Here we evaluated the effect of baseline HCV NS5A, NS5B and NS3 resistance-associated variants (RAVs) on treatment outcome. In addition, NS5A and NS5B RAVs were evaluated in all virologic failures. Methods: Population (n=233) or deep (n=1904) sequencing for the HCV NS5A gene was performed at baseline (BL) for all enrolled

subjects in the phase 2/3 studies (ION-1, 2, 3, LON-ESTAR and Electron arms 12-13, 16-17 and 20-21) and for NS5B at BL in a subset of subjects by population (n=64) or deep (n=1628) SCH727965 concentration sequencing. Deep sequencing of NS5A and NS5B was performed for all subjects who didn’t achieve SVR12. Consensus sequences were generated from deep sequences using 1, 5, 10, 15 and 20% cut-offs (% of total reads). Deep sequencing of NS3 was performed at BL for all treatment-experienced subjects (n=531). Results: Overall, 345/2137 (16.1%) subjects were identified as having BL NS5A RAVs; 318/345

(92.2%) achieved SVR12 following 6,8,12 or 24 weeks treatment with LDV/SOF ± RBV. Of the 1897/1904 subjects who had successful deep sequencing (GT1a, n=1428; GT1b, n=469), GPCR Compound Library 16.8, 11.8, 9.9, 9.0 and 8.4% had NS5A RAVs with 1,5,10,15 and 20% cutoffs, respectively. For all cutoffs, the most frequent NS5A RAVs in GT1b subjects were Y93H and L31M. nearly In GT1a subjects, the most frequent NS5A RAVs with 1% cutoff were K24R>L31M>Q30H>M28T>Y93H>Q30R. With 5, 10, 15 and 20% cutoffs, Q30H and L31M were most frequent. No significant differences in SVR rates were seen for the different cutoffs. A total of 43 subjects with

NS5B sequencing had nucleotide inhibitor (NI) RAVs at BL (L159F+C316N; n=35, L159F; n=1, N142T; n=5, S282G; n=1, L320S; n=1). All subjects with NI RAVs achieved SVR12. 144/268 (53.7%) subjects previously treated with PI+PEG+RBV had BL NS3 RAVs. Of these, 139/144 (96.5%) achieved SVR12. A total of 51/2144 (2.4%) subjects experienced virologic failure or early discontinuation and qualified for resistance analysis. Among these, NS5A RAVs were detected at BL in 22/51 subjects and an additional 17 subjects developed NS5A RAVs at virologic failure. For NS5B, S282T together with NS5A RAVs was detected in one subject; another subject had L159F (2.5%) together with Y93N (>99%) in NS5A; and one subject had V321A (1.1%) without NS5A RAVs. Conclusions: NS5A RAVs are common prior to treatment in HCV GT1 subjects. However, high SVR 12 rates (>90%) with LDV/SOF ± RBV were achieved despite presence of baseline NS5A, NS5B and NS3 RAVs. The majority of virologic failures developed single class LDV NS5A resistance without NS5B RAVs.

Treatment directed at the underlying lesions leading to the recurrent GI bleeding has been the most effective modality for the management of this complex condition. Other antiangiogenic agents such as lenalidomide and vascular endothelial growth factor inhibitors

are options that may be required in the future if thalidomide therapy fails or if untenable adverse effects develop. Dr Perez Botero PLX4032 analysed the data and wrote the paper; Dr Burns provided clinical care, data and contributed to writing the paper; Dr Thompson collected the data, provided clinical care and contributed to writing the paper; Dr Pruthi collated the data, provided clinical care and contributed to writing the paper. The authors stated that they had no interests which might be perceived as posing a conflict or bias. “
“Institute of Biochemistry and Biotechnology (IBB), University of Veterinary and Animal Sciences (UVAS), Lahore, Pakistan “
“Prophylaxis is the regular administration of factor

concentrates in order to prevent spontaneous hemorrhages and is the recommended therapy for patients with severe hemophilia. There is a global consensus about starting prophylaxis early (before the development of joint damage), continuing see more prophylaxis in adolescents and possibly maintaining the prophylaxis into adult age. Maintaining prophylaxis in adults that started it early must be individualized. Starting secondary prophylaxis in adolescents and adults that already have joint damage reduces bleedings and can provide those patients some Farnesyltransferase of the same benefits observed in pediatric patients. The results of the published works are encouraging even yet there is no evidence which shows the efficacy of prophylaxis in these groups. “
“This chapter contains section titles:

