Vortex structure in d-wave superconductors.
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Journal Article↗
Biomedical subjects
N Enomoto
Publications and source records attributed to N Enomoto.
Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene.
Mutations in beta or gamma subunit of the epithelial sodium channel (ENaC) have been found to cause a hereditary form of human hypertension, Liddle syndrome. Most of the mutations reported are either nonsense mutations or frame shift mutations which would truncate the cytoplasmic carboxyl terminus of the beta or gamma subunits of the channel, suggesting that these domains are important for the normal regulation of this channel. We sequenced ENaC in a family with Liddle syndrome and found a missense mutation in beta subunit which predicts substitution of Tyr by His at codon 618, 2 bp downstream from a missense mutation (P616L) that has been reported recently. Presence of this mutation correlates with the clinical manifestations (hypertension, hypokalemia, suppressed aldosterone secretion) in this kindred. Functional expression studies in the Xenopus oocytes revealed constitutive activation of the Y618H mutant indistinguishable from that observed for the deletion mutant (R564stop) identified in the original pedigree of Liddle. Our data suggest that the region between Pro616 and Tyr618 is critically important for regulation of ENaC activity.
Adolescent↗
s- and dxy-wave components induced around a vortex in dx2-y2-wave superconductors.
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Journal Article↗
Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection.
BACKGROUND: A region associated with sensitivity to interferon has been identified in the nonstructural protein 5A (NS5A) of hepatitis C virus (HCV) genotype 1b. The region spans amino acid residues 2209 to 2248 (NS5A2209-2248) of HCV-J, a strain of HCV-1b whose complete genomic sequence has been identified. We examined whether the NS5A2209-2248 sequence present before therapy could be used as a predictor of the response to interferon therapy in patients with chronic HCV-1b infection. METHODS: We retrospectively analyzed 84 patients with chronic HCV-1b infection who had received interferon alfa (total dose, 516 million to 880 million units) for six months. Pretreatment serum samples were analyzed. The amino acid sequence of NS5A2209-2248 was determined by direct sequencing of the HCV genome amplified by the polymerase chain reaction (PCR) and was compared with the established sequence for HCV-J. RESULTS: A complete response, as evidenced by the absence of HCV RNA in serum on nested reverse-transcription PCR for six months after therapy, did not occur in any of the 30 patients whose NS5A2209-2248 sequences were identical to that of HCV-J (wild type). Five of 38 patients (13 percent) with 1 to 3 changes in NS5A2209-2248 (intermediate type) had complete responses, as did all 16 patients with 4 to 11 amino acid substitutions (mutant type), indicating that the mutant type was significantly associated with a complete response (P < 0.001). Although baseline serum HCV RNA levels, as measured by a branched-chain DNA assay, were lower in patients with the mutant type of NS5A2209-2248 than in those with the other types (P < 0.001), multivariate analyses revealed that the number of amino acid substitutions in NS5A2209-2248 was the only variable associated with an independent effect on the outcome of interferon therapy (odds ratio, 5.3; 95 percent confidence interval, 1.6 to 18; P = 0.007). CONCLUSIONS: In patients with chronic HCV-1b infection, there is a substantial correlation between responses to interferon and mutations in the NS5A gene.
Amino Acid Sequence↗
Complete nucleotide sequences of hepatitis B virus genomes associated with epidemic fulminant hepatitis.
