water availability and consumption at the global scale from the Water Model Intercomparison Project (WaterMIP) within the European Union Water and Global Change (EU WATCH) project (9, 10), and Inter-Sectoral Impact Model Intercomparison Project (ISI-MIP) (11) are presented. (Information on how to get access to WaterMIP and ISI-MIP simulation results can be found at www.eu-watch.org and www.isi-mip.org, respectively.) Results from these two projects are synthesized to obtain a large ensemble of impact model results. The integration of results from the different projects is achieved by extracting impacts for time periods of global mean temperature (GMT) increases of 2 and 3 K from the simulations, largely following the method of Tang and Lettenmaier (4). The advantage of this approach is that it allows presenting results in a way that is in line with temperature targets used in climate mitigation discussions.Other studies have focused on future water scarcity using results from WaterMIP and ISI-MIP, but have analyzed changes of naturalized runoff only (3, 12). We here aim to fill this knowledge gap by comparing the different impacts from climate change and direct human impacts and analyzing their interplay. The models included take into account water withdrawals and consumption in different sectors; for more information, see Models and Data and Supporting Information, SI Models and Data. The objectives of this study are to (i) assess the relative contribution of anthropogenic impacts and climate change to river basin scale water fluxes, and (ii) identify areas where climate change can be expected to cause substantial changes in water consumption and water scarcity, focusing on water for irrigation. The effects of future changes in irrigated areas or irrigation practices are not taken into account, and only dams that currently exist are included in the analyses. In this paper, simulations considering man-made reservoirs, water withdrawals, and water consumption are referred to as human impact simulations, whereas the simulations without these disturbances are referred to as naturalized simulations. The results are mainly presented in a way intended to give an overview of impacts at larger spatial scales (river basin and country levels). However, some finer-scale results are included to reveal effects that can be concealed at coarse spatial scales.     

Ultrastructural changes of the air–blood barrier in mice after intratracheal instillation of lipopolysaccharide and ultrafine carbon black particles

Epidemiological studies have indicated associations between exposure to increased concentrations of ambient ultrafine particles and adverse health effects especially in susceptible individuals. To ellucidate the mechanisms underlying the findings from epidemiological studies, mice pretreated with lipopolysaccharide (LPS) (acute lung injury model) were intratracheally instilled with ultrafine carbon black particles (UFCB), and the air–blood barrier was observed to examine the translocation pathway of UFCB from the lung into the systemic circulation. In addition, lung toxicity induced by the intratracheal instillation of LPS and UFCB was studied with the use of electron microscope. LPS treatment induced acute inflammatory changes with increased number of activated macrophages and neutrophils in the degenerated alveolar walls. UFCB were demonstrated on or in the denuded basement membrane in the air–blood barrier; these findings were associated with edematous changes and fragmentation of the cytoplasms of alveolar epithelial cell type 1, and the damages of alveolar epithelial cell type 1 were frequently observed in the close vicinity of the clumps of UFCB. These findings suggest that translocation of the exposed ultrafine particles may be enhanced in the lung tissues with acute inflammatory changes.     

Determination of cellularly processed HLA-A2402-restricted novel CTL epitopes derived from two cancer germ line genes, MAGE-A4 and SAGE.

PURPOSE: For identification of CTL epitopes useful for cancer vaccines, it is crucial to determine whether cognate epitopes are presented on the cell surface of target cancer cells through natural processing of endogenous proteins. For this purpose, we tried to use the cellular machinery of both mice and human to define naturally processed CTL epitopes derived from two "cancer germ line" genes, MAGE-A4 and SAGE. EXPERIMENTAL DESIGN: We vaccinated newly produced HLA-A2402 transgenic mice with DNA plasmids encoding target antigens. Following screening of synthesized peptides by splenic CD8(+) T cells of vaccinated mice, we selected candidate epitopes bound to HLA-A2402. We then examined whether human CD8(+) T cells sensitized with autologous CD4(+) PHA blasts transduced by mRNA for the cognate antigens could react with these selected peptides in an HLA-A2402-restricted manner. RESULTS: After DNA vaccination, murine CD8(+) T cells recognizing MAGE-A4(143-151) or SAGE(715-723) in an HLA-A2402-restricted manner became detectable. Human CTLs specific for these two peptides were generated after sensitization of HLA-A2402-positive CD8(+) T cells with autologous CD4(+) PHA blasts transduced with respective mRNA. CTL clones were cytotoxic toward tumor cell lines expressing HLA-A2402 and cognate genes. Taken together, these CTL epitopes defined in HLA-A24 transgenic mice are also processed and expressed with HLA-A2402 in human cells. The presence of SAGE(715-723)-specific precursors was observed in HLA-A2402-positive healthy individuals. CONCLUSIONS: Two novel HLA-A2402-restricted CTL epitopes, MAGE-A4(143-151) and SAGE(715-723), were identified. Our approach assisted by cellular machinery of both mice and human could be widely applicable to identify naturally processed CTL epitopes.     

Detection of HBV core promoter and precore mutations helps distinguish flares of chronic hepatitis from acute hepatitis B

Background and Aim: Acute exacerbation of chronic hepatitis B has to be distinguished from acute hepatitis, because treatment strategies differ between them. Methods: Mutations in the core promoter and precore region of hepatitis B virus (HBV) were determined in 36 patients with acute exacerbation of chronic hepatitis B, in whom alanine aminotransferase (ALT) increased above 500 IU/L, as well as the 36 patients with acute hepatitis. Results: Mutations in the core promoter (A1762T/G1764A) and precore region (G1896A) were more frequent in patients with acute exacerbation of chronic hepatitis than acute hepatitis (81% vs 19%; P < 0.0001 and 58% vs 6%; P < 0.0001, respectively). Of the 19 patients with mutations in both the core promoter and precore region, 17 (89%) had acute exacerbation of chronic hepatitis. In contrast, among the 32 patients with the wild‐type for both the core promoter and precore region, 29 (89%) developed acute hepatitis. By multivariate analysis, the double mutation in the core promoter was predictive of acute exacerbation in chronic hepatitis with the highest odds ratio at 26.4. Conclusions: In patients with hepatitis B having ALT levels >500 IU/L, mutations in the core promoter and precore region are useful in distinguishing acute exacerbation of chronic from acute HBV infection. Detection of these mutations would be useful for commencing prompt antiviral treatments on patients with acute exacerbation of chronic hepatitis for a better prognosis.