The direct causes of ALF included herbal medication in two patients, SAE of CHB in two, veno-occlusive ABT-263 chemical structure disease in one, extensive radiation-induced liver disease in one, and indeterminate in one. The mean ± standard deviation (SD) weight of the 44 explanted livers in the LT group was 850 ± 378 g. There was no difference in mean weight between the 12 patients with SAE of CHB and the 32 other patients (870

± 428 g versus 843 ± 366 g, P = 0.84). Pathological examination of the explants showed massive or submassive necrosis in all patients and moderate to marked hepatitis in 33 patients (75%). Bridging fibrosis was observed in 23 patients (52.3%), and no or minimal fibrosis in the remainder. No patients had definite features of cirrhosis. The proportion of patients Obeticholic Acid mouse with bridging fibrosis did not differ significantly between patients with SAE of CHB and others

(66.7% versus 46.9%, P = 0.24). Overall patient survival was 42.7% (47 of 110 patients). All 11 patients with contraindications to LT died within 10 weeks of diagnosis (Fig. 3). Of the 55 patients in the no-LT group, 45 (82%) died while awaiting a graft, with a median time from diagnosis to death of 7 days (IQR 4-11 days). Of the 49 patients in the no-LT group who had grade 1 or 2 encephalopathy at enrollment, only six (12.2%) remained at encephalopathy grade 1 or 2, and all six recovered spontaneously. In contrast, 43 (87.8%) of these 49 patients progressed to grade 3 or 4, with only four (9.3%) recovering

spontaneously. All of the survivors (n = 10, 18%) in the no-LT group recovered fully and maintained normal liver function after a median follow-up period of 1,277 days (range, 855–1,841 days). Among the 56 patients who died without transplantation, the most common cause selleckchem of death was cerebral edema (46%) followed by infection (43%). All patients in the LT group progressed to grade 3 or 4 encephalopathy before receiving LT. Four patients received liver grafts from deceased donors on days 2, 5, 6, and 10, respectively, after diagnosis. The median time from diagnosis to adult LDLT was 2.5 days (range, 0–26 days). The 1-year patient survival rate of the adult LDLT group was 85% (34 of 40 patients), significantly higher than that of the no-LT group (P < 0.01), but similar to that of the DDLT group (75%, P > 0.05; Fig. 3). The 1-year graft survival rate for the adult LDLT group was the same as the patient survival rate. Six adult LDLT patients, including one who received a dual-graft and one DDLT patient, died within 6 months as a result of brain edema (n = 2), systemic infection (n = 4), or bleeding (n = 1). One LDLT patient underwent a second transplantation for graft failure caused by acute cellular rejection, but later died of fungal pneumonia and sepsis. None of the 1-year survivors in the LT group (n = 37) died within a median follow-up period of 1,168 days (range, 465–1,989 days).

Cotransfection of miR-33a mimic in transient transfection assay of pMir-hCYP7A1 (1-200) reporter in HepG2 cells resulted in ∼40% inhibition of reporter activity (Fig. 5A), but showed no effect on pMir-hCYP7A1 (203-982) reporter activity (Fig. 5B). These results suggest that the nt 1-200 region of the human CYP7A1 3′-UTR may contain a potential miR-33a target site. Analysis of the sequence in this region identified a putative seed-match

sequence for miR-33a binding (Fig. 5C). Mutations of INCB018424 molecular weight this putative seed-match sequence resulted in elevated basal reporter activity and abolished the inhibitory effect of miR-33a mimic on the mutant reporter (Fig. 5A). As a positive control, miR-33a mimic repressed ABCA1 3′-UTR reporter activity, as expected

(Fig. 5D). These results suggest that a putative miR-33a-binding site, located in the 3′-UTR of human CYP7A1 mRNA, is functional in mediating the inhibitory effect of miR-33a. In vitro and in vivo studies in both WT and humanized CYP7A1-tg mice showed that this miR-33a-mediated regulatory mechanism is functionally conserved in humans selleck chemicals llc and mice. However, we have not identified a functional miR-33a target site in the mouse cyp7a1 mRNA 3′-UTR. In this study, we used Cyp7a1-tg mice as an experimental model to demonstrate that stimulating bile acid synthesis significantly affects hepatic lipid metabolism and homeostasis, as well as to elucidate the underlying molecular mechanism for bile acid signaling in preventing diet-induced hepatic steatosis, IR, and obesity. We demonstrate that stimulating de novo bile acid synthesis results in decreased lipogenesis through mechanisms independent of hepatic FXR signaling. This study unveiled complex links between bile acid, cholesterol, and fatty acid metabolism.

