Biomedical subjects
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Hepatitis C virus (HCV) has been known to infect hosts as a quasispecies. Several reports have shown this using serum samples, but there is little information about quasispecies in the liver. In this study, we evaluated quasispecies in serum and in 3 different parts of the liver in 8 patients with varying severity of chronic hepatitis C by calculating nucleotide diversity, entropy, type of substitution and by phylogenetic analysis. Nucleotide diversity of HCV was different in each sample and ranged from 0.37% +/- 0.31% to 4.10% +/- 1.06%. However, the degree of HCV diversity in serum correlated with that in the liver in each patient (P <.01). Common HCV clones were found both in serum and liver samples in all 6 noncirrhotic patients, but all serum clones were different from the clones from the 2 cirrhotic livers. Phylogenetic analysis showed that the degree of genetic diversity of HCV among the 3 liver samples was significantly high in the 4 patients with fibrosis. These genetic compartmentalizations of HCV did not depend on the type of substitution or the viral load of each liver sample. HCV quasispecies within the liver may be closely related to the viral life cycle and the pathogenesis of persistent infection of HCV.
Human serum contains a soluble form of interferon alfa/beta (sIFN alpha/beta) receptors, the functional and clinical significance of which has not been investigated in patients with chronic hepatitis C. In the present study, serum levels of sIFN alpha/beta receptor were assessed in 81 patients with chronic hepatitis C and correlated with the effectiveness of IFN therapy in these patients. Serum levels of sIFN alpha/beta receptor were significantly higher in patients with chronic hepatitis C than in healthy control patients (P <.0001). In these patients, serum levels of sIFN alpha/beta receptor were correlated with those of alanine transaminase (ALT) (P <.05), (2'-5')serum oligo(A) synthetase (2-5AS) (P <.0001), and pathological stages of liver fibrosis (P <.01). In 55 patients with chronic hepatitis C who underwent IFN therapy, there was an inverse correlation between the pretherapeutic serum levels of sIFN alpha/beta receptor and the rate of increase in serum levels of 2-5AS after the start of IFN (P <.01). Pretherapeutic serum levels of sIFN alpha/beta receptor were significantly lower in patients who showed sustained response to IFN therapy compared with those who did not respond to the therapy (P <.05). Multivariate analysis showed that low levels of serum sIFN alpha/beta receptor (</=4.0 ng/mL) (P <.05) and serological hepatitis C virus genotype II (P <.05) were independent variables contributing to sustained response to IFN therapy. Thus, pretherapeutic serum levels of sIFN alpha/beta receptor were correlated with the effectiveness of IFN therapy, suggesting that sIFN alpha/beta receptor suppresses the effectiveness of IFN therapy in patients with chronic hepatitis C.
Duodenal metastasis from primary lung cancer is extremely rare. It rarely shows any symptoms, and the prognosis for this condition is poor. We herein describe the case of a 46-year-old woman with primary lung cancer who underwent a left upper lobectomy. Severe anemia was observed about 20 days after lobectomy. Gastroduodenoscopy showed duodenal metastasis. Simultaneously, brain metastasis was also detected using magnetic resonance imaging. The patient underwent a local resection of the duodenum and a tumor resection of the brain. Postoperative irradiation of the brain metastases and systemic chemotherapy of the lung metastases were performed, and complete remission occurred. However, abdominal lymph node metastasis recurred, and the patient died 1 year after the lobectomy.
RATIONALE: A previously reported pharmacokinetic interaction between bromperidol and carbamazepine, an inducer of cytochrome P450 (CYP) 3A4, suggests possible involvement of CYP3A4 in the metabolism of bromperidol. OBJECTIVE: We investigated pharmacokinetic interaction between bromperidol and itraconazole, a potent inhibitor of CYP3A4, to clarify the involvement of CYP3A4 in the metabolism of bromperidol and its reduced metabolite. METHODS: Itraconazole 200 mg/day for 7 days was coadministered to eight schizophrenic patients treated with a fixed dose of bromperidol 12 or 24 mg/day for at least 2 weeks. Blood samples were taken before and 1 week after itraconazole coadministration and 1 week after its discontinuation, together with clinical assessments using the Brief Psychiatric Rating Scale (BPRS) and the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale. RESULTS: Plasma concentrations of bromperidol during itraconazole coadministration (16.7+/-4.9 ng/ml) were significantly higher (P<0.01) than before itraconazole coadministration (8.9+/-4.4 ng/ml) and 1 week after its discontinuation (9.9+/-4.3 ng/ml). Plasma concentrations of reduced bromperidol during itraconazole coadministration (3.6+/-2.9 ng/ml) were significantly higher (P<0.01) than before itraconazole coadministration (1.8+/-1.3 ng/ml). No changes were observed in BPRS and UKU scores throughout the study. CONCLUSIONS: The pharmacokinetic interaction between bromperidol and itraconazole is probably due to the inhibitory effect of itraconazole on the metabolism of bromperidol. This study provides in vivo evidence of involvement of CYP3A4 in the metabolism of bromperidol and reduced bromperidol.
