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Direct-acting antiviral (DAA) treatment can achieve a high sustained virological response (SVR) rate in patients with hepatitis C virus (HCV) infection regardless of a history of hepatocellular carcinoma (HCC [+]). We examined 838 patients (370 men, median age: 69 years) who were treated with DAAs for comparisons of clinical findings between 79 HCC (+) (9.4%) and 759 HCC (-) (90.6%) patients and associations with treatment outcome. Male frequency was significantly higher in the HCC (+) group (60.8% vs 42.4%, P = 0.006). There were significant differences between the HCC (+) and HCC (-) groups for platelet count (115 vs 152 ×109 /L, P < 0.001), baseline alpha fetoprotein (AFP) (9.9 vs 4.5 ng/mL, P < 0.001) and the established fibrosis markers of FIB-4 index (4.7 vs 3.0, P < 0.001), AST-to-platelet ratio index (APRI) (1.1 vs 0.7, P = 0.009), M2BPGi (3.80 vs 1.78 COI, P < 0.001) and autotaxin (1.91 vs 1.50 mg/L, P < 0.001). The overall SVR rate was 94.7% and significantly lower in the HCC (+) group (87.3 vs 95.5%, P = 0.001). Multivariate analysis revealed that a history of HCC was independently associated with DAA treatment failure (odds ratio: 3.56, 95% confidence interval: 1.32-9.57, P = 0.01). In conclusion, patients with chronic HCV infection and prior HCC tended to exhibit more advanced disease progression at DAA commencement. HCC (+) status at the initiation of DAAs was significantly associated with adverse therapeutic outcomes. DAA treatment for HCV should therefore be started as early as possible, especially before complicating HCC.

Glecaprevir/pibrentasvir (G/P) are direct-acting antivirals (DAAs) that achieve a high sustained virological response (SVR) rate for hepatitis C virus (HCV) infection. We investigated G/P effectiveness for HCV patients based on real-world experience and the clinical features of retreatment cases. HCV patients (n = 182) were compared for clinical features and outcomes between first treatment (n = 159) and retreatment (n = 23) G/P groups. Overall, 77 patients (42.3%) were male, the median age was 68 years, and 86/66/1/4 cases had genotype 1/2/1+2/3, respectively. An SVR was achieved in 97.8% (178/182) of cases by intention-to-treat analysis and 99.4% (178/179) of cases by per-protocol analysis. There were no remarkable differences between the first treatment and retreatment groups for male (42.8% vs. 39.1%, p = 0.70), median age (68 vs. 68 years, p = 0.36), prior hepatocellular carcinoma (5.8% vs. 8.7%, p = 0.59), or the fibrosis markers AST-to-platelet ratio index (APRI) (0.5 vs. 0.5, p = 0.80) and fibrosis-4 (FIB-4) index (2.2 vs. 2.6, p = 0.59). The retreatment group had a significantly more frequent history of interferon treatment (12.3% vs. 52.2%, p &lt, 0.01) and the Y93H mutation (25.0% vs. 64.7%, p = 0.02). The number of retreatment patients who had experienced 3, 2, and 1 DAA treatment failures was 1, 3, and 19, respectively, all of whom ultimately achieved an SVR by G/P treatment. In conclusion, G/P was effective and safe for both HCV first treatment and retreatment cases despite the retreatment group having specific resistance mutations for other prior DAAs. As G/P treatment failure has been reported for P32 deletions, clinicians should consider resistance mutations during DAA selection.

Today, a Great Power's arsenal extends well beyond the military, embracing soft power and also currency power. The dollar dominates the global economy, used in settling trade and investment deals but also held in reserve in vast quantities by central banks in case of a payments crisis. This demand for dollars keeps US borrowing costs lower than they otherwise would be, reinforcing the country's economic power and helping to pay for the world's strongest armed forces.This Adelphi sets out how the United States has regularly deployed the power of the dollar to put pressure on foes such as Iran, as well as allies including the United Kingdom and Germany. Contributors, including Robert Zoellick, the former head of the World Bank, and John Williamson, a leading expert on currencies, assess how long the US will be able to maintain this ‘exorbitant privilege’ in tandem with a rising China. Beijing, sensing that the global crisis might herald the end of the dollar's supremacy, is eager to gain monetary power by c...