We also uncovered a novel role for miR-33a in the coordinated regulation of hepatic bile acid and cholesterol metabolism. We found that in response to increased conversion of cholesterol to bile acids, this website SREBP2 is induced to stimulate cholesterol synthesis to provide a substrate to CYP7A1, and that miR-33a is coinduced to reduce CYP7A1 mRNA translation. This feed-forward activation of CYP7A1 enzyme activity by cholesterol and feedback inhibition of CYP7A1 translation by miR-33a provide a rapid posttranscriptional mechanism for regulation of bile acid synthesis to maintain hepatic lipid homeostasis. We first showed that a 2-fold to 3-fold stimulation of hepatic CYP7A1 enzyme activity resulted in marked induction of cholesterol synthetic genes and de novo cholesterol synthesis rate in Cyp7a1-tg mice.[6] Stimulation of cholesterol catabolism to bile acids resulted in activation of SREBP2 and all SREBP2-regulated genes in cholesterol metabolism.[17] The ER is a cholesterol-poor organelle,[18] and intracellular cholesterol/oxysterol levels are critical in the regulation of the SREBP2-mediated cholesterol metabolism network.

At the US Food and Drug Administration meeting in March 2010, this matter was extensively studied and discussed. Both patients who developed C. difficile had concurrently

received other antimicrobials known to cause C. difficile infection. Bajaj and Riggio’s suggestion of pulse therapy with rifaximin (to reduce costs) is without precedent or merit in the realm of antimicrobial therapy. Their statement regarding rifaximin that “the current role appears Proteasome inhibitor to be a second-line [therapy]” is again without scientific merit. Lactulose is an effective therapy for hepatic encephalopathy; however, its use and patient compliance are severely limited and restricted by its well-recognized adverse event profile of nausea, vomiting, bloating, diarrhea, and incontinence. Rifaximin is very well tolerated, and it not only improves the duration of remission of hepatic encephalopathy but also lessens the need for repeated hospitalization.2 Both factors require consideration when one mTOR inhibitor is calculating the overall cost of the two agents, their beneficial effects, and patient preference, compliance,

and quality of life. Norman Gitlin M.D.*, * Atlanta Gastroenterology Associates, Atlanta, GA. “
“C/EBPalpha plays an essential role in cellular differentiation, growth and energy metabolism. Here, we investigate the correlation between C/EBPalpha and hepatocellular carcinoma (HCC) patient outcomes, and how C/EBPalpha protects cells against energy starvation. C/EBPalpha protein expression was increased in the majority of HCCs examined (191 pairs) compared with adjacent non-tumor liver tissues in HCC tissue microarrays. Its upregulation was correlated significantly with poorer overall patient

survival in both Kaplan-Meier survival (P = 0.017) and multivariate Cox regression analyses (P = 0.028). Stable C/EBPalpha-silenced cells failed to establish xenograft tumors in nude mice due to extensive necrosis, consistent with increased necrosis in human C/EBPalpha-deficient HCC nodules. Expression of C/EBPalpha protected HCC cells in vitro from glucose and glutamine starvation–induced cell death through autophagy-involved lipid catabolism. Firstly, C/EBPalpha promoted lipid catabolism during starvation, while inhibition of fatty acid beta-oxidation significantly sensitized cell death. Secondly, autophagy was activated selleck chemicals in the C/EBPalpha-expressing cells, and the inhibition of autophagy by ATG7 knock-down or chloroquine treatment attenuated lipid catabolism and subsequently sensitized cell death. Finally, we identified TMEM166 as a key player in C/EBPalpha-mediated autophagy induction and protection against starvation. Conclusion: C/EBPalpha is an important gene that links HCC carcinogenesis to autophagy-mediated lipid metabolism and resistance to energy starvation. Its expression in HCC predicts poorer patient prognosis. (Hepatology 2014;) “
“In a recent article, Piroth et al.