Pre-core/core mutants are frequently observed in patients with fulminant hepatitis. To investigate the extent of molecular characteristics of hepatitis B virus (HBV) genomes implicated in the development of fulminant hepatitis, full-length HBV genomes were sequenced directly from sera of two patients with epidemic fatal fulminant hepatitis, after amplification by the polymerase chain reaction. These two genomes, of 3215 nucleotides, were 99.6% identical, indicating that a common source of HBV potentially caused fulminant hepatitis. Thirty unique nucleotide mutations were commonly found in the two entire HBV genomes. Three were located in the stem-loop structure, changing this element to a more stable structure. Twenty-five unique amino acid substitutions were found in each open reading frame, except for the X and pre-surface 2 genes. One was located in the pre-surface 1 gene; two were in the surface gene; three were in the pre-core gene, including codons 28 (tryptophan to stop codon) and 29 (glycine to aspartic acid); eight were in the core gene; and 11 were in the polymerase gene. The pre-core mutations at codons 28 and 29 were common to the two HBV strains reported previously in patients with epidemic fulminant hepatitis. Thus, HBV genomes associated with epidemic fatal fulminant hepatitis have numerous unique mutations, located mainly in the polymerase gene, as well as the pre-core/core gene, including mutations in the stem-loop structure of the pregenome encapsidation signal sequence. These mutations may be associated with the development of fulminant hepatitis.
Aged↗
Mutations in the core promoter region of hepatitis B virus in patients with chronic hepatitis B.
The core promoter region of hepatitis B virus genomes regulates transcription of the precore and pregenomic mRNAs encoding hepatitis B e antigen (HBeAg) and core antigen that contain target epitopes for cytotoxic T lymphocytes. The prevalence and clinical significance of mutations in this region were investigated. DNA was extracted from six asymptomatic carriers positive for HBeAg, eight asymptomatic carriers positive for an anti-HBe antibody, and 24 patients with chronic liver disease. The core promoter and precore regions of hepatitis B virus genomes were amplified by polymerase chain reaction, and predominant sequences were determined by direct sequencing. Mutations were found in none of the HBeAg-positive asymptomatic carriers but in all of the anti-HBe-positive asymptomatic carriers and the patients with chronic liver disease. Especially, A to T mutations at nucleotide 1762 and G to A mutations at nucleotide 1764 were found in five anti-HBe-positive asymptomatic carriers, and 22 patients with chronic liver disease. These two mutation hot spots were located within binding sites of the nuclear factors, and nucleotide 1762 was also involved in the A, T rich sequence that is located 28 base pairs upstream of the precore mRNA initiation site. Serum HBeAg and DNA polymerase levels were significantly lower in patients with these mutations than those without these mutations, and five individuals with these mutations were positive for anti-HBe despite the absence of the precore stop codon mutation. These mutants may be selected by host immune response to HBeAg and/or core antigen.
Adolescent↗
Selection of hepatitis C virus quasispecies during interferon treatment.
Preliminary studies have shown that hepatitis C virus (HCV) quasispecies populations after interferon therapy are different from those before interferon, suggesting that selection of HCV quasispecies occurs during IFN treatment. To confirm this, fluctuations of HCV quasispecies populations were investigated by single strand conformation polymorphism analysis in eight patients who remained viremic during interferon treatment. In all patients, HCV quasispecies populations changed in 1 to 4 months after the start of interferon therapy. In seven patients, a minor population of HCV quasispecies that was present before the interferon therapy was selected and became predominant during the therapy, whereas the abundance of the other quasispecies was reduced. In the other patients, new HCV quasispecies that had not been detected before interferon therapy appeared and replaced the pretreatment HCV. In contrast, no significant changes were observed during the pretreatment period in these patients. In two patients, deduced amino acid sequences of the hypervariable region were identical despite the difference in nucleotide sequences between interferon-sensitive and interferon-resistant HCV. Thus, selection of HCV quasispecies occurs during interferon treatment and immune responses to the hypervariable region may not be the determining factor of the selection.
Adult↗
Hepatic iron contents and response to interferon-alpha in patients with chronic hepatitis C. Relationship to genotypes of hepatitis C virus.
