Serial cast correction and percutaneous release of hamstrings to correct contractures makes the PWH ambulatory with limited factor corrections [44]. The end-stage HA requires a more simple procedure like arthrodesis, but it puts stress on the other weight-bearing joints, leading to recurrent bleeds. In immature patients with knee arthrodesis recurrence of the deformity in the bony fusion must be avoided by regularly wearing an above knee splint. The most common deformities in ankles and feet include equinus and varus deformities. Supportive orthoses Autophagy high throughput screening and wedged insoles often help to correct deformities. Ankle and triple arthrodesis are done to provide a lasting relief in case conservative

treatment fails. The intramuscular bleeds are usually managed conservatively with factor correction, rest, traction, and gradual mobilisation. Most of the neglected bleedings result in contractures and require various muscle release, tendon lengthening and tendon transfers. Meticulous haemostasis, reducing dead space and early mobilisation leads to a successful outcome. Patient compliance in these conditions is poor in developing countries. The approach to pseudotumours is fast changing in the developing world due to better factor availability and affordability. Early surgical excision remains the hallmark of treatment and we are able to do more surgeries

at selected tertiary care centres with better laboratory backups and CFC. Percutaneous treatment is less often practiced as these tumours are not so small when they present. Surgery in PWH, although requiring a higher level of technical expertise, Fostamatinib supplier is as effective and safe (under see more cover of factor supplementation) as similar procedures in other patients. An effort from the WFH, government and medical community in forming and implementing better strategies is needed.  Haemophilia is a high-cost, low-volume disease with preventable complications which can lead to mortality and morbidity (requiring major surgical interventions). This chapter is not a cookery book, nor a bible, but just a collection of experiences of eight different professionals from both developed and developing countries. Besides their statements

just mentioned, they all put stress on early intervention, especially in children with haemophilia, no matter where they grow up. Haematologist worldwide try to use CFC to prevent bleedings, developments in this field are finally essential for PWH worldwide. Though total prevention of bleedings is not possible yet, in developed countries children with haemophilia can lead a near-normal life. To emphasize and clear up the importance of HTCs, as advocated by the WFH and accepted by all authors as the optimal way to treat PWH in daily care, we have to divide the role of such a team into acute and more chronic situations. If we do so, we run into the phenomenon that in case of chronic situations healthcare workers are more likely to assess PWH and start a proper intervention.

Foster & Dagg, 1972; van der Jeugd & Prins, 2000) and in open areas or areas with short vegetation (Foster & Dagg, 1972; Young & Isbell, 1991), a pattern consistent with our observations in Serengeti. Bercovitch & Berry (2010) suggested that in open terrain, increasing herd size does reduce predation risk for giraffes. In mountain sheep, similar behavior is observed: females and offspring occupy areas where they can detect and evade predation, while Dasatinib in vivo males occupy high-risk areas where they are more likely to encounter predators (Bleich, Bowyer & Wehausen, 1997). Consistent with this idea, claw marks were rarest in

Kirawira, where giraffes commonly gather in large herds in open grassland areas. Although we did not find any relationship between an individual’s mean herd size and claw-mark presence

in Seronera, mean individual herd size may not be a useful measure if individuals are only likely to be attacked when temporarily alone. If adult females generally behave in less risky ways, then why do they have the highest claw-mark prevalence? High claw-mark prevalence in adult females could be partially explained by marks acquired during calf defense. In a study of bottlenose dolphins Tursiops truncatus, Corkeron et al. (1987) observed fresh predation marks on a relatively high number of females with calves, and they suggested that female–calf pairs are more vulnerable Doxorubicin chemical structure to predation. Giraffe calves are an attractive target for lions. Mothers protect their calves by positioning them between their legs and by chasing or kicking at predators (Pratt & Anderson, 1979; Dagg & Foster, 1982). Lions have been observed lunging at nursing females to distract them from their calves, and this may be when they inflict superficial claw marks. In support of this hypothesis, we found a substantial jump in the prevalence of claw marks

among females at age 4–5 years, coincident with the onset of first parturition (Fig. 4a). Injuries incurred during calf defense could also explain why only selleck kinase inhibitor adult female giraffes were observed with marks on 4 or more body regions. In addition, the only observation of an individual surviving more than 1 non-lethal attack was that of an adult female. Observations of fresh claw marks on nursing females would provide additional support for this hypothesis. Adult females may be most susceptible to lethal lion attacks in the last weeks of pregnancy and just after parturition, when females behave more like mature males: pregnant females spend more time browsing in dense vegetation to meet nutritional needs (Young & Isbell, 1991). Females also become solitary shortly before giving birth (Foster & Dagg, 1972; Strauss, pers. obs.) and keep their neonates relatively isolated from other giraffes for up to 3 weeks post-partum (Langman, 1977; Pratt & Anderson, 1979; Mejia, in Moss, 1982), thereby forgoing the vigilance benefits of additional herd members.

