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Biomedical subjects

N Izumi

Publications and source records attributed to N Izumi.

At least 19 recordsLinked to original sources
PubMed1995

Detection and analysis of replicating hepatitis C virus RNA in hepatocellular carcinoma tissues.

Although persistent hepatitis C virus infection is closely associated with the development of hepatocellular carcinoma, the nature of hepatitis C virus replication in the hepatocellular carcinoma tissue has not been fully characterized. To study this, carcinoma and non-carcinoma tissues were obtained from five patients with hepatocellular carcinoma. Total RNA was recovered from each tissue, and a portion of the envelope gene of replicating hepatitis C virus was amplified by minus-strand-specific reverse transcription and nested polymerase chain reaction. The amplified cDNA was examined by single strand conformation polymorphism analysis and sequencing. Hepatitis C virus replication was detected in both carcinoma and non-carcinoma tissues in four patients who were positive for serum hepatitis C virus markers. In one patient, a single species with identical envelope 2 genome was obtained from both carcinoma and non-carcinoma tissues. In the other three patients, the replicating hepatitis C virus existed as a mixture of 2-5 species with different but highly homologous (82-99%) envelope 2 genomes (quasispecies populations). The constitution of viral populations was different between carcinoma and non-carcinoma tissues. A total of ten sequences were recovered; four sequences were found in both tissues, two were found in carcinoma tissues, and four were found in non-carcinoma tissues. The difference in the constitution of quasispecies populations between carcinoma and non-carcinoma tissues confirms the unequivocal replication of hepatitis C virus in both tissues, and may imply the presence of different biological properties among hepatitis C virus with different sequences.

Amino Acid Sequence↗
PubMed1995

Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region.

We have previously demonstrated that sensitivity to interferon is different among hepatitis C virus (HCV) quasispecies simultaneously detected in same individuals and that interferon-resistant HCV quasispecies are selected during the treatment. To determine the genetic basis of their resistance to interferon, HCV genotype-1b was obtained from serum of three patients before and during interferon therapy, and their full-length nucleotide and deduced amino acid sequences were determined. Comparison of the pairs of interferon-resistant and interferon-sensitive HCV isolates in respective individuals demonstrated clusters of amino acid differences in the COOH-terminal half of the NS5A region (codon 2154-2383), which contained a common unique amino acid difference at codon 2218. Additional sequence data of the COOH-terminal half of the NS5A region obtained from six interferon-resistant and nine interferon-sensitive HCV confirmed the exclusive existence of missense mutations in a 40 amino acid stretch of the NS5A region around codon 2218 (from codon 2209 to 2248) in interferon-sensitive HCV. On the other hand, this region of interferon-resistant HCV was identical to that of prototype HCV genotype-1b (HCV-J, HCV-JTa, or HC-J4). We designated this region as the interferon sensitivity determining region. Thus, HCV genotype-1b with the prototype interferon sensitivity determining region appears to be interferon-resistant strains. The specific nature of these mutations might make it possible to predict prognostic effects of interferon treatment.

Adult↗
PubMed1995

Increased gene expression of water channel in cirrhotic rat kidneys.

In patients with liver cirrhosis, impaired water and sodium excretion has been incriminated in the pathogenesis of ascites formation. Increased reabsorption of water in the distal nephron has been shown to play an important role in water retention in cirrhotic rat kidneys. Recently, a complementary DNA (cDNA) for the vasopressin-regulated water channel (the aquaporin of the apical membrane of the kidney collecting duct [AQP-CD]) has been cloned. It is suggested that AQP-CD plays an important role in renal water handling. Therefore, in the present study, to investigate the pathogenic role of the water channel in water retention in liver cirrhosis, gene expression of AQP-CD in the kidney was evaluated in cirrhotic rats. Liver cirrhosis was induced by an intraperitoneal administration of carbon tetrachloride twice a week for 12 weeks in 14 rats. Messenger RNA expression of AQP-CD in whole kidney homogenates determined by Northern blot hybridization was significantly increased in cirrhotic rats (147%; P < .01) and dehydrated rats (206%; P < .0001) compared with control rats. Protein expression of AQP-CD in the homogenates of kidney medulla determined by Western blot analysis was significantly increased in cirrhotic rats (203%; P < .03) compared with control rats. Furthermore, mRNA expression of AQP-CD in the kidney showed a significant correlation with the volume of ascites in cirrhotic rats (r = .62, P < .02). No significant difference was observed in water intake, urinary volume, serum osmolality, serum sodium, and creatinine clearance between control and cirrhotic rats, suggesting that dehydration was unlikely in cirrhotic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Diversity of quasispecies in various disease stages of chronic hepatitis C virus infection and its significance in interferon treatment.