Thyroid Biopsy and Hemophilia Atrial Fibrillation and Bleeding Disorders Chronic Upper Gastrointestinal Bleeding and Hemophilia Hematuria “
“Deterioration of ankle joint function due to repetitive intraarticular or extraarticular bleeding will lead to a plantar flexion contracture and a rigid joint. It is a disabling condition because it will affect posture, gait and load distribution of the foot. To enhance diagnostic clarity, we have developed the following etiological classification [1]: 1  Type 1- Chronic synovitis of the ankle. The severe pain and joint swelling experienced with acute intraarticular hemorrhage of the ankle will drive the ankle into plantar flexion. Repetitive bleeding will result in synovial hypertrophy. Active or passive dorsiflexion will produce synovial impingement and, consequently, a new bleed. What started as an antalgic plantar flexion attitude of the ankle will evolve into a structured protective plantar flexion deformity, due to retraction of the posterior ankle capsule and shortening of the achilles tendon.

Treatment directed at the underlying lesions leading to the recurrent GI bleeding has been the most effective modality for the management of this complex condition. Other antiangiogenic agents such as lenalidomide and vascular endothelial growth factor inhibitors

are options that may be required in the future if thalidomide therapy fails or if untenable adverse effects develop. Dr Perez Botero find more analysed the data and wrote the paper; Dr Burns provided clinical care, data and contributed to writing the paper; Dr Thompson collected the data, provided clinical care and contributed to writing the paper; Dr Pruthi collated the data, provided clinical care and contributed to writing the paper. The authors stated that they had no interests which might be perceived as posing a conflict or bias. “
“Institute of Biochemistry and Biotechnology (IBB), University of Veterinary and Animal Sciences (UVAS), Lahore, Pakistan “
“Prophylaxis is the regular administration of factor

concentrates in order to prevent spontaneous hemorrhages and is the recommended therapy for patients with severe hemophilia. There is a global consensus about starting prophylaxis early (before the development of joint damage), continuing click here prophylaxis in adolescents and possibly maintaining the prophylaxis into adult age. Maintaining prophylaxis in adults that started it early must be individualized. Starting secondary prophylaxis in adolescents and adults that already have joint damage reduces bleedings and can provide those patients some Thalidomide of the same benefits observed in pediatric patients. The results of the published works are encouraging even yet there is no evidence which shows the efficacy of prophylaxis in these groups. “
“This chapter contains section titles:

Thyroid Biopsy and Hemophilia Atrial Fibrillation and Bleeding Disorders Chronic Upper Gastrointestinal Bleeding and Hemophilia Hematuria “
“Deterioration of ankle joint function due to repetitive intraarticular or extraarticular bleeding will lead to a plantar flexion contracture and a rigid joint. It is a disabling condition because it will affect posture, gait and load distribution of the foot. To enhance diagnostic clarity, we have developed the following etiological classification [1]: 1  Type 1- Chronic synovitis of the ankle. The severe pain and joint swelling experienced with acute intraarticular hemorrhage of the ankle will drive the ankle into plantar flexion. Repetitive bleeding will result in synovial hypertrophy. Active or passive dorsiflexion will produce synovial impingement and, consequently, a new bleed. What started as an antalgic plantar flexion attitude of the ankle will evolve into a structured protective plantar flexion deformity, due to retraction of the posterior ankle capsule and shortening of the achilles tendon.

6.5% of all patients discontinued therapy due to AEs. Conclusion:  In everyday clinical practice PEG-IFN therapy

in CHB is well tolerated and can achieve a similar efficacy to that seen in large controlled trials. “
“Biopsy is still the gold standard for the diagnosis of nonalcoholic steatohepatitis but the definition may vary among pathologists, http://www.selleckchem.com/products/Romidepsin-FK228.html a drawback especially in evaluation of biopsies for clinical trials. We previously developed a scoring system (steatosis, activity, fibrosis [SAF]) allowing the use of an algorithm (fatty liver inhibition of progression [FLIP]) for the classification of liver injury in morbid obesity. The aim of this study was to determine whether the use of the SAF score and FLIP algorithm can decrease interobserver variations among pathologists. In a first session, pathologists categorized 40 liver biopsies of patients with nonalcoholic fatty liver disease (NAFLD) according to their own experience. In a second reading session, each pathologist reclassified