Foster & Dagg, 1972; van der Jeugd & Prins, 2000) and in open areas or areas with short vegetation (Foster & Dagg, 1972; Young & Isbell, 1991), a pattern consistent with our observations in Serengeti. Bercovitch & Berry (2010) suggested that in open terrain, increasing herd size does reduce predation risk for giraffes. In mountain sheep, similar behavior is observed: females and offspring occupy areas where they can detect and evade predation, while http://www.selleckchem.com/products/VX-770.html males occupy high-risk areas where they are more likely to encounter predators (Bleich, Bowyer & Wehausen, 1997). Consistent with this idea, claw marks were rarest in

Kirawira, where giraffes commonly gather in large herds in open grassland areas. Although we did not find any relationship between an individual’s mean herd size and claw-mark presence

in Seronera, mean individual herd size may not be a useful measure if individuals are only likely to be attacked when temporarily alone. If adult females generally behave in less risky ways, then why do they have the highest claw-mark prevalence? High claw-mark prevalence in adult females could be partially explained by marks acquired during calf defense. In a study of bottlenose dolphins Tursiops truncatus, Corkeron et al. (1987) observed fresh predation marks on a relatively high number of females with calves, and they suggested that female–calf pairs are more vulnerable selleckchem to predation. Giraffe calves are an attractive target for lions. Mothers protect their calves by positioning them between their legs and by chasing or kicking at predators (Pratt & Anderson, 1979; Dagg & Foster, 1982). Lions have been observed lunging at nursing females to distract them from their calves, and this may be when they inflict superficial claw marks. In support of this hypothesis, we found a substantial jump in the prevalence of claw marks

among females at age 4–5 years, coincident with the onset of first parturition (Fig. 4a). Injuries incurred during calf defense could also explain why only see more adult female giraffes were observed with marks on 4 or more body regions. In addition, the only observation of an individual surviving more than 1 non-lethal attack was that of an adult female. Observations of fresh claw marks on nursing females would provide additional support for this hypothesis. Adult females may be most susceptible to lethal lion attacks in the last weeks of pregnancy and just after parturition, when females behave more like mature males: pregnant females spend more time browsing in dense vegetation to meet nutritional needs (Young & Isbell, 1991). Females also become solitary shortly before giving birth (Foster & Dagg, 1972; Strauss, pers. obs.) and keep their neonates relatively isolated from other giraffes for up to 3 weeks post-partum (Langman, 1977; Pratt & Anderson, 1979; Mejia, in Moss, 1982), thereby forgoing the vigilance benefits of additional herd members.

Foster & Dagg, 1972; van der Jeugd & Prins, 2000) and in open areas or areas with short vegetation (Foster & Dagg, 1972; Young & Isbell, 1991), a pattern consistent with our observations in Serengeti. Bercovitch & Berry (2010) suggested that in open terrain, increasing herd size does reduce predation risk for giraffes. In mountain sheep, similar behavior is observed: females and offspring occupy areas where they can detect and evade predation, while Fludarabine solubility dmso males occupy high-risk areas where they are more likely to encounter predators (Bleich, Bowyer & Wehausen, 1997). Consistent with this idea, claw marks were rarest in

Kirawira, where giraffes commonly gather in large herds in open grassland areas. Although we did not find any relationship between an individual’s mean herd size and claw-mark presence

in Seronera, mean individual herd size may not be a useful measure if individuals are only likely to be attacked when temporarily alone. If adult females generally behave in less risky ways, then why do they have the highest claw-mark prevalence? High claw-mark prevalence in adult females could be partially explained by marks acquired during calf defense. In a study of bottlenose dolphins Tursiops truncatus, Corkeron et al. (1987) observed fresh predation marks on a relatively high number of females with calves, and they suggested that female–calf pairs are more vulnerable see more to predation. Giraffe calves are an attractive target for lions. Mothers protect their calves by positioning them between their legs and by chasing or kicking at predators (Pratt & Anderson, 1979; Dagg & Foster, 1982). Lions have been observed lunging at nursing females to distract them from their calves, and this may be when they inflict superficial claw marks. In support of this hypothesis, we found a substantial jump in the prevalence of claw marks