Recent reports have shown that response to interferon treatment is influenced by hepatic iron contents in patients with chronic hepatitis C. In those reports, however, hepatitis C virus (HCV) genotypes and serum HCV-RNA levels were not examined. The aim of the present study was to investigate whether hepatic iron contents influence the response to interferon in patients with chronic hepatitis C and whether HCV genotypes and serum HCV-RNA levels play a role in this relationship. Among 65 patients with chronic hepatitis C, hepatic iron contents were significantly high in patients with a history of excess drinking of alcohol (more than 80 g/day) compared to those without, and significantly low in female patients before menopause. Having excluded these patients, hepatic iron contents were significantly higher in patients with genotype 1b infection than those with genotype 2a and 2b infection. There was no significant correlation between hepatic iron contents and plasma HCV-RNA levels. Among the patients with genotype 1b infection, hepatic iron contents were significantly lower in the responders to interferon than those in the nonresponders (429 +/- 100 vs 875 +/- 110 micrograms/g liver, P < 0.05). From these results, it is concluded that response to interferon is mainly influenced by HCV genotypes, while hepatic iron contents may play an important role in response to interferon in patients with genotype 1b infection.
Adolescent↗
Specific hepatitis C virus NS5A sequences determine the outcome of interferon treatment.
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Hepatitis C↗
Gene expressions of c-met and hepatocyte growth factor in chronic liver disease and hepatocellular carcinoma.
BACKGROUND/AIMS: The roles of c-met proto-oncogene and hepatocyte growth factor in human livers have not been shown. METHODS: Gene expressions of both c-met and hepatocyte growth factor were quantified in livers with chronic active hepatitis and in cirrhotic livers with hepatocellular carcinoma as well as in normal controls, using competitive reverse transcription polymerase chain reaction. RESULTS: C-met expression was significantly increased in chronic active hepatitis compared with control livers, and c-met expression in chronic active hepatitis correlated with serum alanine aminotransferase levels. Hepatocyte growth factor expression was increased in some patients with chronic active hepatitis compared with controls, and there was a significant correlation between c-met expression and hepatocyte growth factor expression. On the other hand, in hepatocellular carcinoma tissues, c-met expression was increased in some cases, while that in the surrounding non-carcinomatous tissues was similar to normal controls. Hepatocyte growth factor expression was not detected in the hepatocellular carcinoma tissues and was low in the surrounding non-carcinomatous tissues. CONCLUSIONS: These findings suggest that hepatocyte growth factor may be involved in the regeneration of hepatocytes via paracrine mechanism in chronic active hepatitis, while in regulation of c-met expression in hepatocellular carcinoma tissues may be independent of hepatocyte growth factor stimulation.
Alanine Transaminase↗
Sequential changes in full-length genomes of hepatitis B virus accompanying acute exacerbation of chronic hepatitis B.
BACKGROUND/AIM: During the course of persistent hepatitis B virus infection, viral replication markedly decreases after acute exacerbation of liver inflammation accompanied by emergence of antihepatitis B e antibody (anti-HBe) and/or anti-hepatitis B surface antibody (anti-HBs). In some cases, however, persistent viral replication continues even after such exacerbation with or without HBeAg/anti-HBe seroconversion. The aim of the present study was to investigate the extent of genetic variations of HBV in this phenomenon. METHODS: Full-length HBV genomes were amplified by polymerase chain reaction from sera of three patients before and after acute exacerbation and were directly sequenced. RESULTS: In the whole genomes of 3215 nucleotides, only six nucleotide mutations for six amino acid substitutions (2 in the surface gene, 2 in the X gene, 1 in the core gene and 1 in the polymerase gene) were observed in patient 1, 15 mutations for 14 amino acid substitutions (1 in the pre-core codon 28, 4 in the surface gene, 4 in the core gene and 5 in the polymerase gene) were observed in patient 2, and 5 mutations for 6 amino acid substitutions (2 in the surface gene, 2 in the X gene, pre-core stop codon mutation and 1 in the polymerase gene) were observed in patient 3. Substitution in the a determinant of the surface gene, which encodes target epitopes for neutralizing antibodies, as well as those in the pre-core/core gene, which encodes epitopes for cytotoxic T cells, were mainly found. CONCLUSION: HBV that remained after the emergence of anti-HBe and anti-HBs are considered to possess mutations in epitopes for both humoral and cellular immunity. These mutant HBV may be involved in the pathogenesis of persistent hepatic injury after acute exacerbation.