At the US Food and Drug Administration meeting in March 2010, this matter was extensively studied and discussed. Both patients who developed C. difficile had concurrently

received other antimicrobials known to cause C. difficile infection. Bajaj and Riggio’s suggestion of pulse therapy with rifaximin (to reduce costs) is without precedent or merit in the realm of antimicrobial therapy. Their statement regarding rifaximin that “the current role appears ALK inhibitor cancer to be a second-line [therapy]” is again without scientific merit. Lactulose is an effective therapy for hepatic encephalopathy; however, its use and patient compliance are severely limited and restricted by its well-recognized adverse event profile of nausea, vomiting, bloating, diarrhea, and incontinence. Rifaximin is very well tolerated, and it not only improves the duration of remission of hepatic encephalopathy but also lessens the need for repeated hospitalization.2 Both factors require consideration when one Temsirolimus order is calculating the overall cost of the two agents, their beneficial effects, and patient preference, compliance,

and quality of life. Norman Gitlin M.D.*, * Atlanta Gastroenterology Associates, Atlanta, GA. “
“C/EBPalpha plays an essential role in cellular differentiation, growth and energy metabolism. Here, we investigate the correlation between C/EBPalpha and hepatocellular carcinoma (HCC) patient outcomes, and how C/EBPalpha protects cells against energy starvation. C/EBPalpha protein expression was increased in the majority of HCCs examined (191 pairs) compared with adjacent non-tumor liver tissues in HCC tissue microarrays. Its upregulation was correlated significantly with poorer overall patient

survival in both Kaplan-Meier survival (P = 0.017) and multivariate Cox regression analyses (P = 0.028). Stable C/EBPalpha-silenced cells failed to establish xenograft tumors in nude mice due to extensive necrosis, consistent with increased necrosis in human C/EBPalpha-deficient HCC nodules. Expression of C/EBPalpha protected HCC cells in vitro from glucose and glutamine starvation–induced cell death through autophagy-involved lipid catabolism. Firstly, C/EBPalpha promoted lipid catabolism during starvation, while inhibition of fatty acid beta-oxidation significantly sensitized cell death. Secondly, autophagy was activated learn more in the C/EBPalpha-expressing cells, and the inhibition of autophagy by ATG7 knock-down or chloroquine treatment attenuated lipid catabolism and subsequently sensitized cell death. Finally, we identified TMEM166 as a key player in C/EBPalpha-mediated autophagy induction and protection against starvation. Conclusion: C/EBPalpha is an important gene that links HCC carcinogenesis to autophagy-mediated lipid metabolism and resistance to energy starvation. Its expression in HCC predicts poorer patient prognosis. (Hepatology 2014;) “
“In a recent article, Piroth et al.

The

novel findings of this study help to dissect out the role of the complex cellular interactions Buparlisib clinical trial occurring in I/R, with the potential to develop therapeutic interventions to abrogate the sterile inflammatory response. The authors thank Nicole Hays and Junda Chen for their technical assistance in preparing this manuscript. Additional Supporting Information may be found in the online version of this article. “
“Background and Aims:  Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most significant causative factors of gastroduodenal ulcers. Recent reports have demonstrated that NSAIDs can also frequently induce ulceration and erosions of the small intestine. The aim of this study was to examine whether or not roxatidine (an H2 receptor antagonist), which is known to increase gastric mucus in addition to inhibiting gastric acid, might suppress indomethacin-induced small intestinal mucosal injury, through an increase check details in mucus in rats. Methods:  Rats were given two p.o. doses of roxatidine, famotidine or cimetidine before and after the s.c. indomethacin injection. The injured area of the small intestine was analyzed. To examine effects of drugs on small intestinal mucus, rats were also given two p.o. doses of roxatidine, famotidine or cimetidine, and the ratio of the periodic

acid Schiff (PAS)-positive

area to the area of the mucosa in the small intestine was analyzed. In addition, we evaluated the involvement of nitric oxide (NO) and prostaglandins (PG) in the effect of roxatidine on small intestinal selleck screening library mucus. Results:  Roxatidine significantly ameliorated indomethacin-induced small intestinal injury and increased the PAS-stained areas in the small intestinal mucosa, while cimetidine and famotidine had no significant effect. Pretreatment with N-nitro-L-arginine methyl ester but not with indomethacin, suppressed the effect of roxatidine on small intestinal mucus, suggesting that the effect is mediated by endogenous NO but not by PG. Conclusion:  Roxatidine suppressed indomethacin-induced small intestinal injury in rats. One possible mechanism is an increase of small intestinal mucus, mediated by NO. “
“Surgery remains an important treatment modality for many aspects of gastrointestinal cancer. In particular, it is the only definitive treatment for esophageal, gastric, and colorectal cancer, although the outcomes in esophegeal and gastric cancer remain modest. Recent developments in surgery for colorectal cancer, however, have resulted in improved outcomes, particularly with the introduction of mesorectal excision for rectal cancer. Surgery is also indicated for cancers of the liver, biliary tract, and pancreas.

