Impact of Interferon-Free Direct-Acting Antivirals on the Incidence of Extrahepatic Malignancies in Patients with Chronic Hepatitis C.

BACKGROUND: The incidence of extrahepatic malignancies (EHMs) after hepatitis C virus (HCV) eradication by interferon (IFN)-based and IFN-free direct-acting antivirals (DAAs) treatment remains unclear. AIMS: The aim was to evaluate the cumulative incidence of EHMs diagnosed for the first time after the antiviral treatments. METHODS: We analyzed a total 527 patients with chronic HCV infection and without prior history of any malignancies who achieved sustained virological response by antiviral treatments, including IFN-based (n = 242) or IFN-free DAAs (n = 285). The baseline predictors for EHM occurrence were analyzed using Cox regression analysis. RESULTS: Thirty-two patients were diagnosed with EHMs, 14 in IFN-based and 18 in IFN-free DAAs, respectively. The total duration of follow-up was 1,796 person-years in IFN-based and 823 person-years in IFN-free DAAs. The incidence of EHMs in IFN-based and IFN-free DAAs was 7.8 and 21.9 per 1,000 person-years, respectively. The cumulative incidence of EHMs was significantly higher in IFN-free DAAs than IFN-based (p = 0.002). IFN-free DAAs was a single independent predictor for incidence of EHMs (p = 0.012). As for gender, the incidence of EHMs was significantly higher in IFN-free DAAs only in the female cohort (p = 0.002). After propensity score matching, IFN-free DAAs was a single independent predictor for incidence of EHMs in the female patients (p = 0.045). CONCLUSIONS: The incidence of EHMs after HCV eradication is higher in IFN-free DAAs than IFN-based regimens, especially in female patients. We should carefully follow-up not only HCC but also EHMs after IFN-free DAAs regimens.

Type 4B hereditary hemochromatosis due to heterozygous p.D157A mutation in SLC40A1 complicated with hypopituitarism.

Hemochromatosis is a clinical syndrome characterized by iron overload in various organs. We present here a case of type 4 hereditary hemochromatosis due to heterozygous mutation in SLC40A1 gene (p.D157A). SLC40A1 encodes ferroportin, a macromolecule only known as iron exporter from mammalian cells. He first presented symptoms correlated with hypopituitarism. Furthermore, marked hyperferritinemia and high transferrin saturation were revealed in combination with the findings of iron overload in the liver, spleen and pituitary gland by computed tomography and magnetic resonance imaging. Liver biopsy revealed iron deposition in both hepatocytes and Kupffer cells. SLC40A1 mutations are considered to cause wide heterogeneity by various ferroportin mutations. Thus, clinicopathological examinations seem to be very important for diagnosing phenotype of type 4 hemochromatosis in addition to the gene analysis. We diagnosed him as type 4B hereditary hemochromatosis (ferroportin-associated hemochromatosis) by the findings of high transferrin saturation and iron deposition in hepatocytes, and then started iron chelating treatment. We should suspect the possibility of hereditary hemochromatosis even in Japanese with severe iron overload. Although the same mutation in SLC40A1 gene (p.D157A) had been reported to cause "loss of function" phenotype, we considered that the mutation of our case caused "gain of function" phenotype.

Hepatocyte Growth Factor and Primary Systemic Amyloidosis.

A 75-year-old-man experienced liver dysfunction and was diagnosed with decompensated liver cirrhosis. His serum hepatocyte growth factor (HGF) was very high (16.24 ng/ml). Because the etiology was unclear, we considered the possibility of amyloidosis. Biopsy of the mucosa of the stomach, duodenum and rectum demonstrated amyloid deposition. From the findings of Congo red staining and immunohistochemical analyses, we made a diagnosis of systemic amyloid light-chain amyloidosis. Unfortunately, the patient died one month after the diagnosis. We considered that serum HGF was useful for the diagnosis and prediction of prognosis of primary systemic amyloidosis.