Hepatitis C virus (HCV) populations in vivo exist as a mixture of heterogeneous viruses called quasispecies, which have variations in the hypervariable region (HRV). However, the relationship between the diversity of HVR quasispecies, the disease stage, or the interferon (IFN) responsiveness remains to be elucidated. To study these, serum samples were obtained from 42 patients with chronic hepatitis C virus infection; 24 with chronic active hepatitis (CAH) treated with IFN, 9 with cirrhosis, 9 with hepatocellular carcinoma (HCC). HCV quasispecies populations were separated by the single-strand conformation polymorphism (SSCP) method targeted to the HVR. The patients were classified into two groups; a single-band group (n = 12) in which HVR quasispecies was homogeneous and a multiple-band group (n = 30) in which HVR quasispecies was heterogeneous. Patients with multiple bands had significantly more advanced liver disease than those with a single-band group (P = .0082). The percentage of patients with single band were 41% in CAH, 22% in cirrhosis, and 0% in HCC. Multivariate analyses showed that viral diversity was independently related to the progression of liver disease and was not correlated with the duration of infection. We also found that in CAH, the patients who had multiple bands (n = 14) were more resistant to IFN therapy than those who had a single band (n = 10) (P = .002). These results indicate that the diversity of HCV quasispecies becomes more complex as the disease stage progresses and that CAH with more complex diversity shows less IFN effectiveness.

Aged↗
PubMed1995

Systemic hypotension and diuresis by L-arginine in cirrhotic patients with ascites: role of nitric oxide.

To investigate the role of nitric oxide in renal function and hemodynamics in cirrhotic patients with ascites, L-arginine (30 g in 300 mL of distilled water), a substrate for nitric oxide synthase, was infused into six cirrhotic patients with ascites, and the effects were compared with those of saline infusion. Healthy controls (n = 5) were also studied under the same conditions. In the patients, L-arginine infusion significantly decreased systolic and diastolic blood pressures while markedly increasing urinary flow and urinary sodium excretion; no significant changes were seen with saline infusion. In controls, only diastolic blood pressure was decreased by L-arginine infusion, whereas urinary flow and urinary sodium excretion were increased by both L-arginine and saline infusion. In both groups, a similar increase of plasma atrial natriuretic factor (ANF) was seen with L-arginine and saline infusions; endothelin and catecholamines were not affected by either infusion. In both groups, plasma levels of vasopressin were increased by L-arginine infusion. In the cirrhotic patients, urinary excretions of cyclic guanosine monophosphate (cGMP) and nitrates/nitrites (NOx) were significantly increased by L-arginine infusion, whereas no significant changes were seen with saline infusion. In controls, only the excretion of cGMP was increased by L-arginine infusion. In summary, L-arginine infusion induces diuresis and natriuresis accompanied by increased excretions of cGMP and NOx in cirrhotic patients with ascites. This differs from the response in controls, where the increase in urinary sodium excretion is not accompanied by an increase in markers of increased nitric oxide synthesis.

Adult↗
PubMed1995

Limited usage of T-cell receptor beta chains and sequences of the complementarity determining region 3 of lymphocytes infiltrating in the liver of autoimmune hepatitis.