among females at age 4–5 years, coincident with the onset of first parturition (Fig. 4a). Injuries incurred during calf defense could also explain why only selleck chemicals llc adult female giraffes were observed with marks on 4 or more body regions. In addition, the only observation of an individual surviving more than 1 non-lethal attack was that of an adult female. Observations of fresh claw marks on nursing females would provide additional support for this hypothesis. Adult females may be most susceptible to lethal lion attacks in the last weeks of pregnancy and just after parturition, when females behave more like mature males: pregnant females spend more time browsing in dense vegetation to meet nutritional needs (Young & Isbell, 1991). Females also become solitary shortly before giving birth (Foster & Dagg, 1972; Strauss, pers. obs.) and keep their neonates relatively isolated from other giraffes for up to 3 weeks post-partum (Langman, 1977; Pratt & Anderson, 1979; Mejia, in Moss, 1982), thereby forgoing the vigilance benefits of additional herd members.

Participants described acute and persistent pain with the same pain descriptors leading to the conclusion that patients have difficulty distinguishing between acute and persistent pain. This lack of differentiation was further displayed

by the use of factor replacement to treat persistent pain associated with arthritic discomfort (38%) which would be viewed as inappropriate, as well as lack of factor replacement use by 21% of respondents who identified pain as from an acute bleed. Opportunities exist to improve pain management through patient and provider-directed educational programs. “
“Summary.  Recombinant Romidepsin research buy FVIII (rFVIII) has become the best choice for treating bleeding of haemophilia A patients. A plasma- and albumin-free recombinant FVIII (rAHF-PFM, ADVATE®), as the third generation rFVIII, virtually eliminates the risk of blood-borne disease transmission by excluding all human blood derived additives BMN 673 in vitro throughout cell culture, purification and formulation. In this multicentre prospective clinical study we evaluated the efficacy, safety and immunogenicity of ADVATE® in Chinese patients with haemophilia A. Fifty-eight patients enrolled and received ADVATE® treatment. Of the patients enrolled, eight (13.79%) had severe haemophilia, 45 (77.59%)

had moderate haemophilia and five (8.62%) had mild haemophilia. Fifty-four patients completed 6 months of observation. A total of 781 bleeds occurred in these 58 subjects, all evaluable per-protocol.

A total of 984 infusions were administered with a mean of 17.0 ± 11.1 infusions per patient. selleckchem On average, each patient received a mean of 15030.2 ± 7972.7 IU ADVATE® (median 13 625 IU, range 9500–19 750 IU) during 6 months. The majority of bleeding episodes (95.9%) were successfully treated with one or two infusions of ADVATE®. Overall, response to the first ADVATE® treatment was rated as either ‘excellent’ (82.8%) or ‘improved’ (17.2%) in all subjects. All patients tolerated ADVATE® infusions well. One patient (1/58, 1.7%) developed an inhibitor of 4 Betheseda units at day 180 visit. The results of this clinical observational study support that ADVATE® is efficacious, safe and well tolerated in the treatment of Chinese patients with haemophilia A. “
“Summary.  The rare inherited coagulation factor deficiencies (deficiencies of factors I, II, V, VII, XI, XIII, combined FV + FVII deficiency, combined deficiency of the vitamin K dependent factors and von Willebrand disease type 3) have an aggregate prevalence of approximately 1:100 000. They may cause recurrent life or function threatening haemorrhage. In this article we review the available literature on long-term prophylaxis and, where possible, make recommendations on this important area. “
“The use of by-passing agents has substantially improved the care of patients with hemophilia complicated by inhibitors. The availability of these drugs, i.e.