Effect of direct-acting antivirals on platelet-associated immunoglobulin G and thrombocytopenia in hepatitis C virus-related chronic liver disease.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection has been known to cause various extrahepatic autoimmune disorders. The prevalence of platelet-associated immunoglobulin G (PA-IgG) has been high in patients with HCV infection. Because thrombocytopenia in HCV-related liver diseases is a notable problem, we performed prospective study on the effect of direct-acting antivirals (DAAs) treatment on PA-IgG and platelet count. METHODS: A total of 215 patients with HCV-related liver disease were enrolled in this study. The patients who discontinued DAAs or did not undergo adequate laboratory examinations and who did not achieve sustained virologic response were excluded and finally a total of 187 patients were investigated. RESULTS: A total of 171 patients (91.4%) were PA-IgG positive (>46 ng/107 cells) before starting DAAs (baseline). The PA-IgG level elevation was significantly correlated with higher liver inflammation and fibrosis markers (P < 0.05) and lower platelet count (P = 0.000019). The platelet count of the patients with low PA-IgG titer tended to be higher at baseline, end of treatment (EOT), and at 12 and 24 weeks after EOT. The platelet count increased at EOT (P < 0.05) and 24 weeks after EOT (P < 0.01). The PA-IgG levels were significantly decreased at EOT, 12 and 24 weeks after EOT (P < 0.01). Multiple regression analysis found that only platelet count at baseline was closely associated with negative conversion of PA-IgG at 24 weeks after EOT (P = 0.004). CONCLUSIONS: Eradication of HCV by DAAs treatment successfully decreased PA-IgG level and increased platelet count.

Impact of neointimal tissue characterization and heterogeneity of bare-metal stents and drug-eluting stents on the time course after stent implantation evaluated by integrated backscatter intravascular ultrasound.

Pathological studies have suggested the different process of in-stent restenosis (ISR) of bare-metal stents (BMS) and drug-eluting stents (DES). Here, we evaluated the components of neointimal tissue using integrated backscatter intravascular ultrasound (IB-IVUS) and focused on the time course after stent implantation and tissue signal distribution. We evaluated 125 lesions of 125 patients who underwent target lesion revascularization for ISR (BMS: n = 73, DES: n = 52). Volume analysis of a 4-mm length centered on a minimum lumen area in every 1-mm cross-sectional area was performed. For IB-IVUS analysis, color-coded maps were constructed from the default setting based on the integrated backscatter (IB) values (middle-IB value, green: fibrous and low-IB value, blue: lipid pool). For the neointimal tissue volume, we evaluated the ratios of the green (%G) and blue (%B) areas. Tissue signal distribution (TD) was also obtained from the default setting based on IB values in each pixel of IB-IVUS imaging. We compared values of neointimal tissues measured by IB-IVUS between the DES and BMS and time course. The observed period was longer after BMS implantation than after DES implantation (BMS: 2545 days, DES: 1233 days, p < 0.001). Overall, %G and %B were similar between the BMS and DES groups (%G: 55% and 51%, respectively, p = 0.10; %B: 36% and 38%, respectively, p = 0.51); however, TD was significantly higher in the DES group than in the BMS group (1091 vs. 1367, p < 0.001). TD in the DES group remained high during the follow-up periods. However, TD in the BMS group was low in the early phase and significantly increased over time (r = 0.56, p < 0.001). When analyzing the ISR within 2 years after stent implantation, the BMS was distinguished with a sensitivity of 66% and a specificity of 90% (cut-off value: TD = 1135, area under the curve 0.83, 95% confidence interval 0.74-0.92). TD could differentiate neointimal tissue after BMS implantation in the early phase. TD can be a useful index in the observation of neoatherosclerosis.

Identification of 2-phenylethanol with a rose-like odor from anal sac secretions of the small Indian mongoose (Herpestes auropunctatus).