2006). The frequency of MFA sonar ranges from 2.6 to 14 kHz (D’Amico et al. 2009), which is well below http://www.selleckchem.com/products/Gefitinib.html the best hearing range of beaked whales (Cook et al. 2006, Finneran et al. 2009). However, the sonar signals are acoustically similar to the stereotyped calls of killer whales (Orcinus orca), a primary predator of beaked whales (Zimmer and Tyack 2007). It has been hypothesized that the MFA sonar signal may initiate a predator avoidance reaction in the beaked whales, similar to the reaction elicited by killer

whales, that may lead to stranding (Zimmer and Tyack 2007). Studies of killer whale predation on large baleen whales have shown that baleen whales employ two basic strategies for avoiding killer whale

predation: fight and flight (Ford and Reeves 2008). Those species that employ a flight strategy attempt to outdistance the killer whales by maintaining a straight heading at high speeds over PCI-32765 research buy an extended time period (Ford et al. 2005, Ford and Reeves 2008). Of the flight species, both minke (Balaenoptera acutorostrata) and sei whales (Balaenoptera borealis) have been observed to strand themselves in attempts to escape predation by killer whales (Ford et al. 2005, Ford and Reeves 2008). In most cases the stranding itself leads to eventual death, but in rare cases the fleeing whale succeeded in swimming away when the tide rose and thus effectively escaped killer whale predation selleck chemicals llc (Ford and Reeves 2008). It has been hypothesized that beaked whales may employ an avoidance strategy similar to these whales, and that the strandings are the result of either mistaken direction during flight, or a deliberate action taken to avoid what

they may perceive as an immediate threat. Understanding what factors lead beaked whales to strand during navy sonar exercises is an important step in determining how to reduce the risk of these activities. However, the elusive nature of these animals and the diverse factors involved in each stranding incident lead to extreme difficulty in studying this problem. This paper utilizes a controlled exposure experiment to test one beaked whale’s reaction to MFA sonar signals and the calls of mammal-eating killer whales filtered to a frequency bandwidth similar to that of MFA sonar. This experiment was designed to test the above hypothesis that beaked whales respond to killer whale predation calls with a directed prolonged avoidance reaction similar to the flight response of baleen whales. We use the heading data from a tagged beaked whale to develop a method of statistical analysis of avoidance reactions and discuss the implications of the observed reaction. To reduce some of the difficulty associated with locating beaked whales for study, the experiment was conducted on the Atlantic Undersea Test and Evaluation Center (AUTEC) near Andros Island, Bahamas.

Some enteric-coated preparations also have microspheric forms that may more effectively mix with food than those in the tablet forms. Past study by DiMagno et al.[32] and recent study by Dominguez-Munoz et al.[33] confirmed that the best regimen for administrating PERT is to take the enzymes with meals. Try to distribute the enzyme throughout the meal, for example one capsule after the first few bites of food, two more capsules check details in the middle of the meal,

and last capsule after finishing the meal (1-2-1 regimen in case of requiring four capsules per meal or 2-2-2 regimen if requiring six capsules per meal).[24] Response to PERT should mainly be measured by the improvement of patients’ symptoms, weight gain, and nutritional parameters.[13, 14] In selected cases, particularly

the patients who start with subclinical severe PEI, follow up with quantitative fecal fat measurement or 13C-mixed triglyceride breath test[1] may be required to assure normalization of fat digestion because some patients may remain having subclinical malnutrition measured by low prealbumin, transferring, and retinol-binding protein.[1] Increasing the dosage of PERT can normalize this subclinical malnutrition.[1] Patients who are not well responded to adequate PERT should be asked for the compliance. Fecal chymotrypsin can be used to check for the compliance. Then, increase the dose of lipase to 90 000 or 1000 U of lipase/kg/meal should selleck compound be tried. In case the patient had previous upper gastrointestinal