Participants described acute and persistent pain with the same pain descriptors leading to the conclusion that patients have difficulty distinguishing between acute and persistent pain. This lack of differentiation was further displayed

by the use of factor replacement to treat persistent pain associated with arthritic discomfort (38%) which would be viewed as inappropriate, as well as lack of factor replacement use by 21% of respondents who identified pain as from an acute bleed. Opportunities exist to improve pain management through patient and provider-directed educational programs. “
“Summary.  Recombinant selleck inhibitor FVIII (rFVIII) has become the best choice for treating bleeding of haemophilia A patients. A plasma- and albumin-free recombinant FVIII (rAHF-PFM, ADVATE®), as the third generation rFVIII, virtually eliminates the risk of blood-borne disease transmission by excluding all human blood derived additives STA-9090 throughout cell culture, purification and formulation. In this multicentre prospective clinical study we evaluated the efficacy, safety and immunogenicity of ADVATE® in Chinese patients with haemophilia A. Fifty-eight patients enrolled and received ADVATE® treatment. Of the patients enrolled, eight (13.79%) had severe haemophilia, 45 (77.59%)

had moderate haemophilia and five (8.62%) had mild haemophilia. Fifty-four patients completed 6 months of observation. A total of 781 bleeds occurred in these 58 subjects, all evaluable per-protocol.

A total of 984 infusions were administered with a mean of 17.0 ± 11.1 infusions per patient. this website On average, each patient received a mean of 15030.2 ± 7972.7 IU ADVATE® (median 13 625 IU, range 9500–19 750 IU) during 6 months. The majority of bleeding episodes (95.9%) were successfully treated with one or two infusions of ADVATE®. Overall, response to the first ADVATE® treatment was rated as either ‘excellent’ (82.8%) or ‘improved’ (17.2%) in all subjects. All patients tolerated ADVATE® infusions well. One patient (1/58, 1.7%) developed an inhibitor of 4 Betheseda units at day 180 visit. The results of this clinical observational study support that ADVATE® is efficacious, safe and well tolerated in the treatment of Chinese patients with haemophilia A. “
“Summary.  The rare inherited coagulation factor deficiencies (deficiencies of factors I, II, V, VII, XI, XIII, combined FV + FVII deficiency, combined deficiency of the vitamin K dependent factors and von Willebrand disease type 3) have an aggregate prevalence of approximately 1:100 000. They may cause recurrent life or function threatening haemorrhage. In this article we review the available literature on long-term prophylaxis and, where possible, make recommendations on this important area. “
“The use of by-passing agents has substantially improved the care of patients with hemophilia complicated by inhibitors. The availability of these drugs, i.e.

Because the patient was quite constipated and had impressive amounts of stool in his colon, a glycerol enema was given. The following day, as signs of shock were becoming evident, the patient was referred to us. The physical examination of abdomen did not show abnormal findings except for reduced abdominal sounds. Laboratory tests indicated slight anemia (hemoglobin, 10.9 g/dL) and acidosis (pH, 7.391; base excess, −3.2 mmol/L), an elevated white blood cell count (10,900/mm3) and creatine kinase (1342 U/L). An abdominal radiograph Saracatinib chemical structure revealed

massive small bowel gas and an abdominal computed tomography (CT) showed massive intra- (thin arrow in Figure 1 and 2) and extra- (thick arrow in Figure 2) hepatic gas, cholelithiasis (circle in Figure 2) and distended small bowel (Figure 3). Free air was not detected. Based on a diagnosis of massive portal and superior mesenteric venous gas, possibility of bowel ischemia and cholangitis with

pneumobilia, emergency laparotomy was performed. It revealed serous ascites, edematous changes of the jejunal serosa and portal venous gas. Considering the possibility of pneumobilia, therefore, we performed a cholecystectomy with cystic tube drainage and intra-abdominal-lavage. The patient had an uneventful postoperative course. Follow-up CT, performed 3 days postoperatively, confirmed resolution of the portal venous gas. Cultures of bile and ascites that were extracted intraoperatively Nutlin-3a datasheet were negative. Portal venous gas is an uncommon feature of acute abdomen

with a high mortality rate. It selleck screening library has been reported to be associated with various conditions such as ischemic bowel, bowel obstruction, intra-abdominal abcess, gastric ulcer, ulcerative colitis, pancreatitis, suppurative cholangitis and enema. The mechanical causes of portal venous gas are proposed mucosal damage, bowel distension and sepsis caused by gas-producing bacteria. The prognosis of patients is associated with the underlying diseases, therefore, urgent laparotomy is recommended for patients with concurrent signs of bowel necrosis or ischemia. The CT scan in this case revealed massive hepatic portal venous gas, an air-fluid level in the superior mesenteric vein and extensive small bowel pneumatosis intestinalis. Urgent laparotomy was performed to exclude bowel ischemia and severe cholangitis. Despite the massive portal venous gas and pneumatosis intestinalis in this case, laparotomy was probably not required. Retrospectively, the glycerol enema was speculated as the cause of the massive portal venous gas. Contributed by “
“Molloy and colleagues1 report original results about the association between caffeine consumption and the low risk of insulin resistance (IR) and fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD).