Methods. We quantified a total of 8 serum cytokines before, during, and after treatment in 79 genotype 1 chronic HCV patients. Viral ISDR and core region variants were determined by direct sequencing. Results. High levels of interleukin (IL)-12 and IL-18 and more than 2 mutations in the ISDR were associated with a sustained virological response (SVR). Conversely, high baseline IL-10 levels and glutamine at amino acid 70 of the HCV core protein (Gln70) were significantly associated with a nonresponse to treatment, and patients with Gln70 had significantly higher IL-10 levels. In multivariate analysis, low IL-10, high IL-12, and high IL-18 levels were independently associated with an SVR. These 3 cytokine levels were decreased from baseline levels 4 weeks into treatment and remained low in patients with an SVR. Conclusion. Serum IL-10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR and core region., Article, JOURNAL OF INFECTIOUS DISEASES. 203(8):1087-1095 (2011)

— In order to search for some parameters that would make it possible to predict a potentially high risk of evolution from liver cirrhosis to hepatocellular carcinoma (HCC), the DNA content of hepatocytes in patients with liver cirrhosis with or without development to HCC was investigated by means of microspectrophotometry in Feulgen-stained specimens. In patients without development of HCC in more than 5 years of follow-up, 90% or more of tested hepatocytes were diploid, whereas in patients with liver cirrhosis who developed HCC within 3 years the frequency histogram of nuclear DNA content was widely spread from diploid to hyperpolyploid with a small peak of triploid. Furthermore, in the latter group of patients, many of the binucleate cells had different DNA contents in each paired nucleus. In noncancerous portions of HCC, the ploidy histogram of nuclear DNA content was widely spread from diploid to polyploid with different DNA contents of each paired nucleus in binucleate cells, without the small peak of triploid. These results suggest that the deranged cell kinetics of hepatocytes in cirrhosis may be considered to be a state of potentially high risk for the evolution of HCC, and that a patient with liver cirrhosis with such an abnormal hepatocyte DNA content should be followed up carefully for the early diagnosis of HCC.

We report on the identification of the required configuration and binding orientation of nor-tropane alkaloid calystegines against β-glucocerebrosidase. Calystegine B2 is a potent competitive inhibitor of human lysosomal β-glucocerebrosidase with Ki value of 3.3 μM. A molecular docking study revealed that calystegine B2 had a favorable van der Waals interactions (Phe128, Trp179, and Phe246) and the hydrogen bonding (Glu235, Glu340, Asp127, Trp179, Asn234, Trp381 and Asn396) was similar to that of isofagomine. All calystegine isomers bound into the same active site as calystegine B2 and the essential hydrogen bonds formed to Asp127, Glu235 and Glu340 were maintained. However, their binding orientations were obviously different. Calystegine A3 bound to β-glucocerebrosidase with the same orientations as calystegine B2 (Type 1), while calystegine B3 and B4 had different binding orientations (Type 2). It is noteworthy that Type 1 orientated calystegines B2 and A3 effectively stabilized β-glucocerebrosidase, and consequently increased intracellular β-glucocerebrosidase activities in N370S fibroblasts, while Type 2 orientated calystegines B3 and B4 could not keep the enzyme activity. These results clearly indicate that the binding orientations of calystegines are changed by the configuration of the hydroxyl groups on the nor-tropane ring and the suitable binding orientation is a requirement for achieving a strong affinity to β-glucocerebrosidase.

The enantiomers of tagatose are converted to L-DGJ [a noncompetitive inhibitor of human lysosome α-galactosidase A (α-Gal A), K(i) 38.5 μM] and DGJ [a competitive inhibitor of α-Gal A, K(i) 15.1 nM] in 66% yield. L-DGJ and DGJ provide the first examples of pharmacological chaperones that (a) are enantiomeric iminosugars and (b) have synergistic activity with implications for the treatment of lysosomal storage disorders and other protein deficiencies.