surgery or anastomosis that may interfere the mixing between pancreatic enzyme and the food, opening MAPK inhibitor the capsules and administering the enzyme granules directly with meals may solve the problem. If none of the earlier factors is found, co-therapy of PPI with enteric-coating enzymes has been shown to improve steatorrhea in this group of patients.[28] The mechanism is to improve micelle formation, which is often impaired due to bile acid precipitation from the low duodenal pH in CP patients.[34] Finally, search for small intestinal bacterial overgrowth (SIBO) syndrome and other causes of small bowel malabsorption. SIBO can occur in 25–70% of CP patients[35-37] and can be diagnosed by hydrogen breath test or culture of the jejunal fluid aspirate. A 2-week trial of antibiotics, for example metronidazole is also reasonable if the tests for SIBO are unavailable. Parasitic and protozoan infections such as giadiasis[38] should be sought, particularly in patient who has hypoalbuminemia. Algorithm of the management of PERT nonresponders is shown in Figure 1. Every CP patient should be sought for the presence of severe PEI. Diagnosis can be done mainly by clinical ground, with special work-ups in some cases. Treatment comprises of normal-to-high-fat diet with adequate PERT containing lipase 40 000–90 000 U per meal with meals.

Some enteric-coated preparations also have microspheric forms that may more effectively mix with food than those in the tablet forms. Past study by DiMagno et al.[32] and recent study by Dominguez-Munoz et al.[33] confirmed that the best regimen for administrating PERT is to take the enzymes with meals. Try to distribute the enzyme throughout the meal, for example one capsule after the first few bites of food, two more capsules www.selleckchem.com/products/3-deazaneplanocin-a-dznep.html in the middle of the meal,

and last capsule after finishing the meal (1-2-1 regimen in case of requiring four capsules per meal or 2-2-2 regimen if requiring six capsules per meal).[24] Response to PERT should mainly be measured by the improvement of patients’ symptoms, weight gain, and nutritional parameters.[13, 14] In selected cases, particularly

the patients who start with subclinical severe PEI, follow up with quantitative fecal fat measurement or 13C-mixed triglyceride breath test[1] may be required to assure normalization of fat digestion because some patients may remain having subclinical malnutrition measured by low prealbumin, transferring, and retinol-binding protein.[1] Increasing the dosage of PERT can normalize this subclinical malnutrition.[1] Patients who are not well responded to adequate PERT should be asked for the compliance. Fecal chymotrypsin can be used to check for the compliance. Then, increase the dose of lipase to 90 000 or 1000 U of lipase/kg/meal should find more be tried. In case the patient had previous upper gastrointestinal

surgery or anastomosis that may interfere the mixing between pancreatic enzyme and the food, opening PD98059 mw the capsules and administering the enzyme granules directly with meals may solve the problem. If none of the earlier factors is found, co-therapy of PPI with enteric-coating enzymes has been shown to improve steatorrhea in this group of patients.[28] The mechanism is to improve micelle formation, which is often impaired due to bile acid precipitation from the low duodenal pH in CP patients.[34] Finally, search for small intestinal bacterial overgrowth (SIBO) syndrome and other causes of small bowel malabsorption. SIBO can occur in 25–70% of CP patients[35-37] and can be diagnosed by hydrogen breath test or culture of the jejunal fluid aspirate. A 2-week trial of antibiotics, for example metronidazole is also reasonable if the tests for SIBO are unavailable. Parasitic and protozoan infections such as giadiasis[38] should be sought, particularly in patient who has hypoalbuminemia. Algorithm of the management of PERT nonresponders is shown in Figure 1. Every CP patient should be sought for the presence of severe PEI. Diagnosis can be done mainly by clinical ground, with special work-ups in some cases. Treatment comprises of normal-to-high-fat diet with adequate PERT containing lipase 40 000–90 000 U per meal with meals.

However, establishing an accurate differential diagnosis is extremely challenging. Urinary biomarkers of kidney injury distinguish structural from functional causes of ABT-737 price AKI and may facilitate more accurate and rapid diagnoses. We conducted a multicenter, prospective cohort study of patients with cirrhosis and AKI assessing multiple biomarkers for differential

diagnosis of clinically adjudicated AKI. Patients (n = 36) whose creatinine returned to within 25% of their baseline within 48 hours were diagnosed with PRA. In addition, 76 patients with progressive AKI were diagnosed by way of blinded retrospective adjudication. Of these progressors, 39 (53%) patients were diagnosed with ATN, 19 (26%) with PRA, and 16 (22%) with HRS. Median values for neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), and albumin differed between etiologies and were significantly higher in patients adjudicated with ATN. The learn more fractional excretion of sodium (FENa) was lowest in patients with HRS, 0.10%, but did not differ

