Biomedical subjects
K Ohba
Publications and source records attributed to K Ohba.
[Autoimmune liver diseases and their borderline lesions from pathologic standpoint of view].
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Identification of novel first exons in Ad4BP/SF-1 (NR5A1) gene and their tissue- and species-specific usage.
It has been demonstrated that the mammalian Ad4BP/SF-1 (NR5A1) gene is regulated precisely in sex, tissue, and developmental stage specific manners. To clarify the complex transcriptional regulation, we investigated in the present study whether the gene transcription is regulated by multiple promoters accompanied by noncoding first exons. Novel first exons (Io and Ig) were identified downstream of the already identified exon Ia. Nucleotide sequences revealed that Ia and Ig exons were well conserved, whereas Io exon was less conserved among the mouse, rat, and human genes. Interestingly, the splice donor of the mouse and human Io and human Ig exons do not satisfy the consensus sequence. Transcripts containing Ia, Io, and Ig were detected in all rat tissues examined, while the transcript containing Io was undetectable in the corresponding tissues of mice. The lack of exon Io usage in the mouse was confirmed by transient transfection assays with cultured cells. Quantitative RT-PCR analysis revealed that the transcript containing Ig exon was the main product in the pituitary but significantly less in the spleen, suggesting that the regulation of Ad4BP/SF-1 gene transcription in the pituitary and spleen is distinct from that of other tissues. The above findings, together with the structural abnormality at the splice donor site, suggest that acquisition of the multiple first exons enables the Ad4BP/SF-1 gene to be regulated differentially in different animal species and in different tissues in the same animal.
Serial changes in enzyme inhibitory antibody to pyruvate dehydrogenase complex during the course of primary biliary cirrhosis.
To assess the usefulness of enzyme inhibition assay for the diagnosis of primary biliary cirrhosis (PBC), we determined the serial changes in enzymatic inhibitory antibody to pyruvate dehydrogenase complex (PDC) in patients with PBC, and compared the results to those of immunofluorescence and immunoblotting. Forty-nine sera from 19 patients with PBC who were followed-up for at least 16 months were tested for antimitochondrial antibodies (AMA) by indirect immunofluorescence, immunoblotting on bovine heart mitochondria, and enzyme inhibition assay using commercially available TRACE Enzymatic Mitochondrial Antibody (M2) Assay (EMA) kit. Of the 49 sera, 39 (80%), 35 (71%), 38 (78%), 31 (63%), and 36 (73%) were positive for AMA by immunofluorescence, for immunoglobulin G (IgG), IgM, and IgA class antibody against E2 subunit of PDC (PDC-E2) by immunoblotting, and for enzymatic inhibitory antibody to PDC by EMA, respectively. AMA titers determined by immunofluorescence did not change in 9 patients (47%), increased in 4 (21%), decreased in 3 (16%), and fluctuated in 3 (16%) during follow-up. The number of anti-M2 bands by immunoblotting did not change in 9 (47%), increased in 6 (32%), decreased in 2 (11%), and fluctuated in 2 (11%). Units of PDC activity by EMA did not change markedly in 16 (84%), increased in 2 (11%), and fluctuated in 1 (5%). Positive EMA results were common in cases with high levels of serum alkaline phosphatase and IgM, and the units of PDC activity by EMA correlated significantly and inversely with AMA titers by immunofluorescence, and serum reactivity to PDC-E2 by immunoblotting, respectively. There was no correlation between serial changes in biochemical data and units of PDC activity by EMA. In three patients who showed a decrease in AMA titers, AMA titers correlated more with EMA results than immunoblotting. Moreover, in a patient with fluctuating AMA titers, the units of PDC activity by EMA paralleled AMA titers. Our results suggest that EMA is useful for the diagnosis of AMA-positive PBC, and also could be used for monitoring the disease course in PBC.
Management of pancreatic arteriovenous malformation.
Pancreatic arteriovenous malformations (AVM), while extremely rare, are frequently complicated by gastrointestinal bleeding. The elimination of pancreatic AVM is difficult once portal hypertension has developed. We describe herein a patient with congenital AVM of the pancreatic head presenting with recurrent episodes of melena, in whom pylorus-preserving pancreatoduodenectomy provided a means of definitive management. We also review the literature and focus on the diagnostic and therapeutic approaches. Angiography is always necessary to facilitate tactics of treatment, even if diagnosis has been established by non-invasive imaging modalities. To obtain complete regression, total extirpation of the affected organ, or at least the involved portion, should be performed before this disease leads to the lethal complications of gastrointestinal bleeding and portal hypertension. Transcatheter arterial embolization is the only alternative treatment for the control of hemorrhage.
Combination therapy with vascular endothelial growth factor neutralizing antibody and mitomycin C on human gastric cancer xenograft.