The small Indian mongoose (Herpestes auropunctatus) is an invasive species in Okinawa and Amami-Oshima, Japan. Major strategies for their eradication have been the use of baited traps, which suffer from decreasing efficiency with declining populations and the bycatch of native animals. To address these concerns, mongoose-specific lures are required. In this study, we aimed to identify species- and/or sex-specific compounds from anal sac secretions of small Indian mongooses. Volatile compounds emitted from male and female mongoose anal sac secretions were analyzed by thermal desorption-gas chromatography-mass spectrometry. In addition to several fatty acids, 2-phenylethanol was identified as a minor compound, which is uncommon in mammalian secretions but a dominant odorant in roses. Female samples emitted higher levels of 2-phenylethanol than male samples did. These findings indicate that 2-phenylethanol is a female-specific volatile compound of anal sac secretions in small Indian mongooses, and it may be useful as an ingredient of mongoose-specific scent lures.

Recognition of infection, status of outpatient treatment, and treatment history before carcinogenesis in patients with viral hepatitis-associated liver cancer.

We conducted a survey on the recognition of infection, status of outpatient treatment, and treatment history in hepatitis virus-associated hepatocellular carcinoma patients admitted to our department between 2005 and 2014. We compared these parameters in 75 patients with primary hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and 307 patients with hepatitis C virus-associated hepatocellular carcinoma (HCV-HCC). Based on the presence or absence of outpatient treatment in medical institutions at the time of HCC diagnosis, the patients were divided into an outpatient treatment-free group or an outpatient treated group. In addition, the latter group was divided into three subgroups depending on the department consulted:the Department of Internal Medicine group, the Department of Gastroenterology group, and a hepatologist-treated group. Patients in the outpatient treatment-free group accounted for 40.0% of patients with HBV-HCC. In the outpatient treated group (60.0%), 21.3% were treated in the Department of Internal Medicine, 22.7% in the Department of Gastroenterology, and 16.0% were treated by a hepatologist. The percentage of HBV-HCC patients in the outpatient treatment-free group was 1.9 times higher than that in the HCV-HCC group and 0.6-fold higher in the hepatologist-treated group. Of the HBV-HCC patients, non-recognizers who were not diagnosed with a viral infection accounted for 21.3%, and non-outpatients who had not consulted a hospital despite the recognition of infection accounted for 33.3%. These percentages were approximately 2 times higher than in HCV-HCC patients. Of the HBV-HCC patients, 66.7% in the hepatologist-treated group had received nucleic acid analogue preparations. On the other hand, one patient in each of the Department of Internal Medicine and Department of Gastroenterology groups (approximately 6.0%) had received a nucleic acid analogue, lamivudine, despite the appearance of a resistant strain. In the HBV-HCC patients, the proportions of "non-recognizers" and "non-outpatients" were higher than in the HCV-HCC patients, suggesting a lack of appropriate treatment.

Association of a polymorphism of the interleukin 6 receptor gene with chronic kidney disease in Japanese individuals.

AIM: Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified in Caucasian populations by genome-wide association studies (GWASs). The aim of the present study was to examine a possible association of chronic kidney disease (CKD) with 29 polymorphisms previously identified as susceptibility loci for CAD by meta-analyses of GWASs. METHODS: The study population comprised 2247 Japanese individuals, including 1588 subjects with CKD [estimated glomerular filtration rate (eGFR) of <60 mL min(-1) 1.73 m(-2) ] and 659 controls (eGFR of ≥90 mL min(-1) 1.73 m(-2) ). The genotypes for 29 polymorphisms of 28 candidate genes were determined. RESULTS: The χ(2) test revealed that rs4845625 (T→C) of IL6R, rs4773144 (A→G) of COL4A1, rs9319428 (G→A) of FLT1, and rs46522 (T→C) of UBE2Z were significantly (P < 0.05) related to CKD. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidaemia revealed that rs4845625 of IL6R (P = 0.0008; dominant model; odds ratio, 1.49), rs4773144 of COL4A1 (P = 0.0252; dominant model; odds ratio, 1.28), and rs9319428 of FLT1 (P = 0.0260: additive model; odds ratio, 0.77) were significantly associated with CKD. The serum concentration of creatinine was significantly (P = 0.0065) greater and eGFR was significantly (P = 0.0009) lower in individuals with the TC or CC genotype of IL6R than in those with the TT genotype. CONCLUSION: The rs4845625 of IL6R may be a susceptibility locus for CKD in Japanese individuals.