Three patients with malignant bone tumors of the proximal femur underwent implantation of an endoprosthesis with reconstruction of the joint capsule and hip abductors using artificial mesh.
We investigated the expression of the drug resistance-related genes, multidrug resistance gene 1 (MDR1), multidrug resistance associated protein gene (MRP), and the DNA topoisomerase IIalpha, DNA topoisomerase IIbeta, and glutathione-S-transferase pi gene (GST-pi) in three human hepatoma cell lines (HepG 2, HuH 7, SK-Hep-1) with or without drug treatment with interferon-alpha (IFN-alpha) and cisplatin (CDDP), by a reverse transcription-polymerase chain reaction (RT-PCR) method and a competitive PCR method. The signals of the MDR1, MRP, topoisomerase IIalpha, and topoisomerase IIbeta genes in HepG2 were weakened when IFN-alpha was added to CDDP. In SK-Hep-1, the administration of CDDP alone increased the signals of MDR1 while the addition of IFN-alpha decreased the signals, and the signals of GST-pi were decreased by IFN-alpha plus CDDP. In summary, our results concerning the expression of drug resistance-related genes in three human hepatoma cell lines demonstrate that IFN-alpha may modulate the mechanism of resistance to CDDP in liver cancer.
Helicobacter pylori infection is associated with chronic infiltration by various cell types, including T cells, whose cytokine production may regulate the inflammatory reaction as well as local immune response to the bacterium. We prospectively analyzed the constituents of the cellular infiltrates and the cytokines produced by T cells in antral biopsies obtained from 73 subjects with and without H. pylori infection, before and after eradication therapy, and compared them with a histological grade of gastritis. We found that T cells predominated in cell number, followed by granulocytes/monocytes and plasma cells in both H. pylori-infected and H. pylori-uninfected subjects. Despite the absence of H. pylori infection, more than 70% of gastric CD4-positive T cells obtained from uninfected tissue produced interferon-gamma (IFN-gamma) in the cytosol. Upon receptor cross-linking of a CD3 and a CD28 molecule, T cells in both infected and uninfected tissue continuously secreted a far greater amount of IFN-gamma than those in peripheral blood mononuclear cell controls for a period of cell culture, whereas the increase in interleukin-4 (IL-4) was very small, and no increase in IL-2 secretion was seen. In H. pylori-infected patients, IFN-gamma secretion was correlated with the grade of mononuclear cell infiltration and decreased to an uninfected control level after eradication therapy. We did not see the effect of eradication on IL-4 secretion. Anti-H. pylori antibody of the IgG2 subclass was remarkably increased in H. pylori-infected subjects. These results together suggest that gastric T cells are already differentiated to produce a large amount of IFN-gamma by a mechanism unrelated to H. pylori infection. H. pylori infection appeared to activate T cells to secrete even more IFN-gamma, which may contribute to maintaining a perpetual inflammation in H. pylori-infected stomach.
The distribution of hyaluronan and versican in the dental pulp of the young rat was mapped histochemically. The pattern of staining showed considerable variation between different teeth and different specimens. The most common pattern was a strong reaction for hyaluronan and a weak reaction for versican in the subodontoblastic region, with the reverse deeper in the pulp. This was not an entirely consistent pattern and there was considerable regional variation in the staining intensity for both molecules. The localization of these molecules at similar sites could thus indicate related roles in the connective tissue matrix rather than any chemical bonding between them.
We investigated whether the apolipoprotein E (apoE) and the angiotensin-converting enzyme (ACE) genotypes contribute to the variance in low-density lipoprotein (LDL) particle size in Japanese subjects (n = 136; M/F= 106/30). ACE polymorphism was associated with neither LDL size nor individual lipid levels. In contrast, the subjects with the epsilon2 allele of the apoE genotype had significantly lower levels of total cholesterol (P = 0.002) and LDL cholesterol (P = 0.004) compared with those without the epsilon2 allele. The subjects with the epsilon4 allele had a significantly smaller LDL particle size than those without the epsilon4 allele (P = 0.012). Separate analyses of the male subjects showed similar associations. A stepwise regression analysis revealed the epsilon4 allele to be an independent contributing variable that could affect LDL particle size. Our results suggest that the apoE genotype is associated with the development of atherosclerotic disease, since the epsilon2 and epsilon4 alleles relate to a decrease in LDL cholesterol levels and a decrease in LDL particle size, respectively.
