Natural killer cells are a key component in the immune control of viral infections. Their functions are controlled by inhibitory receptors for major histocompatability complex (MHC) class I, ...including the killer cell immunoglobulin‐like receptors (KIR). KIR2DL3 in combination with its cognate human leukocyte antigen (HLA)‐C ligand has been shown to be associated with spontaneous resolution of viremia following hepatitis C virus (HCV) infection. In order to determine if this gene combination is advantageous across all potential outcomes following HCV exposure, we studied individuals with apparent resistance to HCV infection who remain seronegative and aviremic despite long‐term injection drug use and also individuals chronically infected with HCV who successfully clear HCV with treatment. Homozygosity for KIR2DL3 in combination with group 1 HLA‐C allotypes was more frequent in exposed seronegative aviremic individuals as compared to those with chronic HCV (25.0% versus 9.7%, P = 0.003, odds ratio OR = 3.1, 95% confidence interval CI = 1.3‐7.1) in a model similar to that found for those spontaneously resolving HCV. In individuals undergoing treatment for HCV, those with KIR2DL3 and group 1 HLA‐C were more likely to make a sustained virological response (SVR) (P = 0.013, OR = 2.3, 95% CI = 1.1‐4.5). KIR and HLA‐C protection in both treatment response and spontaneously resolving HCV was validated at the allelic level, in which KIR2DL3‐HLA‐Cw*03 was associated with SVR (P = 0.004, OR = 3.4, 95% CI = 1.5‐8.7) and KIR2DL3/KIR2DL3‐HLA‐Cw*03 was associated with spontaneous resolution of HCV infection (P = 0.01, OR = 2.3, 95% CI = 1.2‐4.4). Conclusion: KIR and HLA‐C genes are consistently beneficial determinants in the outcome of HCV infection. This advantage extends to the allelic level for both gene families. (HEPATOLOGY 2010.)
Objective
Hepatorenal syndrome (HRS) is the most lethal cause of renal impairment in cirrhosis. Magnetic resonance elastography (MRE) is a diagnostic test that characterises tissues based on their ...biomechanical properties. The aim of this study was to assess the feasibility of MRE for detecting HRS in cirrhotic patients.
Methods
A prospective diagnostic investigation was performed. Renal MRE was performed on 21 hospitalised patients with cirrhosis and ascites. Six patients had HRS, one patient had non-HRS renal impairment, and 14 patients had normal renal function. The MRE-measured renal stiffness was compared against the clinical diagnosis as determined by clinical review alongside laboratory and radiologic results.
Results
The MRE-measured renal stiffness was significantly lower in patients with HRS (median stiffness of 3.30 kPa at 90 Hz and 2.62 kPa at 60 Hz) compared with patients with normal renal function (median stiffness of 5.08 kPa at 90 Hz and 3.41 kPa at 60 Hz) (
P
≤ 0.014). For the detection of HRS, MRE had an area under the receiver operating characteristic curve of 0.94 at 90 Hz and 0.89 at 60 Hz. MRE had excellent inter-rater agreement, as assessed by Bland-Altman and intraclass correlation coefficient (> 0.9).
Conclusion
MRE shows potential in the detection of HRS.
Key Points
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Magnetic resonance elastography (MRE) shows promise in the detection of hepatorenal syndrome
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MRE has the potential to track renal disease in a clinical population
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MRE is a reliable diagnostic test with excellent inter-rater agreement
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To investigate whether modification of liver complement factor H (CFH) production, by alteration of liver CFH Y402H genotype through liver transplantation (LT), influences the development of ...age-related macular degeneration (AMD).
Multicenter, cross-sectional study.
We recruited 223 Western European patients ≥ 55 years old who had undergone LT ≥ 5 years previously.
We determined AMD status using a standard grading system. Recipient CFH Y402H genotype was obtained from DNA extracted from recipient blood samples. Donor CFH Y402H genotype was inferred from recipient plasma CFH Y402H protein allotype, measured using enzyme-linked immunosorbent assays. This approach was verified by genotyping donor tissue from a subgroup of patients. Systemic complement activity was ascertained by measuring levels of plasma complement proteins using an enzyme-linked immunosorbent assay, including substrates (C3, C4), activation products (C3a, C4a, and terminal complement complex), and regulators (total CFH, C1 inhibitor).