Establishment of a primary hepatocyte culture from the small Indian mongoose (Herpestes auropunctatus) and distribution of mercury in liver tissue.

The present study established a primary hepatocyte culture for the small Indian mongoose (Herpestes auropunctatus). To determine the suitable medium for growing the primary hepatic cells of this species, we compared the condition of cells cultured in three media that are frequently used for mammalian cell culture: Dulbecco's Modified Eagle's Medium, RPMI-1640, and William's E. Of these, William's E medium was best suited for culturing the hepatic cells of this species. Using periodic acid-Schiff staining and ultrastructural observations, we demonstrated the cells collected from mongoose livers were hepatocytes. To evaluate the distribution of mercury (Hg) in the liver tissue, we carried out autometallography staining. Most of the Hg compounds were found in the central region of hepatic lobules. Smooth endoplasmic reticulum, which plays a role inxenobiotic metabolism, lipid/cholesterol metabolism, and the digestion and detoxification of lipophilic substances is grown in this area. This suggested that Hg colocalized with smooth endoplasmic reticulum. The results of the present study could be useful to identify the detoxification systems of wildlife with high Hg content in the body, and to evaluate the susceptibility of wildlife to Hg toxicity.

Differential population responses of native and alien rodents to an invasive predator, habitat alteration and plant masting.

Invasive species and anthropogenic habitat alteration are major drivers of biodiversity loss. When multiple invasive species occupy different trophic levels, removing an invasive predator might cause unexpected outcomes owing to complex interactions among native and non-native prey. Moreover, external factors such as habitat alteration and resource availability can affect such dynamics. We hypothesized that native and non-native prey respond differently to an invasive predator, habitat alteration and bottom-up effects. To test the hypothesis, we used Bayesian state-space modelling to analyse 8-year data on the spatio-temporal patterns of two endemic rat species and the non-native black rat in response to the continual removal of the invasive small Indian mongoose on Amami Island, Japan. Despite low reproductive potentials, the endemic rats recovered better after mongoose removal than did the black rat. The endemic species appeared to be vulnerable to predation by mongooses, whose eradication increased the abundances of the endemic rats, but not of the black rat. Habitat alteration increased the black rat's carrying capacity, but decreased those of the endemic species. We propose that spatio-temporal monitoring data from eradication programmes will clarify the underlying ecological impacts of land-use change and invasive species, and will be useful for future habitat management.

Recovery of train-of-four ratio to 0.70 and 0.90 is delayed in type 2 diabetes with vecuronium-induced neuromuscular block.

CONTEXT: The recovery profile of train-of-four ratio to more than 0.70 in patients with diabetes mellitus has not been well investigated. OBJECTIVE: Our primary objective was to evaluate the spontaneous recovery profile of neuromuscular block by vecuronium until train-of-four ratio more than 0.90 in patients with type 2 diabetes mellitus compared with controls, using first dorsal interosseous electromyography. DESIGN: Single-centre prospective case-control study. SETTING: The operating theatres of Fukuoka University Hospital. PATIENTS: Fourteen adults with type 2 diabetes mellitus (diabetes mellitus group) and 14 control patients (control group) were included in this study. INTERVENTION: Evoked responses to train-of-four stimuli were measured by electromyography at the first dorsal interosseous muscle. General anaesthesia was induced with propofol, fentanyl and remifentanil. Vecuronium (0.1  mg kg) was administered to all patients. Anaesthesia was maintained with propofol, fentanyl and remifentanil. The neuromuscular block was assessed until spontaneous recovery to train-of-four ratio more than 0.90. MAIN OUTCOME MEASURES: Recovery times to train-of-four ratio 0.70 and 0.90. RESULTS: Recovery times to train-of-four ratio 0.70 and 0.90 were significantly longer in the diabetes mellitus group than the control group (P = 0.041 and P = 0.027, respectively). The time from train-of-four ratio 0.25 to 0.90 was also significantly longer in the diabetes mellitus group than the control group (P = 0.029). In five of 14 patients in the diabetes mellitus group, the time from train-of-four ratio 0.25 to 0.90 was longer than 60  min, which is longer than the duration of action of neostigmine. The time from train-of-four ratio 0.25 to 0.90 was longer than 60  min in only one of 14 in the control group. CONCLUSION: Recovery times to train-of-four ratio 0.70 and 0.90 were delayed in patients with type 2 diabetes mellitus. Neuromuscular block by vecuronium should be carefully monitored in patients with type 2 diabetes mellitus until recovery of train-of-four ratio to a safe level is confirmed.