BACKGROUND: The CYP2D6*10 (*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of about 50%. In this study we studied the effects of the *10 allele on the steady-state plasma concentrations (Css) of haloperidol and reduced haloperidol. METHODS: The subjects were 67 Japanese inpatients with schizophrenia who had only the wild-type or *10 alleles. Thirty-four patients were homozygous for the wild-type allele, and 26 were heterozygous and 7 were homozygous for the *10 allele. All patients had been receiving 12 mg/day haloperidol for at least 2 weeks. Plasma concentrations of haloperidol and reduced haloperidol were measured by HPLC. RESULTS: The mean +/- SD values of haloperidol Css in the patients with 0, 1, and 2 *10 alleles were 22.8+/-11.0, 30.1+/-10.6, and 31.2+/-21.2 nmol/L, respectively, and those values for reduced haloperidol were 6.1+/-2.9, 9.5+/-3.7, and 9.9+/-6.2 nmol/L, respectively. The mean haloperidol Css was significantly (P < .05) higher in the patients with 1 *10 allele than in those with no *10 alleles. The mean Css of reduced haloperidol was significantly (P < .05) higher in the patients with 1 and 2 *10 alleles than in those with no *10 alleles. CONCLUSION: This study suggests that the *10 allele plays an important role in controlling the Css of both haloperidol and reduced haloperidol, especially in Asian subjects.
Calcium signaling plays important roles in mammalian fertilization, such as the calcium wave in egg and the acrosome reaction (AR) in sperm. The calcium wave is accompanied by a transient increase of cytosolic calcium, which is mediated by inositol 1,4,5-triphosphate (IP3) induced calcium release (IICR). During AR, it is commonly recognized that influx of extracellular calcium causes a dramatic increase of cytosolic calcium. Participation of IICR in the phenomena, however, remains unclear. To investigate whether IICR also participates in calcium mobilization during AR, the present study examined the existence of the IP3 receptor family (IP3R type 1, 2 and 3) in human sperm and their changes during the reaction. Immunoblot analyses showed the existence of IP3R types 1 and 3 in human sperm, but IP3R type 2 was undetectable. The expression of IP3R type 1 was diminished after AR and was also detected in the vesiculated membrane fragment which was released by the fusion of the plasma membrane and the outer acrosomal membrane during AR. In contrast, the expression of IP3R type 3 on the blot was similar before and after the reaction. Immunohistochemical observations suggested that IP3R type 1 localized in the anterior portion of the sperm head and the expression was decreased after AR. IP3R type 3 was observed in the posterior portion of the sperm head, midpiece, and tail, and little change was found even after AR. The [3H]-IP3 binding assay suggested stoichiometric interactions between IP3 and IP3Rs of non-acrosome reacted and acrosome reacted human sperm.
The effects of purinoceptor subtypes on hippocampal extracellular serotonin levels were determined by using in vivo microdialysis. Perfusion with adenosine-5'-triphosphate (ATP) for 20 min produced concentration-dependent changes in hippocampal extracellular serotonin levels, which consisted of an initial rise phase, with levels increasing to 309% of control with 100 microM ATP, followed by a later rebound reduction phase, with levels decreasing to 6% of control. The P2X1-7 active P2 purinoceptor agonist, 2-methylthioATP (2-MeSATP: 100 microM) increased the extracellular serotonin level drastically (638%), while the P2X1,3 active P2 purinoceptor agonist, alpha, beta-methylene-L-ATP (alpha, beta-meATP: 100 microM) produced a small increase (132%) in the serotonin level. The P2X1,2,3,5,7 active P2 purinoceptor antagonist, suramin (100 microM), reduced the basal serotonin level (86%) and the ATP-evoked initial rise phase (from 309 to 254%) without affecting the late reduction phase. The adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT: 50 microM) potentiated the rising phase (167%) and abolished the subsequent ATP-evoked reduction phase. Perfusion with CPT and an adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX: 10 microM), reduced the ATP-evoked initial rise (to 181%) and abolished the late reduction phases of serotonin release. These results indicate that ATP-evoked hippocampal serotonin release is composed of an initial rise phase and a later reduction phase. The ATP-evoked initial rise phase might be produced by an activation of P2X purinoceptor function, whereas the late reduction phase was modulated by the activation of adenosine A1 receptor function by adenosine, metabolized from ATP in the synaptic cleft.