To study the role of antigen-specific T lymphocytes in the pathogenesis of autoimmune hepatitis, messenger RNA of T-cell receptors (TCR) was analyzed in liver biopsy specimens from four patients with autoimmune hepatitis. Using the TCR beta-chain variable region family specific oligonucleotides, a remarkable bias for the usage of beta-chain variable region 3 was detected in all four patients. Therefore, nucleotide and amino acid sequences of the complementarity-determining region 3 rearranged to the beta-chain variable region 3, which is a putative contact site for peptide fragments from antigens bound in the groove of the human leukocyte antigen molecule, was further analyzed in randomly selected 10 clones from each patient. An Asp-Arg-Pro motif in the complementarity-determining region 3 was identified in three of four patients with human leukocyte antigen DR4, and this motif was always rearranged to the beta-chain junctional region 1.2. From these results, beta-chain variable region 3+, Asp-Arg-Pro+, beta-chain junctional region 1.2+ T-cell clones may be among the responsible lymphocytes involved in the liver damage in autoimmune hepatitis, especially in patients with human leukocyte antigen DR4. Thus, an analysis of the complementarity-determining region 3 may give us an important clue to clarify characteristics of target antigens included in autoimmune hepatitis.

Adult↗
PubMed1992

Clinical significance of elevated plasma endothelin concentration in patients with cirrhosis.

Endothelin is a newly discovered potent vasoconstrictor peptide. To explain the clinical significance of endothelin in patients with chronic liver diseases, we measured the plasma concentration of endothelin in patients with chronic hepatitis (n = 15), cirrhosis with ascites (n = 8) and cirrhosis without ascites (n = 12), and we compared the findings with the plasma concentration of endothelin in normal controls (n = 14). The plasma endothelin concentration was significantly higher in patients with cirrhosis with ascites than in normal controls (8.3 +/- 2.3 pg/ml vs. 3.3 +/- 1.4 pg/ml, mean +/- S.D., p less than 0.001), whereas no significant difference was observed between normal controls and the other groups of patients (cirrhosis without ascites = 5.0 +/- 1.3 pg/ml; chronic hepatitis = 3.8 +/- 1.2 pg/ml). In patients with cirrhosis, the plasma endothelin concentration showed a significant negative correlation with creatinine clearance (r = -0.73, p less than 0.01), but no significant correlation was observed between plasma endothelin concentration and fractional excretion of filtered sodium. Furthermore, plasma endothelin levels were significantly higher in patients with endotoxemia than in those without (10.1 +/- 2.1 pg/ml vs. 4.9 +/- 1.2 pg/ml, p less than 0.001). From these results, elevated plasma endothelin, which has a close relation to endotoxemia, may play a contributory role in kidney dysfunction in patients with cirrhosis.

Aldosterone↗
PubMed1992

V1-receptor mediated GSH efflux by vasopressin from rat hepatocytes.

Vasopression increases sinusoidal efflux of GSH in the perfused rat liver. The mechanism of this effect was studied in the perfused rat liver and in isolated rat hepatocytes. Vasopressin stimulated GSH efflux in both systems and a V1-receptor antagonist (OPC-21268) significantly inhibited the effect of vasopressin suggesting that vasopressin stimulates GSH efflux from rat hepatocytes via V1-receptor.

Angiotensin Receptor Antagonists↗
PubMed1992

Possible involvement of protein kinase C and calcium in GSH efflux from Hep G2 cells.

We investigated the effects of protein kinase C modulations and calcium mobilization on GSH efflux in Hep G2 cells. GSH efflux from Hep G2 cells was increased by a phorbol ester. Staurosporine, an inhibitor of protein kinase C, diminished phorbol ester-stimulated GSH efflux from the cells. GSH efflux was negatively correlated with extracellular calcium concentrations. Verapamil enhanced GSH efflux, whereas ATP decreased GSH efflux. The latter effect was diminished in the absence of extracellular calcium. Protein kinase C and calcium mobilization may be crucial factors in GSH efflux from human hepatocytes.

Adenosine Triphosphate↗
PubMed1992

Formation of cholic acid from 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestanoic acid in human skin fibroblasts.