Two Cases with Isolated Splenic Sarcoidosis Diagnosed by an Ultrasound-guided Fine-needle Aspiration Biopsy.

Asymptomatic splenic nodules were detected incidentally in two middle-aged women at an annual checkup. They showed no abnormalities on laboratory tests, but imaging studies revealed splenic nodules. No other localized lesions were found. Splenic nodules were hypoechoic on ultrasonography (US), hypovascular on contrast-enhanced computed tomography, and showed a low intensity on T2-weighted magnetic resonance imaging. We performed US-guided percutaneous aspiration biopsies using 21-gauge needles without complications, including bleeding. Pathological specimens showed noncaseating granulomas, so both patients were diagnosed with isolated splenic sarcoidosis. A US-guided fine-needle aspiration biopsy is a safe and useful method for diagnosing splenic nodules.

Additional copies of CBX2 in the genomes of males of mammals lacking SRY, the Amami spiny rat (Tokudaia osimensis) and the Tokunoshima spiny rat (Tokudaia tokunoshimensis).

Tokudaia osimensis (the Amami spiny rat) and Tokudaia tokunoshimensis (the Tokunoshima spiny rat) have a sex chromosome composition of XO/XO, no Y chromosome. The mammalian sex-determining gene, SRY, is also absent in these species, which indicates that these spiny rats exhibit a novel sex-determining mechanism that is independent of SRY. To identify a candidate gene that controls this mechanism, the copy numbers and chromosomal locations of 10 genes with important functions in gonadal differentiation were determined: ATRX, CBX2 (M33), DMRT1, FGF9, NR0B1 (DAX1), NR5A1 (Ad4BP/SF1), RSPO1, SOX9, WNT4, and WT1. Multiple bands were detected for NR0B1 in Southern blot analysis, which suggested the presence of multiple copies of the gene in the genomes of these two species. CBX2 was localized to two loci in both sexes of the two species by fluorescence in situ hybridization mapping: 3q24 and 6p11.2 in T. osimensis and 10q25-q26 and 14q12-q13.1 in T. tokunoshimensis. Quantification of copy numbers in the two species by quantitative real-time PCR indicated that there were two or three more copies of CBX2 per haploid genome in males (T. osimensis, n = 3; T. tokunoshimensis, n = 2) than in females (T. osimensis, n = 4; T. tokunoshimensis, n = 2), whereas NR0B1 was present as a single copy in both. The results suggest that additional copies of CBX2 in males might be involved in a novel sex-determining mechanism in species that lack SRY.

Phylogenetic relationships of three species within the family Heligmonellidae (Nematoda; Heligmosomoidea) from Japanese rodents and a lagomorph based on the sequences of ribosomal DNA internal transcribed spacers, ITS-1 and ITS-2.