the same slides by using the FLIP algorithm and SAF score, blinded to their first evaluation. The experiment was repeated with two different groups of pathologists at varying levels of training in liver pathology. The percentage of biopsy interpretation concordant with reference evaluation increased from 77% to 97% in Group 1 and from 42% to 75% in Group 2 after the use of the SAF score and FLIP algorithm. The strength of concordance Nabilone in classification increased in Group 1 from moderate (κ = 0.54) to substantial (κ = 0.66) GSK-3 activity and from fair (κ = 0.35) to substantial (κ = 0.61) in Group 2 with application of the algorithm. With regard to the SAF score, concordance was substantial in Group 1 for steatosis (κ = 0.61), activity (κ = 0.75), and almost perfect for fibrosis (κ = 0.83 after pooling 1a, 1b, and 1c together into a single score F1). Similar trends were observed in Group 2 (κ = 0.54 for S, κ = 0.68 for A, and κ = 0.72 for F). Conclusion: The FLIP algorithm based on the SAF score

should decrease interobserver variations among pathologists and are likely to be implemented in pathology practice. (Hepatology 2014;60:565–575) “
“Increasing evidence suggests that hepatic fibrosis and pathological angiogenesis are interdependent processes that occur in parallel. Endothelial cell invasion is requisite for angiogenesis, and thus studies of the mechanisms governing liver endothelial cell (LEC) invasion during cirrhosis are of great importance. Emerging research implicates amoeboid-type motility and membrane blebbing as features that may facilitate invasion through matrix-rich microenvironments. Aquaporins (AQPs) are integral membrane water channels, recognized for their importance in epithelial secretion and absorption. However, recent studies also suggest links between water transport and cell motility or invasion.

6.5% of all patients discontinued therapy due to AEs. Conclusion:  In everyday clinical practice PEG-IFN therapy

in CHB is well tolerated and can achieve a similar efficacy to that seen in large controlled trials. “
“Biopsy is still the gold standard for the diagnosis of nonalcoholic steatohepatitis but the definition may vary among pathologists, R428 supplier a drawback especially in evaluation of biopsies for clinical trials. We previously developed a scoring system (steatosis, activity, fibrosis [SAF]) allowing the use of an algorithm (fatty liver inhibition of progression [FLIP]) for the classification of liver injury in morbid obesity. The aim of this study was to determine whether the use of the SAF score and FLIP algorithm can decrease interobserver variations among pathologists. In a first session, pathologists categorized 40 liver biopsies of patients with nonalcoholic fatty liver disease (NAFLD) according to their own experience. In a second reading session, each pathologist reclassified

the same slides by using the FLIP algorithm and SAF score, blinded to their first evaluation. The experiment was repeated with two different groups of pathologists at varying levels of training in liver pathology. The percentage of biopsy interpretation concordant with reference evaluation increased from 77% to 97% in Group 1 and from 42% to 75% in Group 2 after the use of the SAF score and FLIP algorithm. The strength of concordance Decitabine in classification increased in Group 1 from moderate (κ = 0.54) to substantial (κ = 0.66) find more and from fair (κ = 0.35) to substantial (κ = 0.61) in Group 2 with application of the algorithm. With regard to the SAF score, concordance was substantial in Group 1 for steatosis (κ = 0.61), activity (κ = 0.75), and almost perfect for fibrosis (κ = 0.83 after pooling 1a, 1b, and 1c together into a single score F1). Similar trends were observed in Group 2 (κ = 0.54 for S, κ = 0.68 for A, and κ = 0.72 for F). Conclusion: The FLIP algorithm based on the SAF score

should decrease interobserver variations among pathologists and are likely to be implemented in pathology practice. (Hepatology 2014;60:565–575) “
“Increasing evidence suggests that hepatic fibrosis and pathological angiogenesis are interdependent processes that occur in parallel. Endothelial cell invasion is requisite for angiogenesis, and thus studies of the mechanisms governing liver endothelial cell (LEC) invasion during cirrhosis are of great importance. Emerging research implicates amoeboid-type motility and membrane blebbing as features that may facilitate invasion through matrix-rich microenvironments. Aquaporins (AQPs) are integral membrane water channels, recognized for their importance in epithelial secretion and absorption. However, recent studies also suggest links between water transport and cell motility or invasion.

