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Background and Aims Alcoholic liver diseases often evolve to acute-on-chronic liver failure (ACLF), which increases the risk of (multi-)organ failure and death. We investigated the development and characteristics of alcohol-related ACLF and evaluated prognostic scores for prediction of mortality in Asian patients with active alcoholism. Methods A total of 205 patients who were hospitalized with severe alcoholic liver disease were included in this retrospective cohort study, after excluding those with serious cardiovascular diseases, malignancy, or co-existing viral hepatitis. The Chronic Liver Failure (CLIF) Consortium Organ Failure score was used in the diagnosis and grading of ACLF, and the CLIF Consortium ACLF score (CLIF-C ACLFs) was used to predict mortality. Results Patients with ACLF had higher Maddrey discriminant function, model for end-stage liver disease (MELD), and MELD-sodium scores than those without ACLF. Infections were more frequently documented in patients with ACLF (33.3% vs 53.0%; P = 0.004). Predictive factors for ACLF development were systemic inflammatory response syndrome (odds ratio [OR], 2.239; P < 0.001), serum sodium level (OR, 0.939; P = 0.029), and neutrophil count (OR, 1.000; P = 0.021). For prediction of mortality at predefined time points (28-day and 90-day) in patients with ACLF, areas under the receiver-operating characteristic were significantly greater for the CLIF-C ACLFs than for Child-Pugh, MELD, and MELD-sodium scores. Conclusions Infection and systemic inflammatory response syndrome play an important role in the development of alcohol-related ACLF in Asian patients with active alcoholism. The CLIF-C ACLFs may be more useful for predicting mortality in ACLF cases than liver-specific scoring systems. [ABSTRACT FROM AUTHOR]

Key points Hypoxia is thought to depolarize glomus cells by inhibiting the outward K+ current, which sets in motion a cascade of ionic events that lead to transmitter secretion, increased afferent carotid sinus nerve activity and increased ventilation., Our study of Na+-permeable channels in glomus cells has revealed that hypoxia not only inhibits TASK background K+ channels but also indirectly activates a non-selective cation channel with a single channel conductance of 20 pS. Under physiological conditions, the reversal potential of the cation channel is ∼ -28 mV, indicating that Na+ influx is also involved in hypoxia-induced excitation of glomus cells., Activation of the 20 pS cation channel is present when the O2 content is 5% or less, indicating that Na+ influx occurs during moderate to severe hypoxia (<5% O2), but not mild hypoxia (>5% O2)., The 20 pS cation channel is directly activated by a rise in intracellular Ca2+. Thus, factors that elevate intracellular Ca2+ such as hypoxia, extracellular acidosis and high external KCl all activate the cation channel. A feed-forward mechanism may be present in which an initial depolarization-induced rise in intracellular Ca2+ opens the Na+-permeable cation channel, and the Na+ influx causes additional depolarization and influx of Ca2+ into glomus cells., Abstract The current model of O2 sensing by carotid body chemoreceptor (glomus) cells is that hypoxia inhibits the outward K+ current and causes cell depolarization, Ca2+ influx via voltage-dependent Ca2+ channels and a rise in intracellular [Ca2+] ([Ca2+]i). Here we show that hypoxia (<5% O2), in addition to inhibiting the two-pore domain K+ channels TASK-1/3 (TASK), indirectly activates an ∼20 pS channel in isolated glomus cells. The 20 pS channel was permeable to K+, Na+ and Cs+ but not to Cl− or Ca2+. The 20 pS channel was not sensitive to voltage. Inhibition of TASK by external acid, depolarization of glomus cells with high external KCl (20 m m) or opening of the Ca2+ channel with FPL64176 activated the 20 pS channel when 1 m m Ca2+ was present in the external solution. Ca2+ (10 μ m) applied to the cytosolic side of inside-out patches activated the 20 pS channel. The threshold [Ca2+]i for activation of the 20 pS channel in cell-attached patches was ∼200 n m. The reversal potential of the 20 pS channel was estimated to be −28 mV. Our results reveal a sequential mechanism in which hypoxia (<5% O2) first inhibits the K+ conductance and then activates a Na+-permeable, non-selective cation channel via depolarization-induced rise in [Ca2+]i. Our results suggest that inhibition of K+ efflux and stimulation of Na+ influx both contribute to the depolarization of glomus cells during moderate to severe hypoxia. [ABSTRACT FROM AUTHOR]