We evaluated AMD status and recipient and donor CFH Y402H genotype.
In LT patients, AMD was associated with recipient CFH Y402H genotype (P = 0.036; odds ratio OR, 1.6; 95% confidence interval CI, 1.0-2.4) but not with donor CFH Y402H genotype (P = 0.626), after controlling for age, sex, smoking status, and body mass index. Recipient plasma CFH Y402H protein allotype predicted donor CFH Y402H genotype with 100% accuracy (n = 49). Plasma complement protein or activation product levels were similar in LT patients with and without AMD. Compared with previously reported prevalence figures (Rotterdam Study), LT patients demonstrated a high prevalence of both AMD (64.6% vs 37.1%; OR, 3.09; P<0.001) and the CFH Y402H sequence variation (41.9% vs 36.2%; OR, 1.27; P = 0.014).
Presence of AMD is not associated with modification of hepatic CFH production. In addition, AMD is not associated with systemic complement activity in LT patients. These findings suggest that local intraocular complement activity is of greater importance in AMD pathogenesis. The high AMD prevalence observed in LT patients may be associated with the increased frequency of the CFH Y402H sequence variation.
The authors have no proprietary or commercial interest in any materials discussed in this article.
The synthesis of the guanidine MesN{C(NCy2)}N(H)Mes (LH; Mes = 2,4,6‐Me3C6H2, Cy = cyclohexyl), and its use as a proligand for the synthesis of alkaline earth metal complexes are reported. Described ...herein are (i) an unusual Hauser base cubane, (ii) a homoleptic and a base‐stabilized magnesium complex featuring the same guanidinate ligands, and (iii) the comparison of a series of alkaline earth (Mg, Ca, Sr, Ba) bis(guanidinate) complexes, which allows the opportunity to compare the changing trends in bonding as the Group is descended. The reaction between LH and MeMgI(OEt2)2 yields the Hauser base as a mixture of the tetramer Mg4L4(μ3‐I)4 (1a) and dimer Mg2L2(μ‐I)2(OEt2)2 (1b), and the reaction with two equivalents of MgnBu2 leads to the formation of four‐coordinate MgL2 (2), which features a square‐planar geometry for the magnesium cation, or five‐coordinate MgL2(THF) (3), depending on the solvent used. 1a is the first crystallographically‐characterized cubane structure to consist of four LAeX (L = ligand, X = halide) units. The complexes AeL2(THF)2 (Ae = Ca, 4; Ae = Sr, 5) and BaL2 (6) were synthesized via redox transmetallation/ligand exchange reactions. Complex 6 is the first example of a homoleptic, monomeric barium complex of the NCN ligand family, with the structure stabilized by a number of barium‐arene interactions in the solid state.
The guanidine MesN{C(NCy2)}N(H)Mes (Mes = 2,4,6‐Me3C6H2, Cy = cyclohexyl) is used to stabilize (i) an unusual Hauser base cubane, (ii) a homoleptic and a base‐stabilized magnesium complex featuring the same guanidinate ligands, and (iii) a series of alkaline earth (Mg, Ca, Sr, Ba) bis(guanidinate) complexes, which allows the opportunity to compare the changing trends in bonding as the Group is descended.
Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject ...of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and a spectrum of liver fibrosis stages were stained for p16, αSMA, and picrosirius red (PSR). Primary human HSCs were cultured in conditioned media derived from senescent or control HepG2 cells. Expression of inflammatory and fibrogenic genes in HSCs cultured in conditioned media were studied using RT-PCR. ELISAs were undertaken to measure factors known to activate HSCs in the conditioned media from senescent and control HepG2 cells and serum samples from healthy volunteers or patients with biopsy-proven cirrhosis. There was a strong association between proportion of senescent hepatocytes and hepatic stellate cell activation. Both proportion of hepatocyte senescence and hepatic stellate cell activation were closely associated with fibrosis stage. Inflammatory and fibrogenic genes were up-regulated significantly in HSCs cultured in conditioned media from senescent HepG2 cells compared with control HepG2 cells. PDGF levels were significantly higher in the conditioned media from senescent hepatocytes than control HepG2-conditioned media, and in serum samples from patients with cirrhosis than healthy volunteers. In conclusion, this ‘proof of concept’ study revealed activation of human HSCs by media from senescent HepG2 cells, indicating direct involvement of factors secreted by senescent hepatocytes in liver fibrosis.