01). Although these data are preliminary and require independent confirmation, it is possible that these polymorphisms could increase RAC1 expression enough in vivo to decrease efficacy of thiopurine therapy when administered at a standard dose. The authors reported a non-significant trend toward higher frequencies of the −289C and VNTR-3 alleles in IBD patients who did not develop leucopenia on azathioprine (P = 0.079, OR = 0.18, 95% CI 0.02–1.49).37

This observation arguably supports the hypothesis that these promoter polymorphisms do increase RAC1 expression in vivo and may influence the efficiency and toxicity of thiopurine therapy. Does an ABCC4 polymorphism account for enhanced thiopurine sensitivity?  Multi-drug resistance protein 4 (MRP4) is an ATP-dependent efflux pump that is able to transport 6-TGNs out of cells.38 Overexpression of this pump and the concurrent downregulation of influx transporters (plasma membrane Selleckchem KU57788 nucleoside transporters, NTs) have

been shown to confer resistance of human leukemic cell lines to thiopurine drugs.39 Analysis of the accumulation and efflux of radio-labeled 6-mercatopurine, revealed that the leukaemic cells that overexpressed MRP4 effluxed 72.3% of 6-mercaptopurine as 6TGNs into the culture medium within 1 h compared with 23.7% of 6-TGNs by the control cell line.39 Conversely, murine models have demonstrated that a deficiency in MRP4 expression results in accumulation of 6-TGNs LY294002 to toxic concentrations in myeloid progenitor cells. Krishnamurthy et al.40 tested the 6-mercaptopurine sensitivity of Mrp4+/+ and Mrp4−/− mice by administering intraperitoneal injections of this thiopurine to the mice each day for 15 days. By day 13 all Mrp4−/− Racecadotril mice were dead, whereas > 75% of wild type mice were alive at day 15. Bone marrow cell 6-TGN concentrations in Mrp4−/− mice

were 10 times higher than the concentrations found in Mrp4+/+ mice. Moreover myeloid progenitor cells after 5 days of treatment were reduced by 74% in Mrp4−/− mice but only by < 20% in Mrp4+/+ mice.40 The gene coding for human MRP4 (ABCC4) is highly polymorphic.41 At least one variant has been identified that significantly impairs the functioning of this pump and may explain why some IBD patients who have normal TPMT activity, still develop 6-TGN-induced myelotoxicity. The nonsynomous ABCC4 SNP 2269G>A (rs3765534, E857K) codes a variant MRP4 protein, which is unable to effectively localize to the plasma membrane.40 In HEK293 cells the 5-fold reduction in cell surface expression resulted in enhanced 6-mercaptopurine cytotoxicity, with an EC50 of 9.7 µmol/L versus 17.3 µmol/L in cells expressing the wild type (2269G) allele (P < 0.05).40 The frequency of the minor allele (2269A) is 15–22% in Japanese and 8.3% in Han Chinese, but less than 1% in Caucasians and Africans. Ban et al.

For walruses, annual survival of juvenile and adult walruses, 4–20 yr of age, must be approximately 0.96–0.99 to compensate for their low fecundity (DeMaster 1984, Fay et al. 1997). Mature females give birth to a single calf, birth intervals are typically ≥2 yr (Fay 1982), and calves are believed to have annual survival rates ranging from 0.5 to 0.9 (Fay et al. 1997). Hence, recruitment into the adult age classes is expected to be low, while adult survival is high; hence, the number of cows should be relatively stable from year to year. We note, however, that small changes in survival and slow rates of decline will likely be undetectable (see Harris et al. 2008). Other issues

that may complicate interpretation of walrus calf:cow ratios Fulvestrant solubility dmso Selleck INCB024360 include classification error, repeatability of surveys, and the timing of surveys: Interpreting the age ratios clearly depends upon

how well observers can classify walruses to different sex and age categories. During the 1981 survey, Fay and Kelly (1989) compared untrained observers with trained observers in their ability to classify walruses based upon Fay’s classification scheme. They determined that all observers differentiated adults from juvenile age classes equally well, but that untrained observers tended to overestimate calves and underestimate yearlings. Fay and Kelly (1989) believed this was likely due to untrained observers not realizing that calves have dark pelage and that yearling tusks are hard to observe why unless their heads are tilted up. Training corrected this issue. A more important question is how often trained observers make classification errors. Calves and yearlings are easily recognized; calves due to their small size and dark pelage, yearlings due to their small size, lighter pelage, and “nubbin” tusks. However, classifying adult females requires comparing the ratio of tusk length to snout width and depth as visually depicted in Figure 1. Unfortunately, the range of tusk length to snout depth ratios overlap by 50% between animals 4–5 yr of age and those