Whether 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestanoic acid (THCA) was converted into cholic acid in human skin fibroblasts was examined. THCA was incubated with subcellular fractions of cultured skin fibroblasts in the presence of NAD+, ATP, CoA, and Mg2+. The reaction products were analyzed by thin-layer chromatography and high-performance liquid chromatography after p-bromophenacyl ester derivatization. The highest specific activity was found in the light mitochondrial fraction (2.71 nmol/mg protein/h). The specific activity was about 9-fold higher than that in heavy mitochondrial fraction. The peroxisomal fraction prepared from the light mitochondrial fraction by sucrose gradient centrifugation was also able to catalyze the conversion of THCA into cholic acid. The specific activity in this fraction was a further 2.2-fold higher than that in the light mitochondrial fraction. These results suggest that cultured human skin fibroblasts are able to convert THCA into cholic acid, and that the activity exists in peroxisomes.

Catalase↗
PubMed1992

Methacholine inhalation challenge in children with idiopathic chest pain.

Bronchial reactivity to inhaled methacholine (MCH) was evaluated in 32 patients with 'idiopathic' chest pain. Each pain was recurrent in nature. The incidence of cases with a provocative concentration causing a 20% fall in the forced expiratory volume in 1 sec (PC20) of 10 mg/ml or less was 62.5% (20 cases), while it was only 11.1% (three cases) in 27 healthy controls. Seventeen patients had no personal history of allergic diseases, elevated serum IgE level or positive house dust mite-specific IgE antibody. Among these 17, eight (47.1%) had a PC20 of 10 mg/ml or less, the incidence of which was also higher than that of the healthy controls. During the challenge, eight patients complained of chest pain similar to that experienced before. The present results indicate that bronchial hyper-reactivity is an important cause of 'idiopathic' chest pain. Patients with unexplained chest pain should be considered for inhalation challenge.

Adolescent↗
PubMed1990

Red blood cell aluminum in patients with renal failure and effect of desferrioxamine infusion.

Red blood cell (RBC) aluminum (Al) in patients with renal failure on different treatments was studied. Nondialyzed renal failure patients had high levels of RBC Al, but low serum Al levels. However, their RBC Al levels were lower than those of patients on hemodialysis (HD) and continuous ambulatory peritoneal dialysis. In addition, HD patients who were not given Al-containing medications showed high levels of RBC Al, which suggests that there may be a source of Al other than medications. When desferrioxamine (DFO) was administered to these HD patients, the changes in RBC Al levels after DFO infusion were independent of those in serum Al levels and blood hemoglobin levels. In an in vitro study, RBC Al was removed using an ultrafiltration membrane, which showed that RBC Al exists in a bound form. These results suggest that Al accumulates in RBCs of renal failure patients independently of serum Al levels, and that the improvement of anemia by DFO may not be due to the direct removal of RBC Al.

Adult↗
PubMed1990

[A clinical trial of transarterial chemoembolization for hepatocellular carcinoma using 4'-0-tetrahydropyranyladriamycin].

A clinical trial of transarterial chemoembolization for hepatocellular carcinoma using pirarubicin (4'-0-tetrahydropyranyladriamycin, THP) was performed. Although adriamycin has been widely utilized for chemoembolization on the hepatocellular carcinoma, myocardial toxicity has been occasionally observed as its serious side effect. THP has an advantage that myocardial and gastrointestinal complications are less frequent than adriamycin. Ten patients with hepatocellular carcinoma were included in this study. Emulsion of 30-60 mg of THP and lipiodol was administered through a catheter inserted into the right or left hepatic artery, and thereafter, transarterial embolization was performed. PR was observed in seven of the ten patients and MR in two. Only one patient showed NC. Serum alpha-fetoprotein levels decreased in nine of the ten patients, and PIVKA II in the peripheral blood disappeared in all five patients that had been positive before the chemo-embolization four weeks after the treatment. Side effects included nausea in two patients just after administration of THP, but leukopenia below 2,000/cmm, was not observed in any of the patients. No other serious side effect was observed. From these results, THP was suggested to be a useful chemotherapeutic agent for hepatocellular carcinoma.