Backgrounds & aims Intrahepatic recurrence of hepatocellular carcinoma ( HCC) after radiofrequency ablation ( RFA) occurs as a result of direct dissemination or de novo oncogenesis. Hepatocellular carcinogenesis is related to the progression of cirrhosis, and noninvasive fibrosis scoring systems reflect the severity of hepatic fibrosis. Hence, the aim of this study was to elucidate the correlation between noninvasive fibrosis indices and intrahepatic distant recurrence ( IDR) of HCC after RFA. Methods Patients with hepatitis B virus ( HBV)-related, solitary HCC undergoing RFA were prospectively enrolled. Noninvasive serum fibrosis indices were calculated at the time of RFA. IDR was defined as recurrent HCC beyond >2 cm from the ablation margin of RFA. Predictors of IDR and overall survival were analysed by a Cox regression model. Results Two hundred forty-six patients received RFA as initial treatment, and the median follow-up duration was 19.7 months (IQR, 11.9-29.8). Among these cases, 133 (45.9%) showed IDR after RFA. In multivariable analysis, serum alpha-fetoprotein ( AFP) (HR, 1.000; 95% CI, 1.000-1.001; P = 0.001) and age-platelet index ( API) (1.19; 1.01-1.39; P = 0.033) were independent predictors of IDR. In particular, patients with API ≤7 showed a significantly higher recurrence-free survival rate than patients with API >7 ( P = 0.004). With regard to overall survival, male sex (4.69; 1.52-14.52; P = 0.007), serum bilirubin (2.78; 1.31-5.90; P = 0.008) and AFP (1.000; 1.000-1.001; P = 0.006) were significantly correlated with shortened survival. Conclusion High levels of AFP and API predict IDR of HBV-related HCC after RFA. Therefore, noninvasive fibrosis indices could play an important role in predicting IDR of HCC following percutaneous ablation. [ABSTRACT FROM AUTHOR]

Background and Aim: Patients with persistently active hepatitis B virus (HBV) replication are at high risk for progression to liver cirrhosis and hepatocellular carcinoma (HCC). The influence of the viral load of HBV on intrahepatic recurrence after local ablation therapy in patients with HBV-related HCC has not been elucidated. We aimed to evaluate predictors of intrahepatic recurrence and clarify the correlation between viral load and intrahepatic recurrence after percutaneous ablation. Methods: Patients with HBV-related, solitary HCC undergoing radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI), between October 2004 and December 2008 were prospectively enrolled. Statistical analyses were performed using the Kaplan-Meier method and Cox regression model to identify risk factors for intrahepatic recurrence. Results: A total of 145 patients (male, 81.4%; mean age, 55.3 years) were included. Ninety patients (62.1%) had serum HBV DNA ≥ 2000 IU/mL. The median follow-up duration was 28.9 months (range, 12.0-57.0) and 63 patients (43.4%) experienced intrahepatic tumor recurrence. Multivariate analysis indicated that seropositivity for hepatitis B envelope antigen (HBeAg) was an independent negative predictor of intrahepatic recurrence (hazard ratio, 0.473; P = 0.026) and late (≥ 1 year) recurrence (HR, 0.288; P = 0.012). The serum alpha fetoprotein (AFP) level also significantly predicted late recurrence (HR, 1.001; P = 0.005). However, neither the ablation method nor serum HBV DNA titers were correlated with intrahepatic recurrence. Conclusions: These findings show that HBeAg-negativity and serum AFP levels were associated with late intrahepatic recurrence of HCC, implicating HBeAg-negativity as a risk factor for de novo recurrence after percutaneous ablation in HBV-related HCC. [ABSTRACT FROM AUTHOR]