6–9 yr of age. For these two age classes, the range of tusk length to snout width ratios also overlap by 47% (Fig. 2). If 4–5-yr-olds are classified as adults, this will bias calf:cow ratios low as it artificially inflates the denominator of the ratio. However, the bias should be low because there are relatively few 4–5-yr-olds in the sample compared to the number of cows. For example, assume the percentage of 4–5-yr-olds misclassified is exactly 50%, representing a worst-case scenario. Across all survey years, 527 calves, 536 4–5-yr-olds, and 5,435 cows were classified. If 50% of the 4–5-yr-olds had been misclassified as adult females then the true number of cows should be 5,435 − 536 = 4,899. Hence, the true calf:cow ratio would be 527/4,899 = 0.108, while the biased calf:cow ratio is 527/5,435 = 0.097. This is an absolute difference of 0.01 or approximately 1 calf per 100 cows.

For walruses, annual survival of juvenile and adult walruses, 4–20 yr of age, must be approximately 0.96–0.99 to compensate for their low fecundity (DeMaster 1984, Fay et al. 1997). Mature females give birth to a single calf, birth intervals are typically ≥2 yr (Fay 1982), and calves are believed to have annual survival rates ranging from 0.5 to 0.9 (Fay et al. 1997). Hence, recruitment into the adult age classes is expected to be low, while adult survival is high; hence, the number of cows should be relatively stable from year to year. We note, however, that small changes in survival and slow rates of decline will likely be undetectable (see Harris et al. 2008). Other issues

that may complicate interpretation of walrus calf:cow ratios see more learn more include classification error, repeatability of surveys, and the timing of surveys: Interpreting the age ratios clearly depends upon

how well observers can classify walruses to different sex and age categories. During the 1981 survey, Fay and Kelly (1989) compared untrained observers with trained observers in their ability to classify walruses based upon Fay’s classification scheme. They determined that all observers differentiated adults from juvenile age classes equally well, but that untrained observers tended to overestimate calves and underestimate yearlings. Fay and Kelly (1989) believed this was likely due to untrained observers not realizing that calves have dark pelage and that yearling tusks are hard to observe Olopatadine unless their heads are tilted up. Training corrected this issue. A more important question is how often trained observers make classification errors. Calves and yearlings are easily recognized; calves due to their small size and dark pelage, yearlings due to their small size, lighter pelage, and “nubbin” tusks. However, classifying adult females requires comparing the ratio of tusk length to snout width and depth as visually depicted in Figure 1. Unfortunately, the range of tusk length to snout depth ratios overlap by 50% between animals 4–5 yr of age and those

6–9 yr of age. For these two age classes, the range of tusk length to snout width ratios also overlap by 47% (Fig. 2). If 4–5-yr-olds are classified as adults, this will bias calf:cow ratios low as it artificially inflates the denominator of the ratio. However, the bias should be low because there are relatively few 4–5-yr-olds in the sample compared to the number of cows. For example, assume the percentage of 4–5-yr-olds misclassified is exactly 50%, representing a worst-case scenario. Across all survey years, 527 calves, 536 4–5-yr-olds, and 5,435 cows were classified. If 50% of the 4–5-yr-olds had been misclassified as adult females then the true number of cows should be 5,435 − 536 = 4,899. Hence, the true calf:cow ratio would be 527/4,899 = 0.108, while the biased calf:cow ratio is 527/5,435 = 0.097. This is an absolute difference of 0.01 or approximately 1 calf per 100 cows.

Therefore, we decided to use PBDL for this study. In BDL lobes, F4/80-positive cells were increased. The Ale-lip treatment succeeded in deleting F4/80-positive cells (Fig. 1A). Thus, Ale-lip injection can be utilized as a new tool for Kupffer cell depletion. Inflammatory cytokines mainly produced from Kupffer cells were up-regulated in BDL lobes, whereas the Ale-lip treatment markedly inhibited the production of TNF-α

and IL-1β (Fig. 1B). Kupffer cell-depleted mice showed an increase of ABT-263 injured lesion in BDL lobes and serum ALT level after the surgery (Fig. 1C). Interestingly, 24 hours after common BDL (Supporting Fig. 2) as well as PBDL (Fig. 1C), there were no significant differences in histological liver injury and elevated ALT activities between control and Kupffer cell-depleted mice. These findings indicate that Kupffer cells were not involved in the early stage of liver damage that occurs by BDL, but in the late click here stage. As previously reported,20 treatment with TNF-α plus GalN strongly induced hepatocyte destruction and massive hemorrhage with apoptotic cells in nonligated lobes of PBDL animals, whereas hemorrhagic damage and hepatocyte apoptosis were blunted in BDL lobes (Supporting Fig. 3A-C). Kupffer cell depletion itself did not induce hepatocyte apoptosis (Supporting Fig. 3D). In Kupffer cell-depleted livers, GalN plus TNF-α treatment induced hemorrhagic liver damage and hepatocyte apoptosis