Disclosures: The following people have nothing to disclose: Debolina Ray, Sharon DeMorrow, Fanyin Meng, Julie Venter, Heather L. Francis, Laura Hargrove, Kelly McDaniel, Syeda H. Afroze, Paolo Onori, Eugenio Gaudio, Shannon S. Glaser, Gianfranco Alpini BACKGROUND: The multi-drug resistance protein 3 (MDR3/ABCB4, Mdr2 in rodent) is a critical determinant of biliary phosphatidylcholine (PC) secretion. Clinically, mutations and deficiencies in MDR3 result in cholestatic liver injury and MDR3 is a potential therapeutic target. Fibrates are FDAapproved hypolipidemic agents and have been shown to upregulate Mdr2 expression via the nuclear receptor,

PPARα. AZD9291 Fenofibrate (FF) can improve liver function in some patients with cholestatic liver disease. AIM: We previously demonstrated that fenofibrate significantly up-regulated MDR3 mRNA and protein expression in primary cultures of human hepatocytes and stimulated MDR3 promoter activity in Y-27632 mw HepG2 cells (Hepatology, Vol. 56, 4

(Supplement), p. 541A, October 2012). The aim of this study is to determine the mechanism by which fenofibrate regulates human MDR3 gene expression and whether fenofibrate regulates biliary PC secretion. METHODS: In silico analysis of the 5′-upstream region of human MDR3 gene revealed several PPARα response elements (PPRE). The direct binding of PPARα to the human MDR3 promoter was determined by EMSA using the TNT T7 quick-coupled transcription/translation system and by ChIP assays carried out in monolayers of HepG2 cells and primary human hepatocytes cultured in a matrigel sandwich. Site-directed mutagenesis of selected PPREs was

performed using a QuikChange Site-Directed Mutagenesis kit. Collagen sandwich cultured rat hepatocytes were used to measure secretion of fluorescent PC into bile canaliculi. RESULTS: Cotransfection of the MDR3 promoter with hPPARa/hRXRa expression plasmids increased luciferase activity by 2-fold in the 6-10 kb upstream region when treated with FF. Targeted mutagenesis of three novel PPREs located at −6775/-6797 bp, −7197/-7219 bp, and −8554/-8576 bp upstream of the transcription start site reduced click here activation of the MDR3 promoter by FF. EMSA and ChlP assays show direct binding of PPARα to the MDR3 promoter. Treatment of primary rat hepatocytes with FF significantly increased secretion of fluorescent PC into bile canaliculi by 2-fold vs. control (37 ± 9% vs. 18 ± 5. 5%, respectively). CONCLUSIONS: Taken together, our findings indicate that fenofibrate activates MDR3 gene transcription via the binding of PPARa to three novel and functionally critical PPREs in the MDR3 promoter. Fenofibrate treatment further stimulated biliary PC secretion in rat hepatocytes, thereby providing a functional correlate.

F4/80 antibody staining displayed similar macrophage accumulation in livers of the two groups (Fig. 5B). Interleukin-6 (IL-6) has been implicated in progenitor cells and inflammatory responses in the liver.20 As expected, the serum level of IL-6 and liver IL-6 messenger RNA (mRNA) expression were significantly higher

in HBx mice than in WT (Fig. 5C). Increased IL-6 pathway activity in HPCs is critical for disturbed growth and tumorigenic differentiation of these liver precursors,13 acting through activation of STAT3 and transcription activity. Clearly, although DDC treatment increased the levels of P-STAT3 in both the WT and HBx liver tissues at 1 and 4 months, HBx mice exhibited higher activity of P-STAT3 (Fig. 5D). This was consistent with a recent report that HBx enhanced the synthesis and secretion of IL-6, which may be through an MyD88-dependent LBH589 pathway to the activation of both