between those with PRA, 0.27%, or ATN, 0.31%, P = 0.54. The likelihood of being diagnosed with ATN increased step-wise with the number of biomarkers above optimal diagnostic cutoffs. Conclusion: Urinary biomarkers of kidney injury are elevated in patients with cirrhosis and AKI due to ATN. Incorporating biomarkers into clinical decision making has the potential to more accurately guide treatment by establishing which patients have structural injury underlying their AKI. Further research is required to document biomarkers specific to HRS. (Hepatology 2014;60:622–632) “
“We read with interest the article by Peng et al. investigating the potential beneficial effects of culture expanded autologous mesenchymal stem cells (MSCs) in patients with liver selleck screening library failure caused by hepatitis B virus (HBV).1 Though it is reassuring that MSC therapy delivered via the hepatic artery in this group of patients appears to be safe and feasible, there are several areas of the article that would

benefit from clarification. It would be helpful if the investigators could provide data regarding HBV viral load, genotype, and E antigen status for each patient in the trial, as they are important risk factors for progressive liver disease and hepatocellular carcinoma.2, 3 These data, in addition to hepatitis C virus coinfection, are required before robust conclusions about the efficacy of MSC therapy can be made. Patients on antiviral treatment were excluded from the trial. We would like the investigators to clarify whether HBV antiviral therapy was given at any time to the enrolled patients. This is of importance, because the efficacy of antiviral therapy in this patient group has been well established for over a decade.4, 5 In contrast, the antiviral, antifibrotic, and regenerative effects of MSCs have not been proven.

To determine the Ag persistence after Ad-HCV-NS3 infection, we analyzed the expression of FLAG-tagged

HCV-NS3 protein in the liver by IP-western blot after administration of 2 × 107, 1 × 109 or 1 × 1010 PFU of the virus. The Ag expression in the liver could be found in both core (+) and core (−) mice on 21 days after infection with 1 × 1010 PFU. When 1 × 109 PFU of Ad-HCV-NS3 was administrated, HCV NS3-protein was almost cleared from the liver of core (−) mice at day 21 post-infection, whereas the Ag expression persisted in the liver of core (+) mice until day 21 post-infection (Fig. 6). It is important to note that the loss of Ag expression in the liver of core (−) mice after infection with 1 × 109 PFU coincided with the high HCV-NS3-specific CD8 T-cell

response at 14 days post-infection (Fig. 2c), whereas Ag persistence in the liver of core (+) mice after infection with 1 × 109 PFU or the liver of core (−) and core (+) mice after infection with 1 × 1010 PFU was associated Selleckchem GSK2126458 with strongly diminished Ag-specific CD8 T-cell response (Fig. 2c). It is likely that the expression of core protein and the high amount of Ag in the liver contributed to the functional exhaustion of HCV-NS3-specific CD8 T cells. IN THIS STUDY, we found an impaired response of HCV-NS3-specific intrahepatic CD8 T cell in a high dose setting (1 × 1010 PFU) of Ad-HCV-NS3 infection. Furthermore, higher levels of expression of regulatory molecules, Tim-3 and PD-1, by intrahepatic CD8 T cells and Obeticholic Acid PD-L1 by intrahepatic APC were observed in HCV core Tg mice and the expression increased dependent selleck chemicals llc on infectious dose. In addition, we found a significant inverse correlation

between the percentages of IFN-γ-producing cells and expression of regulatory molecules in Ag-specific intrahepatic CD8 T cells. These results indicated that high infectious dose and the presence of HCV core gene were strongly involved in ineffective CD8 T-cell responses. Recently, a novel mechanism of T-cell dysfunction was demonstrated in a murine model of chronic LCMV infection.[24] It was found that the expression of PD-1 was upregulated on dysfunctional LCMV-specific CD8 T cells in mice.[24] In vivo blockade of PD-1/PD-L1 interaction restored the functions of LCMV-specific CD8 T cells and reduced the viral titer.[24] More recently, other inhibitory receptors such as Tim-3 have also been studied as the factors that can cause T-cell impairments in chronic viral infections.[25] These influential discoveries led to extensive investigations of inhibitory receptors in the regulation of T cells in human chronic viral infections.[25, 26] Chronic HCV infection in humans is characterized by CD8 T-cell exhaustion and dysfunction.[27] As in chronic LCMV infection, the expression of PD-1 is similarly upregulated on the virus-specific CD8 T cells in chronic HCV infection, and HCV-specific PD-1high T cells are functionally impaired.[28-30] Also, Tim-3 is overexpressed on HCV-specific dysfunctional CD8 T cells.