Antiangiogenic therapy has been proposed as a new strategy for the treatment of solid tumors. To enhance the therapeutic effect of antiangiogenic agents, combination with conventional anticancer therapy should be investigated. In the present study, we investigated the therapeutic effect of the combination of vascular endothelial growth factor neutralizing antibody (VEGF Ab) and mitomycin C (MMC) on MT-2, a human gastric cancer xenograft. When small pieces of MT-2 were transplanted orthotopically into 62 nude mice, liver metastasis developed 6 weeks after transplantation. The VEGF Ab (100 micro g / mouse) was administered i.p. in the VEGF Ab group (n = 14) and the combination group (n = 16) twice a week from day 10 after transplantation. MMC (2 mg / kg) was administered in the MMC group (n = 16) and the combination group (n = 16) on days 10, 17 and 24 after transplantation. Compared with the control group, in which saline solution was administered i.p., all three treatments inhibited tumor growth significantly and the effects of MMC and combination therapy were potent. Liver metastases were also inhibited significantly by the administration of VEGF Ab alone, MMC alone or combination therapy. Liver metastasis developed in 9 mice of the control group, 3 of the VEGF Ab group, and 4 of the MMC group, but no mice had liver metastasis in the combination therapy group. However a significant body weight loss and a decrease in spleen weight were observed in the MMC and combination groups, with no significant difference between the two groups. These results suggest that combination therapy with VEGF Ab and MMC may be a potent therapy for human gastric cancer.
[An autopsy case of cholangiocellular carcinoma producing granulocyte colony-stimulating factor].
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[Hyperplastic nodules of the liver (4 cm in diameter) in a patient with alcoholic liver cirrhosis].
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[de Lange syndrome].
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Amino acid substitutions in NS5A region of GB virus C and response to interferon therapy.
GB virus C (GBV-C) is related to hepatitis C virus (HCV) and has a similar genomic structure. Some predictors for the efficacy of interferon (IFN) therapy on HCV have been reported: genotype, viral load, IFN dose, and the amino acid substitutions in the NS5A region, designated as the interferon sensitivity determining region (ISDR). To evaluate the correlation between the amino acid substitutions in the GBV-C NS5A region and the response to IFN therapy, single-strand conformation polymorphism (SSCP) analysis was performed in the 12 concomitantly GBV-C-and HCV-infected patients who received IFN therapy at three time points: before, end-point, and after the IFN therapy. The region in the GBV-C NS5A studied includes the amino acids that exhibit some homology to the ISDR and the various substitutions. By SSCP analysis, amplicons were separated into 1-4 bands, which indicated the existence of heterogeneity in each host. However, the deduced amino acid sequences in these bands exhibited no characteristic differences among these strains irrespective of response to IFN therapy. Of the 32 strains separated by SSCP, 7 strains were responders, and 25 were nonresponders. The mean amino acid substitution, compared with the consensus sequence of nonresponders, was 1.00+/-0.93 among responders, and 1.40+/-0.85 among non-responders (P= NS). No correlation between the amino acid sequence in the GBV-C NS5A region and response to IFN therapy was found, indicating that the GBV-C NS5A region dose not act as the ISDR.
Protein kinase C mediates tumor necrosis factor-alpha-induced inhibition of obese gene expression and leptin secretion in brown adipocytes.
Previously we showed that tumor necrosis factor-alpha (TNF-alpha) inhibits lipoprotein lipase (LPL) activity and its gene expression, an early marker of adipocyte differentiation, in cultured brown adipocytes. To know whether TNF-alpha also affects late events in brown adipocyte maturation, we examined the effect of TNF-alpha on obese gene expression and leptin secretion in mouse brown adipocytes differentiated in culture. TNF-alpha caused a concentration-dependent decrease in leptin accumulation in culture medium and leptin mRNA amount in brown adipocytes which constitutively express the ob gene. Time-course study showed that TNF-alpha significantly suppressed leptin secretion during incubation for 16, 24 and 48 h. Since some effect of TNF-alpha is mediated by activation of protein kinase C (PKC), the role of PKC in TNF-alpha-induced downregulation of ob gene expression and leptin secretion was studied. The suppressive effect of TNF-alpha on both ob gene expression and leptin secretion was blocked by PKC inhibitors such as bisindolylmaleimide I (BIM) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7). Incubation of brown adipocytes with TNF-alpha (20 ng/ml, 15 min) caused a rapid shift of PKC activity from the cytosolic to the membrane fraction, suggesting an activation of PKC by TNF-alpha in brown adipocytes. This effect of TNF-alpha was blocked by a selective PKC inhibitor, BIM. These results suggest that TNF-alpha promotes dedifferentiation of the brown adipocytes as evidenced by a downregulation in ob gene expression and leptin secretion via PKC-dependent mechanisms.
New adipogenic cell lines derived from C3H10T1/2.
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Seroprevalence of hepatitis B virus, hepatitis C virus and GB virus-C infections in Siberia.