BMP9, originating from the liver, and BMP10 are circulating BMPs that preserve vascular endothelial integrity. We assessed BMP9, BMP10 and soluble endoglin (sEng) levels and their relationships to ...liver disease severity and associated pulmonary vascular syndromes in a cohort of well-characterised liver disease patients.
Plasma samples from patients with liver disease (n = 83) and non-disease controls (n = 21) were assayed for BMP9, BMP10 and sEng. Levels were also assessed in a separate cohort of controls (n = 27) and PoPH patients (n = 8). Expression of mRNA and immunohistochemical staining was undertaken in liver biopsy specimens. Plasma BMP activity was assessed using an endothelial cell bioassay.
Plasma BMP9 and BMP10 levels were normal in patients with compensated cirrhosis or fibrosis without cirrhosis, but markedly reduced in patients with decompensated cirrhosis, including those with hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PoPH). Liver biopsy specimens revealed reduced mRNA expression and immunostaining for these ligands. Patient plasma samples with reduced BMP9 and BMP10 levels exhibited low BMP activity that was restored with exogenous BMP9. Endoglin mRNA expression was increased in cirrhotic livers and elevated circulating sEng levels in PoPH and HPS patients suggested increased endothelial sEng shedding in these syndromes.
Plasma BMP9 and BMP10 levels are reduced in decompensated cirrhosis, leading to reduced circulating BMP activity on the vascular endothelium. The pulmonary complications of cirrhosis, PoPH and HPS, are associated with markedly reduced BMP9 and BMP10 and increased sEng levels, suggesting that supplementation with exogenous ligands might be a therapeutic approach for PoPH and HPS.
Alpha1‐antitrypsin is the most abundant circulating protease inhibitor. The severe Z deficiency allele (Glu342Lys) causes the protein to undergo a conformational transition and form ordered polymers ...that are retained within hepatocytes. This causes neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. We have developed a conformation‐specific monoclonal antibody (2C1) that recognizes the pathological polymers formed by α1‐antitrypsin. This antibody was used to characterize the Z variant and a novel shutter domain mutant (His334Asp; α1‐antitrypsin King's) identified in a 6‐week‐old boy who presented with prolonged jaundice. His334Asp α1‐antitrypsin rapidly forms polymers that accumulate within the endoplasmic reticulum and show delayed secretion when compared to the wild‐type M α1‐antitrypsin. The 2C1 antibody recognizes polymers formed by Z and His334Asp α1‐antitrypsin despite the mutations directing their effects on different parts of the protein. This antibody also recognized polymers formed by the Siiyama (Ser53Phe) and Brescia (Gly225Arg) mutants, which also mediate their effects on the shutter region of α1‐antitrypsin. Conclusion: Z and shutter domain mutants of α1‐antitrypsin form polymers with a shared epitope and so are likely to have a similar structure. HEPATOLOGY 2010
Background & Aims Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to ...antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection. Methods Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was measured by flow-FISH in 135 HCV-RNA-positive, treatment-naïve patients and 41 healthy controls in relation to clinical outcome. Results Shorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis ( p = 0.003), independent of male sex ( p = 0.04), CMV positivity ( p = 0.003), previous HBV infection ( p = 0.007), and age ( p = ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage ( p <0.001), portal tract inflammatory grade ( p = 0.035), prothrombin time ( p <0.001) and bilirubin ( p = 0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p = 0.009) with an age-adjusted hazard ratio of 0.93 (0.90–0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy ( p = 0.001) independent of other factors. Conclusions CD4+ T-lymphocyte telomere length, independent of age, was related to inflammatory grade, fibrosis stage, laboratory indices of severity, subsequent hepatic decompensation and treatment outcome in patients with chronic HCV infection.
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