The distribution of pyrrolidine-type iminosugars with a long-side chain appears to be restricted to the relatively unrelated plant families Moraceae, Campanulaceae, and Hyacinthaceae. In a search for glycosidase inhibitors in these plant families, we isolated the 1,4-dideoxy-1,4-imino-d-lyxitol (DIL) glucoside bearing the 1,2,11-trihydroxyundec-4-ene side chain at the C-1α position from the roots of Adenophora triphylla. This iminosugar was a powerful and selective inhibitor of coffee bean α-galactosidase, with an IC 50 value of 8 μM. © 2010 Phytochemical Society of Europe.

HBV-DNAの組込みのあるPLC/PRF/5と組込みのないMahlavu, KIM-1の3種のヒト由来培養肝癌細胞を基材とし,112名の肝癌患者血清を用いて,蛍光抗体補体法により肝癌細胞特異的核抗原の検索を行った.2名のB型肝癌患者血清がPLC/PRF/5の核と反応した.他の2細胞系には特異な核抗原はみられなかった.PLC/PRF/5にみられた特異蛍光は,すでに報告されたHepatitis B Nuclear Antigen (HBNA)である.抗HBNA抗体を含む2血清はMahlavu, KIM-1および肝癌以外の癌細胞(HeLa, HEp 2)と反応せず,正常肝,胎児肝,正常細胞とも反応しなかった.この2血清中の抗体はPLC/PRF/5以外の培養細胞により吸収されず,また牛胎児血清でも吸収されなかった.以上よりHBNAはPLC/PRF/5に特異的な核抗原であることが確認された.HBNAはB型肝癌発生過程で何等かの役割を担っている核蛋白と考えられる.

肝炎・肝硬変の経過観察中に肝細胞癌(以下肝癌)の合併を認めた44例に対し臨床病理学的検討を行った.血中HBs抗原・HBs抗体の陽性率は,IAHA法でそれぞれ35.7%, 67.4%であった.死亡時血中HBs抗原陽性例では生前の初回肝生検組織内(肝炎・肝硬変)にHBs抗原が全例に認められたことにより,これらはHB・Virusの持続感染例であった.追跡例の肝機能検査値をretrospectiveにみると,latent cirrhosisに肝癌の発症が多いことが示唆されたが,α-fetoprotein(以下AFP)等による肝癌の早期診断には限界があった.肝炎から肝癌へと進展するには長年月を要するが,少数例ながら亜急性肝炎から短期間に肝癌へと進展した例も認められた.また慢性肝炎例の組織の一部に異様なadenomatous hyperplasiaの所見を認め4年後に肝癌へと進展した症例もあり,慢性肝炎時よりすでに肝癌の前駆状態が発生する可能性が示唆された.

サルファ剤に起因したと思われる続発性胆汁性肝硬変症の1剖検例について主として胆管病変につき検討した成績を報告した.症例は43歳の女性で感冒様症状のためSulfamethopyrazine(900mg/日)3日間服用後に発黄.発症初期に血清IgA低値が認められ自己抗体,血清IgM高値等は認められなかった.発症初期の肝組織像は小葉周辺の広範な壊死と胆汁うっ滞像を示し,全経過3年3カ月で胆汁性肝硬変症により死亡した.剖検肝の胆管系は主として40μ前後の小葉間胆管を中心に消失が著しく,残存している中等大小葉間胆管および隔壁性胆管の上皮には変性が認められた.全経過中4回肝組織像を検討したがRubinらのCNSDCに相当する病変は認められなかった.薬剤のアレルギー反応により広範な肝細胞壊死がおこり,一次的ないし二次的に中等大の胆管にも病変が波及し,さらに小型小葉間胆管の消失をきたし最終的に胆汁性肝硬変症へと進展したものと推察された.