with the cleavage of poly (ADP-ribose) polymerase (PARP), which is the downstream target of caspase-3, both in nonligated and BDL lobes (Fig. 2A-C). In the BDL lobes, proliferation cell nuclear antigen (PCNA) or Ki67-positive hepatocytes were increased with up-regulation of cyclin E expression (Fig. 2D-F), indicating that BDL induces hepatocyte regeneration. In Kupffer cell-depleted livers the expressions of PCNA, Ki67, and

cyclin E were decreased (Fig. 2D-F). Thus, Kupffer cells are important for survival and regeneration of hepatocytes after BDL. Fibrosis was induced in BDL lobes as demonstrated by Sirius red staining, hydroxyproline content, expression of α-smooth muscle actin (α-SMA) and desmin, Farnesyltransferase and messenger RNA (mRNA) expression of collagen-α1(I) and transforming growth factor (TGF)-β1 (Fig. 3). Kupffer cell-depleted mice showed reduced fibrosis in BDL lobes (Fig. 3). The number and the activation of HSCs were decreased by Kupffer cell depletion as assessed by desmin and α-SMA expression, respectively. These results suggest that the decrease in the fibrogenic response by Kupffer cell depletion is due to a lack of signal from Kupffer cells to activate and proliferate HSCs. To further elucidate the mechanisms by which Kupffer cells contribute to BDL-mediated functional changes in liver injury, survival of hepatocyte, regeneration, and fibrosis, we focused on ASMase. The protein level of ASMase (Supporting Fig.

We found that RFA resulted in a lower survival rate and higher recurrence rate than resection, with 14 cases of intrahepatic recurrence (42%), nine cases of local recurrence (27%), five cases of tumor seeding (15%) and one case of lymph node metastasis (3%) noted among the RFA-treated patients. In comparison, there were three cases of intrahepatic recurrence (20%) and two cases of tumor seeding (13%) in the resection group. The treatment for recurrent tumors was selected based on tumor location, tumor size, tumor number and liver function. Resection was performed in four

cases (14%) to treat a recurrent tumor in the RF group. In addition, re-RFA, TAE and arterial injection chemotherapy were performed in six (21%), five (17%) and 11 cases (38%), respectively, to treat recurrent tumors in the RF group. Due to rapid tumor progression, the recurrent tumor was not treated in selleck chemical three cases (10%) in the RF group. These patients had ascites and icterus that rapidly

worsened. In comparison, re-resection, http://www.selleckchem.com/products/Maraviroc.html RFA, TAE and arterial injection chemotherapy were performed in one (20%), two (40%), one (20%) and one case (20%), respectively, as treatment for a recurrent tumor in the resection group. None of the patients were treated with antiviral therapy after RFA or resection. In the long-term follow up, only one patient died due to renal failure in the resection group. All the other patients died due to recurrence of HCC. These findings need to be interpreted while considering the potential limitations of this study, which include its retrospective nature and the relatively small number of patients, as well as the fact that the pathology of resected tumors could not be evaluated preoperatively without a biopsy. Therefore, our findings need to be confirmed by other prospective studies that include a larger number of patients. In conclusion, we suggest that, on the basis of our findings, poorly differentiated HCC tumors should be treated using resection, even if the tumors are small in size. THE AUTHORS

EXPRESS their sincere gratitude to Keita Oogake (Clinical engineer of Meiwa Protein kinase N1 Hospital) and Hidehiko Waki (Clinical technologist of Meiwa Hospital), who assisted with the RFA procedure, and Takashi Matsunaga (Department of Medical Informatics, Osaka Medical Center and Cardiovascular Diseases), who assisted with the statistical analysis. “
“Although nonalcoholic steatohepatitis (NASH) is associated with hypercholesterolemia, the underlying mechanisms of this association have not been clarified. We aimed to elucidate the precise role of cholesterol in the pathophysiology of NASH. C57BL/6 mice were fed a control, high-cholesterol (HC), methionine-choline-deficient (MCD), or MCD+HC diet for 12 weeks or a control, HC, high-fat (HF), or HF+HC diet for 24 weeks.