Adult↗
Distribution of hepatitis C virus RNA in the liver and its relation to histopathological changes.
To investigate a cellular mode of HCV-infection in the liver and its pathological implications in relation to histopathological changes or clinical data, we studied the distribution of HCV-RNA in the livers of 21 patients with HCV-related chronic liver disease (chronic active hepatitis, 14 cases; cirrhosis, 7 cases) using the in situ hybridization technique. In situ hybridization was performed on 4% paraformaldehyde-fixed frozen sections with digoxigenin-labeled DNA probe deduced from the core region of HC-J4. In situ hybridization showed positive signals in the liver specimens of 20/21 cases. The signals were localized in the cytoplasm of hepatocytes. The distribution pattern of positive cells was individually different, whereas the pattern was identical in the right and left lobes. There were no correlations of the HCV-positive cell number with serum aminotransferase levels at biopsy or with genotypes of HCV. The positive hepatocytes were occasionally associated with infiltrating mononuclear cells, and they were sparsely distributed in the area of piecemeal necrosis. These findings suggest that factors such as host immunoreaction to the virus may be more important than its direct cytopathy in the pathogenesis of chronic hepatitis C virus infection.
Alanine Transaminase↗
A prospective study of hepatitis C virus infection after needlestick accidents.
There have been few prospective studies of hepatitis C virus (HCV) infection after needlestick accidents in hospital employees. In the present study, the prevalence and features of HCV infection after needlestick accidents were evaluated prospectively measuring serum HCV-RNA. Subjects were 56 employees who had HCV needlestick accidents. To monitor the development of hepatitis, the serum ALT levels and HCV-related seromarkers, such as first generation anti-HCV (RIA), second generation anti-HCV (PHA) and HCV-RNA (RT-PCR) were measured every month for at least 12 months after the accidents. Three of 56 (5.4%) recipients developed HCV infection. HCV-RNA was detected in all three recipients within 4 months after the exposure, and second-generation HCV antibody was detected in two of three recipients. The detection of HCV-RNA was earlier than that of HCV antibody. Two of three HCV-infected recipients developed type C acute hepatitis and one of two received interferon therapy; however, the other case received no medication. The detection of HCV-related seromarkers and the elevation of ALT levels were transient in these three recipients: thus, none developed chronic hepatitis. In conclusion, HCV infection developed in 5.4% of recipients within 4 months after HCV accidents. All of these HCV-infected recipients showed fair prognosis. HCV-RNA was a beneficial parameter for early detection of HCV infection.
Accidents, Occupational↗
Induction of antinuclear antibody after interferon therapy in patients with type-C chronic hepatitis: its relation to the efficacy of therapy.
BACKGROUND: The prevalence of antinuclear antibody (ANA) and interferon (IFN)-induced ANA has been documented in patients with chronic hepatitis C. In the present study we evaluated whether the induction pattern of ANA after IFN therapy is related to the efficacy of IFN therapy. METHODS: Forty-four patients with chronic hepatitis C were enrolled. Autoimmune hepatitis was excluded in all. ANA was measured every month before, during, and for 6 months after IFN therapy (total dose, 336-480 M units). RESULTS: Eight of the 44 (18%) patients were positive for ANA before IFN therapy (group I). In group I six of the eight ANA-positive patients showed an increase in ANA titers during the therapy. Twenty-two of 36 (61%) ANA-negative patients turned positive for ANA, with titers of 1:80 or less during IFN therapy (group II). In 14 of the 36 (39%) ANA-negative patients ANA remained negative throughout the therapy (group III). The rates of sustained responders with a negativity of serum hepatitis C virus RNA and with normal alanine aminotransferase levels for at least 6 months after the cessation of therapy in groups I, II, and III were 25%, 23%, and 21%, respectively, giving no significant difference in the efficacy of therapy. No serious side effect was observed during the therapy. CONCLUSIONS: Administration of IFN frequently produced an induction of ANA or an increase in its titer, which did not affect the efficacy of IFN therapy.