Nematodes of the family Heligmonellidae (Heligmosomoidea; Trichostrongylina) reside in the digestive tracts of rodents and lagomorphs. Although this family contains large numbers of genera and species, genetic information on the Heligmonellidae is very limited. We collected and isolated adult worms of three species in Japan that belong to the family Heligmonellidae, namely Heligmonoides speciosus (Konno, 1963) Durette-Desset, 1970 (Hs) from Apodemus argenteus, Orientostrongylus ezoensis Tada, 1975 (Oe) from Rattus norvegicus and Lagostrongylus leporis (Schulz, 1931) (Ll) from Pentalagus furnessi, and sequenced the entire internal transcribed spacer regions, ITS-1 and ITS-2 of ribosomal DNA. ITS-1 of Hs, Oe and Ll was 426, 468 and 449 bp in length, and had a G+C content of about 41, 41 and 37 %, respectively. ITS-2 of Hs, Oe and Ll was 297, 319 and 276 bp in length and had a G+C content of about 38, 40 and 28%, respectively. The data of Hs, Oe and Ll were compared with those of two other known species within the family Heligmonellidae, Calorinensis minutus (Dujardin, 1845) (Cm) and Nippostrogylus brasiliensis (Travassos, 1914) (Nb), and with those of two species of Heligmosomidae (Heligmosomoidea), Heligmosomoides polygyrus bakeri and Ohbayashinema erbaevae. Phylogenetic analysis placed Hs, Oe and Ll in the same clade with Cm and Nb, forming a Heligmonellidae branch in both ITS-1 and ITS-2, separate from the Heligmosomoidea branch. These results demonstrated that the ITS-1 and ITS-2 sequences are useful for differentiating the Heligmonellidae nematode species. This study is the first to describe the ITS-1 and ITS-2 sequences of Hs, Oe and Ll.

Rapid Progression of Liver Fibrosis Induced by Acute Liver Injury Due to Immune-related Adverse Events of Atezolizumab.

A 72-year-old woman with advanced lung cancer had received systemic chemotherapy including atezolizumab. About three months after the initial administration of atezolizumab, her liver enzyme levels increased. The histopathological findings of the initial liver biopsy revealed acute inflammatory infiltrate, predominantly CD3+, CD4+ and CD8+ T lymphocytes, in the hepatic lobules. We diagnosed her with atezolizumab-induced immune-related acute hepatitis. Oral corticosteroid therapy successfully improved the elevation of serum aminotransferases. A sequential liver biopsy demonstrated the rapid progression of liver fibrosis. Because hepatocellular carcinoma occurs most often in advanced cases of chronic liver disease, we should pay close attention to immune-related acute hepatic injury when treating patients with advanced liver diseases using atezolizumab.

Characterization of rabbit hepatitis E virus isolated from a feral rabbit.

Rabbit hepatitis E virus (HEV) has been detected among rabbits and recently isolated from immunocompromised patients, suggesting zoonotic transmission. In this study, HEV infection among feral rabbits (Oryctolagus cuniculus) was assessed by detection of anti-HEV antibodies and HEV RNA. The prevalence of anti-HEV antibodies in sera was of 33 % (20/60) and HEV RNA was detected from only one of fecal swabs (1.7 %, 1/58). Furthermore, one naïve rabbit was intravenously inoculated with the suspension of the HEV-positive fecal specimen, exhibiting persistent HEV shedding in feces, intermittent viremia, seroconversion to anti-HEV IgM and IgG, and high alanine aminotransferase (ALT) values, indicating persistent HEV infection. The isolate JP-59 had a length of 7,282 bp excluding a poly (A) tail and possessed the characteristic 93 bp-insertion in ORF1. Phylogenetic analysis indicated that JP-59 formed a cluster with other rabbit HEV isolates from rabbits and human origin. The JP-59 shared the nucleotide sequence identities less than 87 % with other rabbit HEVs, suggesting that a novel rabbit HEV strain was circulating in Japan.

Prevalence of serum antibodies to Toxoplasma gondii in the small Indian mongoose (Herpestes auropunctatus) on Amami-Oshima Island, Japan.

Prevalence of antibodies to Toxoplasm gondii was studied using the latex agglutination (LA) method, followed by sucrose density gradient centrifugation (SDGC) method on the small Indian mongoose (Herpestes auropunctatus), which inhabits Amami-Oshima Island. Of the 362 samples, 38 (10.5%) revealed positive. Single or double peaks in the 7-8 and/or 12-14 fraction to LA titer by SDGC indicated the early stage of T. gondii infection. It is suggested that domestic/feral cats play an important role for spreading this zoonotic pathogen to the mongoose as well as other species that are endemic to this island. Future studies are warranted to prevent the transmission of T. gondii among cats and wild animals in order to maintain the ecosystem health.