nuclear factor kappa B BMN 673 in vitro (NF-κB) and ERK/p38 mitogen-activated protein (MAP) kinases in hepatic and hepatoma cells.21 In our results we also found that there was stronger activation of ERK and P38 in HBx murine livers compared with WT mice (Fig. 5D). In addition, tumors derived from liver of HBx mice fed with DDC for 7 months also showed higher activation of STAT3, ERK, and P38 compared with adjacent nontumor liver tissues (Fig. 5D). The results suggested that an increase of IL-6 production and its signaling activity may contribute to HBx-induced malignant transformation of HPCs. The Wnt/β-catenin signaling pathway is known to be responsible for activation and transformation of stem/progenitor cells.10-12 To identify if this pathway is involved in expansion and tumorigenicity of check details HPCs, we detected the activity of Wnt/β-catenin signaling pathway in WT and HBx transgenic mice. As shown in Fig. 6A, mRNA levels of CyclinD1 and c-myc, well-known downstream targets of Wnt/β-catenin signaling, increased in HPCs isolated from HBx mice, and immunoblotting analysis of whole liver lysates showed similar results (Fig. 6B). Using

immunohistochemical labeling, we observed stronger β-catenin staining in both cytoplasmic and nuclear of HPCs in HBx mice than those in WT mice (Fig. 6C). It is known that phosphorylation of GSK-3β is a major mechanism that leads to increased cellular expression of β-catenin.22 Therefore, we compared he kinase activity of GSK-3β between HBx mice and WT mice. Consistent with this notion, we found that phosphorylation of GSK-3β at the Ser9 residue in HBx mice was much stronger than that detected in WT mice (Fig. 6D). In addition, tumors isolated from liver of HBx mice fed with DDC for 7 months also showed higher cytoplasmic and nuclear β-catenin staining and phosphorylation of GSK-3β (Fig. 6B,E). These results suggest that higher activation of the Wnt/β-catenin pathway in HBx mice may be necessary for the expansion and transformation of HPCs.

F4/80 antibody staining displayed similar macrophage accumulation in livers of the two groups (Fig. 5B). Interleukin-6 (IL-6) has been implicated in progenitor cells and inflammatory responses in the liver.20 As expected, the serum level of IL-6 and liver IL-6 messenger RNA (mRNA) expression were significantly higher

in HBx mice than in WT (Fig. 5C). Increased IL-6 pathway activity in HPCs is critical for disturbed growth and tumorigenic differentiation of these liver precursors,13 acting through activation of STAT3 and transcription activity. Clearly, although DDC treatment increased the levels of P-STAT3 in both the WT and HBx liver tissues at 1 and 4 months, HBx mice exhibited higher activity of P-STAT3 (Fig. 5D). This was consistent with a recent report that HBx enhanced the synthesis and secretion of IL-6, which may be through an MyD88-dependent buy Cobimetinib pathway to the activation of both

nuclear factor kappa B R788 price (NF-κB) and ERK/p38 mitogen-activated protein (MAP) kinases in hepatic and hepatoma cells.21 In our results we also found that there was stronger activation of ERK and P38 in HBx murine livers compared with WT mice (Fig. 5D). In addition, tumors derived from liver of HBx mice fed with DDC for 7 months also showed higher activation of STAT3, ERK, and P38 compared with adjacent nontumor liver tissues (Fig. 5D). The results suggested that an increase of IL-6 production and its signaling activity may contribute to HBx-induced malignant transformation of HPCs. The Wnt/β-catenin signaling pathway is known to be responsible for activation and transformation of stem/progenitor cells.10-12 To identify if this pathway is involved in expansion and tumorigenicity of selleck inhibitor HPCs, we detected the activity of Wnt/β-catenin signaling pathway in WT and HBx transgenic mice. As shown in Fig. 6A, mRNA levels of CyclinD1 and c-myc, well-known downstream targets of Wnt/β-catenin signaling, increased in HPCs isolated from HBx mice, and immunoblotting analysis of whole liver lysates showed similar results (Fig. 6B). Using

immunohistochemical labeling, we observed stronger β-catenin staining in both cytoplasmic and nuclear of HPCs in HBx mice than those in WT mice (Fig. 6C). It is known that phosphorylation of GSK-3β is a major mechanism that leads to increased cellular expression of β-catenin.22 Therefore, we compared he kinase activity of GSK-3β between HBx mice and WT mice. Consistent with this notion, we found that phosphorylation of GSK-3β at the Ser9 residue in HBx mice was much stronger than that detected in WT mice (Fig. 6D). In addition, tumors isolated from liver of HBx mice fed with DDC for 7 months also showed higher cytoplasmic and nuclear β-catenin staining and phosphorylation of GSK-3β (Fig. 6B,E). These results suggest that higher activation of the Wnt/β-catenin pathway in HBx mice may be necessary for the expansion and transformation of HPCs.