Aged↗
PubMed1990

Urinary polyamine excretion measured by a simple enzymatic method is clinically useful as an expression of hepatic regeneration in liver diseases.

Polyamines have been known to play an important role in hepatic regeneration. In the present study, we measured the amount of urinary polyamine excretion in various liver diseases using a simple enzymatic method. Urinary polyamine excretion was elevated above the normal range in 21 out of 47 cases with fulminant hepatic failure, acute hepatitis, chronic active hepatitis, and liver cirrhosis. No change, however, was observed in 11 patients with chronic inactive hepatitis. In fulminant hepatic failure, two patients with urinary polyamine concentrations above 100 mumoles/g.cr. recovered, while two patients with concentrations of 56.2 and 26.7 mumoles/g.cr., died. In acute hepatitis, urinary polyamine excretion was significantly less in the recovery stage compared with the acute stage. When insulin and glucagon infusion therapy was performed in patients with liver cirrhosis without ascites, urinary polyamine excretion was significantly elevated after three days. These results suggest that measuring the amount of polyamine in urine is clinically useful for monitoring hepatic regeneration.

Biogenic Polyamines↗
PubMed1989

Clinical significance of serum antibodies against alcohol-altered hepatocyte membrane in alcoholic liver disease.

The clinical significance of serum antibodies against alcohol-altered rabbit hepatocytes was evaluated in 91 patients with alcoholic liver disease. Patients were divided into two groups according to the presence or absence of those antibodies at the time of first admission, and their clinical, biochemical, and histological findings were compared. In 38 seropositive patients, the total amount of ethanol consumption as well as serum activity of glutamate-oxaloacetate transaminase, serum levels of total bilirubin, gamma-globulin, IgG, and IgA were all significantly higher than in 53 seronegative patients. In addition, the extent of fibrosis, alcoholic hyalin, cholestasis, and lymphocytic and polymorpholeukocytic infiltrations in the liver were all significantly greater in the seropositive patients. Histological changes were compared in the 16 patients who continued to drink alcohol and who received repeated liver biopsies. Seven out of eight patients who were seropositive at the time of the first liver biopsy showed histological deterioration, whereas one of the eight seronegative patients showed a slight progression. These results suggest that the presence of serum antibodies against alcohol-altered liver cell membrane delineates a group of alcoholic patients with severe, advanced liver disease characterized by a tendency to progress with continued alcohol ingestion.

Alanine Transaminase↗
PubMed1989

Mechanism of increased hepatotoxicity of acetaminophen by the simultaneous administration of caffeine in the rat.

The simultaneous administration of caffeine has been shown to potentiate acetaminophen-induced hepatotoxicity. In the present study, the mechanisms of this effect were studied. Male Sprague-Dawley rats, fasted for 18 hr, were given acetaminophen (0.5 g/kg) and/or caffeine (0.1 g/kg) i.p. Two hours later, the depletion of hepatic reduced glutathione (GSH) induced by acetaminophen was more pronounced by the concomitant administration of caffeine, although the effect of caffeine alone on the hepatic GSH content was minimal at this dose. Covalent binding of a reactive metabolite of acetaminophen to hepatic proteins was increased by caffeine although the free acetaminophen content in the liver was not affected. In isolated rat hepatocytes prepared from normal animals, caffeine enhanced acetaminophen-induced GSH depletion and potentiated covalent binding of the reactive metabolite to cellular proteins. The extracellular release of GSH + oxidized glutathione was decreased by acetaminophen, and this decrease was potentiated further by the addition of caffeine. In the cells, the production of acetaminophen-GSH conjugate also was increased in the presence of caffeine, whereas that of glucuronide conjugate was decreased. In microsomes, NADPH-dependent production of acetaminophen-GSH conjugate was increased in the presence of caffeine. Thus, caffeine appears to potentiate acetaminophen-induced hepatotoxicity mainly by enhancing the production of a reactive metabolite of acetaminophen by mixed function oxidases. To what extend caffeine-induced GSH depletion plays a role is to be clarified.

Acetaminophen↗