Importance of a Liver Biopsy in the Management of Wilson Disease.

A 37-year-old Wilson disease patient treated with D-penicillamine visited our hospital for the evaluation of his liver function. Laboratory data showed a low serum copper level and ceruloplasmin. The ratio of urinary copper to urinary creatinine in a spot urinary analysis after 4 days' cessation of D-penicillamine was under 0.1. We concluded that the copper chelation was excessive and changed D-penicillamine to zinc acetate. However, his liver function test results did not normalize. We performed a liver biopsy and discovered a high copper content. The liver dysfunction was improved after resuming chelating therapy. Accurate measurement of the hepatic copper content via a biopsy is important for the adequate management of this disease.

Increased soluble IL-2 receptor levels during interferon and ribavirin treatment are associated with a good response in genotype 2a/2b patients with chronic hepatitis C.

OBJECTIVES: Serum levels of soluble interleukin-2 receptor (sIL-2R) are known to serve as a marker for the activation of T lymphocytes. We measured serum levels of sIL-2R in patients with chronic hepatitis C (CHC) during interferon (IFN)-based treatment to determine the correlation between those levels and therapeutic efficacy, and to clarify whether there is a difference in the activation of T lymphocytes among HCV genotypes after the treatment. METHODS: Forty-four patients received IFN-alpha2b monotherapy (group IFN-M), whereas 82 patients received the combination therapy with IFN-alpha2b and ribavirin (group IFN+R). We measured serum sIL-2R levels in these patients before (T0) and 2 weeks (T2) after the treatment. RESULTS: The sustained virologic response rates in genotype 2a/2b patients were significantly higher than those in genotype 1b patients in both groups (P<0.005). In sustained virologic responders, sIL-2R levels at T2 were significantly higher than those at T0 in both groups (P<0.001). In nonresponders, sIL-2R levels at T2 were not different from those at T0 in group IFN-M, but were significantly higher than those at T0 in group IFN+R (P=0.0072). In genotype 1b patients, sIL-2R levels at T2 were not different from those at T0 in group IFN-M, but were significantly higher than those at T0 in group IFN+R (P=0.0064). In genotype 2a/2b patients, sIL-2R levels at T2 were significantly higher than those at T0 in both groups (P<0.0005). CONCLUSION: These findings suggest that the activation of T lymphocytes after IFN-based treatment contributes to a high-sustained virologic response rate, especially in genotype 2a/2b patients.

Subcellular distribution and potential detoxification mechanisms of mercury in the liver of the Javan mongoose (Herpestes javanicus) in Amamioshima Island, Japan.

In a previous study, we showed that Hg accumulated to high levels in the liver of the Javan mongoose (Herpestes javanicus), a terrestrial mammal that lives on Amamioshima Island, Japan. This suggests a sophisticated mechanism of hepatic Hg detoxication. Assay of the subcellular localization of Hg and the expression of protective enzymes provides important clues for elucidating the mechanism of Hg detoxication. In the present study, the concentrations of 11 elements (Mg, Cr, Mn, Fe, Cu, Zn, Se, Rb, Cd, total Hg [T-Hg] and organic Hg [O-Hg], and Pb) were determined in the liver and in five liver subcellular fractions (plasma membrane, mitochondria, nuclei, microsome, and cytosol) of this species. As the T-Hg level increased, T-Hg markedly distributed to the plasma membrane. The T-Hg levels in all subcellular fractions correlated with Se levels. Although the T-Hg level in the microsomal fraction was relatively low, the ratio of O-Hg to T-Hg was significantly lower in the microsomes than in the other fractions. Significant positive correlations were found between the level of glutathione-S-transferase-pi, a marker of oxidative stress, and the O-Hg and T-Hg levels, but the correlation was better with O-Hg than with T-Hg. Western blot analysis of thioredoxin reductase 2 (TrxR2), a protein involved in protecting cells from mitochondrial oxidative stress, showed that the level of TrxR2 correlated with that of T-Hg. High TrxR2 levels may be one mechanism by which the Javan mongoose attenuates the toxicity of the high Hg levels present in the liver.