BACKGROUND/AIMS: In cirrhosis, despite a decrease in the total number of hepatocytes, a normal serum albumin level is maintained during the compensatory stage of the disease in many cases. Therefore, to elucidate the mechanism in hepatocytes related to the regulation of the serum albumin level, the albumin-synthesizing ability of individual hepatocytes was investigated in cirrhotic rats. METHODS: Cirrhotic rats were prepared by oral administration of furfural to male Wistar rats for 20 weeks. Albumin-synthesizing abilities of liver and of isolated hepatocyte culture were evaluated by measuring the albumin concentration in blood and culture supernatant. Expressions of albumin mRNA were compared using Northern blotting. Furthermore, transcriptional activity of the albumin gene was measured using the promoter domain of the gene. RESULTS: The total number of hepatocytes in rat cirrhotic liver was significantly decreased compared to that in normal rat liver. However, there were no significant differences in levels of serum albumin or albumin mRNA expression between cirrhotic and normal liver. In primary hepatocyte culture, albumin mRNA expression, the amount of albumin secretion and the albumin promoter activity were clearly enhanced in cirrhotic hepatocytes compared to normal hepatocytes. CONCLUSION: Although the total number of hepatocytes was decreased in the rat cirrhosis models used in this study, the serum albumin level was maintained and albumin-synthesizing ability was enhanced at the transcriptional level in the individual hepatocytes. These results suggest that the maintenance of serum albumin levels in compensated cirrhosis may be due to enhanced albumin synthesis by the hepatocytes.
We investigated the renal protective effect of nifedipine (2-nitrophenyl derivative BAY a 1040) in streptozotocin (STZ)-induced spontaneously hypertensive rats (SHRs, 8 weeks of age). Diabetic SHRs were treated with 40 mg/kg/day of nifedipine or efonidipine as controls for 16 weeks. Dosage of nifedipine or efonidipine was chosen after preliminary studies demonstrated that it showed moderate antihypertensive action (more than a 20% decrease in systemic blood pressure after treatment). In the diabetic SHR, the excretion of urinary albumin was increased and reached 4.41 +/- 0.08 mg/day at 24 weeks. The levels of urinary albumin in the diabetic SHR after treatment with nifedipine were significantly less than those in the diabetic SHR at 24 weeks (p < 0.01). Levels of the ratio of creatinine clearance to body weight were significantly decreased in the diabetic SHR after treatment with nifedipine. In light microscopy, the ratio of glomerular tufts to Bowman's areas was significantly decreased compared with those in the diabetic SHRs (p < 0.05). These findings suggest that nifedipine inhibits the development of albuminuria and glomerular enlargement in STZ-induced diabetic SHRs. There was no significant difference in the changes in antihypertensive or antialbuminuric effects between nifedipine and efonidipine. Thus, nifedipine, as well as efonidipine, may become a useful antihypertensive drug with a renal protective effect.
A high-performance liquid chromatographic method has been developed for the simultaneous determination of risperidone and its major active metabolite 9-hydroxyrisperidone in plasma. Risperidone and 9-hydroxyrisperidone in plasma were extracted using a CN bonded-solid phase cartridge, followed by, C4 reversed-phase HPLC separation. Risperidone, 9-hydroxyrisperidone and trazodone as an internal standard were detected by ultraviolet absorbance at 280 nm. It was possible to determine risperidone in the concentration range of 1.0-100.0 ng/ml(-1) and 9-hydroxyrisperidone at a range of 2.0-200.0 ng/ml(-1). The detection limits of risperidone and 9-hydroxyrisperidone were 0.5 and 1.0 ng/ml(-1), respectively. The mean recoveries of risperidone and 9-hydroxyrisperidone added to plasma were less than 92.0 and 92.6%, with a coefficient of variation of less than 10.6 and 10.5%, respectively. This method has been used for the simultaneous determination of steady-state plasma concentration (Css) of risperidone and 9-hydroxyrisperidone in schizophrenic patients treated with 3-, 6-, and 12-mg risperidone oral doses per day.
To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.
To study the mechanisms of antiepileptic action of zonisamide (ZNS), we determined the effects of ZNS on extracellular, total levels and re-uptake activity of serotonin (5-HT) in rat striatum and hippocampus. After acute administrations, plasma ZNS concentrations associated with anticonvulsive action (effective concentrations) increased the total levels of 5-HT, its metabolise (5-hydroxyindoleacetic acid: 5-HIAA) and precursor (5-hydroxytryptophan: 5-HTP). After chronic administration of ZNS, effective plasma concentrations also increased the extracellular and total levels of 5-HT, 5-HIAA, and 5-HTP. On the other hand, after both acute and chronic administrations of ZNS, a supra-effective ZNS concentration either decreased or did not affect the total levels of these substances. Therefore, the stimulatory effects of ZNS on the 5-HT system were reduced by an increase in ZNS concentration to supra-effective concentrations. ZNS concentrations of 30-1000 microM did not affect hippocampal 5HT re uptake activity in vitro. These results suggest that ZNS has biphasic effects on the 5-HT system, in that effective concentrations of ZNS enhance and supra-effective concentrations of ZNS reduce the function of the 5-HT system. These biphasic effects of ZNS on the 5-HT system may be involved in the mechanisms of action of the antiepileptic and psychotropic effects, and side effects of ZNS.