経時的に経過を観察できた急性B型肝炎7例中3例の初期血清に凝集法によりHBe抗原を検出し,うち1例ではanti-HBeへのseroconversionを認めた.HBe抗原検出例と非検出例の間に病態,予後の面で差異を認めなかった.1.5～2年間経過観察したHBs抗原陽性慢性肝疾患ではHBe抗原陽性例にGOT, GPTの変動するものが多く,14例中10例では200Kuを越える増悪を認めた.anti-HBeが検出された15例中6例は最近2年間50Ku以下で推移した.5症例につき経時的に肝機能検査とともに凝集法によりHBV関連抗原抗体を測定すると,GOT,GPTの変動増悪に際してHBs抗原価,HBe抗原価も変動を示すが,その位相は必ずしも同じではなかった.またGOT, GPTの増悪を契機にHBe抗原が減衰消失する症例も見られた.又anti-HBeが高抗体価で持続する慢性肝疾患でもGOT, GPTが著明に変動する症例が存在することが明らかとなり,かかる症例の予後が注目された.

HBs抗原陽性肝疾患166例およびAsC 113例につき血清中のHBs抗原抗体,anti-HBcの測定とともに,MO法および凝集法によりHBe抗原抗体を検出測定しその臨床的意義を検討した.凝集法によりHBe抗原はAsCの30/113 (26.5%),肝疾患例の43/166 (25.9%)に検出され,MO法に比べ各々6.1%, 16.9%検出率が上昇した.対象症例をAsC群,PH・CH群,LC・HCC群に大別すると,HBe抗原価はAsC群>PH・CH群>LC・HCC群の順に高抗原価を示しその差は有意であった.anti-HBe抗体価はAsC群,PH・CH群がLC・HCC群より高抗体価を示した.また3群ともHBe抗原陽性例はanti-HBe陽性例に比し有意に高いHBs抗原価を示した.HBs抗原価とHBe抗原価はAsC群では有意の相関を示したが,肝疾患例ではその相関に乏しかった.凝集法の導入によりHBV感染症におけるHBe抗原抗体系の動態が定量的により明らかとなり,MO法による知見を確認した.

Hepatitis B surface antigen (HBs-Ag) and hepatitis B core antigen (HBc-Ag) in hepatic tissue of 3 cases with various liver diseases were investigated by immunofluorescent method. Virus-like particles were demonstrated by electron microscopy in the nuclei of these 3 cases. The localization of HBs-Ag was restricted in cytoplasma or on the surface of hepatocyte, while HBc-Ag was almost in the hepatocytic nuclei. However, there was unexplainable discrepancy between the distribution of HBs-Ag and that of HBc-Ag, as more the former in number and less that latter, of hepatocytes. The size of virus-like particles in nuclei was 22-27 nm in diameter. Most of them were hollow, but some of them were wholly electron dense. Their distribution was various from case to case. Discussion was made on the correlation between the presence of Hepatitis B virus and HBs-Ag or HBc-Ag.

e-antigen and anti-e were assayed in sera of asymptomatic HBs-Ag carriers and of patients with liver diseases. Thirteen out of 34 (38.2%) asymptomatic carriers were positive for e-antigen, which was in sharp contrast to the reports from USA and Europe. e-antigen was detected to a greater extent in patients with chronic active hepatitis, reversely anti-e in patients with chronic persistent hepatitis. However, e-antigen was found rarely in patients with cirrhosis and never in 23 cases with hepatoma positive for HBs-Ag. HBc-Ag in the liver was detected in 4 out of 8 e-antigen positive asymptomatic carriers and in 4 out of 5 patients with chronic liver diseases with e-antigen respectively, and moreover in 3 out of 14 anti-e positive cases, so that the presence of anti-e did not necessarily mean the negativity of HBc-Ag in the liver. Anti-HBc titer, however, was lower in anti-e positive sera than in e-antigen positive ones. This may implicate the decreased replication of HBV in cases with anti-e. These results emphasize that the investigation of e-antigen/anti-e is mandatory for the evaluation of the prognosis of asymptomatic carriers and of patients with chronic hepatitis.