TREK-2 (K2P10.1), a member of the two-pore domain K+ (K2P) channel family, provides the background K+ conductance in many cell types, and is a target of neurotransmitters that act on receptors coupled to Gs and Gq. We report here that TREK-2 exhibits small (TREK-2S) and large (TREK-2L) conductance phenotypes when expressed in mammalian cell lines (COS-7, HEK293, HeLa) and in Xenopus oocytes. TREK-2S phenotype shows a noisy open state with a mean conductance of 54 pS (+40 mV). TREK-2L phenotype shows a full open state (202 pS) with several short-lived sub-conductance levels. Both phenotypes were strongly activated by arachidonic acid, membrane stretch (−40 mmHg) and intracellular acidification (pH 6.4). Phosphorylation of TREK-2 produced by treatment of cells with activators of protein kinases A and C, and okadaic acid (a serine/threonine phosphatase inhibitor) decreased the current contributed by TREK-2S and TREK-2L, and caused partial switching of conductance levels from those of TREK-2S and TREK-2L to more intermediate values. Under this condition, TREK-2 exhibited six conducting levels and one closed level. TREK-2 mutants in which putative protein kinases A and C phosphorylation sites were mutated to alanines (S326A, S359A, S326A/S359A) displayed mostly TREK-2S and TREK-2L phenotypes. However, S326D and S359D mutants (as well as the double mutants) that mimic the phosphorylated state showed all six conducting levels and low channel activity. The S326A and S359A mutants did not significantly affect the intrinsic voltage dependence of TREK-2 in Mg2+-free solution. Phenotypes resembling TREK-2S and TREK-2L were also observed in cerebellar granule neurons that express TREK-2 mRNA. These results show that TREK-2 exhibits two primary modes of gating that give rise to two channel phenotypes under dephosphorylated conditions, and that its phosphorylation shifts the gating mode to include intermediate conducting levels. This represents a novel mechanism by which receptor agonists modulate the function of a K+ channel to alter cell excitability. [ABSTRACT FROM AUTHOR]

TASK-1 and TASK-3 are functional members of the tandem-pore K+ (K2P) channel family, and mRNAs for both channels are expressed together in many brain regions. Although TASK-1 and TASK-3 subunits are able to form heteromers when their complementary RNAs are injected into oocytes, whether functional heteromers are present in the native tissue is not known. Using cultured cerebellar granule (CG) neurones that express mRNAs of both TASK-1 and TASK-3, we studied the presence of heteromers by comparing the sensitivities of cloned and native K+ channels to extracellular pH (pHo) and ruthenium red. The single-channel conductance of TASK-1, TASK-3 and a tandem construct (TASK-1/TASK-3) expressed in COS-7 cells were 14.2 ± 0.4, 37.8 ± 0.7 and 38.1 ± 0.7 pS (-60 mV), respectively. TASK-3 and TASK-1/TASK-3 (and TASK-3/TASK-1) displayed nearly identical single-channel kinetics. TASK-3 and TASK-l/ TASK-3 expressed in COS-7 cells were inhibited by 26 ± 4 and 36 ± 2%, respectively, when pHo was changed from 8.3 to 7.3. In outside-out patches from CG neurones, the K+ channel with single channel properties similar to those of TASK-3 was inhibited by 31 ± 7% by the same reduction in pHo. TASK-3 and TASK- 1/TASK-3 expressed in COS-7 cells were inhibited by 78 ± 7 and 3 ± 4%, respectively, when µM ruthenium red was applied to outside-out patches. In outside-out patches from CG neurones containing a 38 pS channel, two types of responses to ruthenium red were observed. Ruthenium red inhibited the channel activity by 77 ± 5% in 42% of patches (range: 72-82%) and by 5 ± 4% (range: 0-9%) in 58% of patches. When patches contained more than three 38 pS channels, the average response to ruthenium red was 47 ± 6% inhibition (n = 5). These electrophysiological studies show that native 38 pS K+ channels of the TASK family in... [ABSTRACT FROM AUTHOR]