We studied the seroprevalence of hepatitis B virus (HBV), hepatitis C virus (HCV) and GB virus-C (GBV-C) infections in 348 Siberian natives who lived in the Kamchatka Peninsula of Russia. Of 348 samples studied, the seroprevalence of HBsAg and anti-HBs were 11.8% (41 of 348 samples) and 35.9% (125 of 348 samples), respectively. The prevalence of HCV infection was 1.4% (5 of 348 samples), and that of GBV-C RNA, using RT-PCR methods, was 7.5% (26 of 348 samples). In Siberia, the prevalences of HBV and GBV-C infections were about tenfold higher than those in Japan. The prevalence of HBsAg in subjects under 50 years of age was significantly higher than that in those over 50 years old (P < 0.05). Because HBV infection is highly endemic in Siberia, we propose that the community-based mass immunization must be conducted as soon as possible in this area.
Augmentative effect of pulsatility on the wall shear stress in tube flow.
Wall shear stress (WSS) has been considered to play an important role in the physiological and metabolic functions of the vascular endothelial cells. We investigated the effects of the pulse rate and the maximum flow rate on the WSS to clarify the influence of pulsatility. Water was perfused in a 1/2 inch transparent straight cylinder with a nonpulsatile centrifugal pump and a pulsatile pneumatic ventricular assist device (VAD). In nonpulsatile flow (NF), the flow rate was changed 1 to 6 L/min by 1 L/min increments to obtain standard values of WSS at each flow rate. In pulsatile flow (PF), the pulse rate was controlled at 40, 60, and 80 bpm, and the maximum flow rate was varied from 3.3 to 12.0 L/min while the mean flow rate was kept at 3 L/min. The WSS was estimated from the velocity profile at measuring points using the laser illuminated fluorescence method. In NF, the WSS was 12.0 dyne/cm2 at 3 L/min and 33.0 dyne/cm2 at 6 L/min. In PF, the pulse rate change with the same mean, and the maximum flow rate did not affect WSS. On the other hand, the increase in the maximum flow rate at the constant mean flow rate of 3 L/min augmented the mean WSS from 13.1 to 32.9 dyne/cm2. We concluded that the maximum flow rate exerted a substantial augmentative effect on WSS, and the maximum flow rate was a dominant factor of pulsatility in this effect.
[Morning blood glucose determination in the monitoring of metabolic control in type 2 elderly diabetic cases treated by oral hypoglycemic agents].
Daily blood glucose profiles were measured in 163 Type 2 elderly diabetic cases to evaluate whether a fasting (before breakfast) or a post-prandial (after breakfast) blood glucose concentration is able to predict blood glucose values throughout the day. In the diet-treated alone group (n = 61), the percentage of daily blood glucose profiles having plasma glucose values less than the 08:00 hours (before breakfast) value were as follows: 59.0%, 32.8%, 59.0%, and 55.7% at 18.00 (before supper), 24.00, 03.00, 06.00 hours, respectively. In group treated by oral hypoglycemic agents (OHA) (n = 102), these were as follows: 45.1%, 26.5%, 52.9%, and 67.6%, respectively. In the OHA group, the mean plasma glucose value at 08:00 hours was significantly higher in patients with the lowest plasma glucose levels between 60-79 mg/dl than in patients with these levels between 80-99 mg/dl (103.7 +/- 19.6 vs 118.7 +/- 16.9 mg/dl, p < 0.01), but that at 10:00 hours was similar in the two groups (218.8 +/- 43.9 vs 214.5 +/- 40.1 mg/dl). In patients with lowest plasma glucose levels of between 60-99 mg/dl, the 08:00 hours value correlated positively with that of 24:00 (r = 0.40), 03.00 (r = 0.53), and the 06.00 hours value (r = 0.69), but no correlation was observed with the 18.00 hours value. On the other hand, the 10:00 hours value was not associated with these time-points values. Our results reveal that before breakfast plasma glucose values are more predictive of low blood glucose values in the night during sleep than after-breakfast blood glucose values, but do not predict low blood glucose values before supper in patients on OHA.
[Amoebic liver abscess].
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Interferon-alpha therapy exerts selective pressure on hepatitis C virus quasispecies equilibrium.
Two patients with chronic hepatitis C virus (HCV) genotype 2b infection were studied. They responded biochemically to interferon (IFN) but had early virological and later biochemical relapse. The HCV quasispecies equilibrium in these patients was studied by a combination of cloning, sequencing and construction of phylogenetic trees. Another patient with chronic HCV genotype 2b infection was followed every 6 months for 30 months (including one episode of biochemical exacerbation) to serve as the control. Quasispecies equilibrium drifted during IFN therapy but moved back in the direction of the original equilibrium during biochemical relapse. In the control patient, there was no significant drifting throughout the follow-up period. These data suggest that IFN therapy exerts selective pressure on HCV quasispecies equilibrium.