Antibodies, Antinuclear↗
[Surgery for aortic valvular disease with congenital quadricuspid aortic valve].
A case of quadricuspid aortic valve is reported. A 69-year-old man was hospitalized with chest oppression at rest and abnormal electrocardiogram and diagnosed aortic regurgitation by echocardiography and aortic angiography. Aortic regurgitation was grade III according to Seller. Aortic valve replacement was performed successfully with a 21 mm St. Jude Medical valve. The aortic valve showed four cusps consisting of two equal larger cusps and two equal smaller cusps which was type C according to Hurwitz. Each valve was thickened and adhered, and fenestrations were found at each commissure. The right coronary ostium was small but not displaced. Twenty five cases in literature which were corrected surgically are also reviewed. Quadricuspid aortic valve is a rare anomaly but must be considered as a malformation which leads to severe valve failure in later life.
Aged↗
[A case of pancreatic pleural effusion and ascites treated successfully with conservative measures including octreotide and nafamostat mesilate].
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Anti-Inflammatory Agents, Non-Steroidal↗
Detection of hepatitis C virus RNA in hepatocellular carcinoma by in situ hybridization.
BACKGROUND: Hepatocellular carcinoma frequently is associated with chronic hepatitis C virus (HCV) infection. The presence of HCV in hepatocellular carcinoma has been detected by reverse-transcription polymerase chain reaction of antigenomic HCV RNA, a tissue-specific replicative form of the virus. Now, however, this method of detecting the presence of HCV has been invalidated by reports of antigenomic RNA in the blood or in peripheral blood mononuclear cells. METHODS: In situ hybridization of HCV RNA was conducted with digoxigenin-labeled cDNA from the core region on surgical specimens of noncancerous and cancerous areas from 12 patients with chronic hepatitis C with or without cirrhosis associated with hepatocellular carcinoma. Several control experiments were also performed, including RNase digestion before hybridization, hybridization with the use of a negative control, and immunohistochemical staining of HCV-core protein. RESULTS: The in situ hybridization showed positive signals both in noncancerous and cancerous areas of the liver tissue in eight cases. Positive signals were confined to neoplastic cells and nonneoplastic hepatocytes. There were fewer HCV-positive cells in the cancerous area than in the surrounding noncancerous area. CONCLUSIONS: In situ detection of HCV presents direct evidence of HCV infection in the neoplastic cells of hepatocellular carcinoma and suggests that neoplastic cells may lose their affinity for HCV in the course of malignant transformation.
Carcinoma, Hepatocellular↗
Comparison of the hypervariable region of hepatitis C virus genomes in plasma and liver.
Nucleotide sequences of the hypervariable region of hepatitis C virus genomes obtained from plasma change rapidly during the course of infection and are believed to play a part in immunological escape and consequently in the development of persistent infection. It is not known, however, whether these changes also occur in the liver. To clarify this aspect, RNA was extracted from the plasma and liver tissue of eight patients with chronic hepatitis C. After cDNA synthesis, DNA fragments that included the hypervariable region were amplified by the polymerase chain reaction. Consensus nucleotide sequences were determined directly from the polymerase chain reaction products by the dideoxy chain termination method. The diversity of the hypervariable region was analyzed further by the polymerase chain reaction-single strand conformation polymorphism analysis. Consensus nucleotide sequences of the hypervariable region were identical between the plasma and the liver in each patient. The polymerase chain reaction-single strand conformation polymorphism analysis showed multiple DNA bands that represented different hypervariable region sequences. Comparison of the single strand conformation polymorphism patterns revealed that the number, the mobility, and the density of bands were the same between the plasma and the liver. It is concluded that the population and the diversity of hepatitis C virus quasispecies as detected by the hypervariable region sequence are the same between the plasma and the liver despite rapid mutations, indicating that rapid changes in the population of hepatitis C virus quasispecies also occur in the liver.
Amino Acid Sequence↗