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Biomedical subjects

H Yoshitomi

Publications and source records attributed to H Yoshitomi.

At least 37 records · Page 2Linked to original sources
PubMed1999

Valproic acid elimination rate and urinary excretion of its glucuronide conjugate in patients with epilepsy.

We previously encountered a patient with epilepsy who exhibited rapid elimination of sustained-release valproic acid (VPA) administered at the dose of 2.8 g/d as a sodium salt. The purpose of this study was to clarify the relationship between the VPA elimination rate and the proportion of the dose excreted in urine as its glucuronide conjugate (VPA-G) in epileptic patients. Twenty-four-hour urine was collected from four epileptic patients who had taken VPA orally (age: 16-39 y, weight: 50-63 kg, dose: 1.0-2.8 g/d). VPA and its metabolites were detected by gas chromatography-mass spectrometry. The amounts of VPA, VPA-G, 3-keto VPA, and 3-OH VPA excreted in the 24-h urine were 1.8-13.2, 178-2158, 125-320, and 8.6-18.7 mg (converted into VPA), respectively, and 0.2-0.5, 20.5-88.7, 5.8-18.7, and 0.6-1.0% of the dose administered, respectively. The dose of VPA correlated well with the proportion of the dose excreted in urine as VPA-G in each patient, and the patients administered a high dose excreted a large amount of VPA-G in the urine. Thus, differences in the VPA-G production rate may be one of the major variable factors affecting the elimination of administered VPA. We also present a dynamic model of VPA in the kidney which may explain the VPA elimination phenomena in humans on the basis of the data obtained here regarding the concentrations of VPA and its metabolites in plasma and their urinary excretion levels.

Adolescent↗
PubMed1999

Differential diagnosis of left ventricular mural thrombi by myocardial contrast echocardiography: a preliminary study.

Two-dimensional echocardiography has become the procedure of choice to diagnose left ventricular mural thrombi. However, small or flat thrombi may be difficult to distinguish from myocardium. The spatial distribution of the ventricular myocardial blood flow can be imaged with myocardial contrast echocardiography (MCE). The authors presumed that the absence of arterial supply to a fresh thrombus may allow MCE to distinguish between thrombus and myocardium. In the 2 cases presented here, MCE was performed with the same technique as that used for the purpose of visualization of myocardial perfusion; as a result, an apical mural thrombus, indistinct from myocardium before MCE, was visualized as a contrast defect during imaging. Conversely, myocardium that mimicked a thrombus was imaged by MCE as a contrast-opacified area. These findings suggest that MCE after reperfusion therapy is useful to distinguish mural thrombi from myocardium.

Aged↗
PubMed1999

A preliminary study for clinical pharmacokinetics of oral fluorine anticancer medicines using the commercial MRI system 19F-MRS.

These preliminary studies of dynamic natural abundance 19F-magnetic resonance spectroscopy (19F-MRS) on 5-FU based medicines were performed in the human liver using commercial 1.5 T MRI equipment. A single tuned, custom-made circular shape surface coil with a diameter of 15 cm operating at 60 MHz was used for the 19F-MRS study. Localized proton shimming with a whole body coil was performed with adequate volume to include the observing area of the surface coil, and the line width of the water signal was less than 40 Hz. Very different spectroscopic appearance patterns of 5-FU were observed. We examined whether the pharmacokinetics in the liver of orally administered 1-hexylcarbamoyl-5-fluorouracil (HCFU) differ from those of orally administered 5'-deoxy-5-fluorouridine (5'-DFUR). This preliminary study suggested the 19F-MRS technique could be a useful method of evaluating in vivo the metabolism of 5-FU based medicines.

Administration, Oral↗
PubMed1999

[Endothelial-derived nitric oxide mediates the peripheral vasodilatory effects of amrinone in humans].

Amrinone, which is used for the treatment of acute congestive heart failure, has vasodilatory and positive inotropic effects through the increment of intracellular cyclic adenosine monophosphate. Recent in vitro investigations have shown that amrinone has an endothelium-dependent vasodilatory effect. The present study examined whether amrinone shows this endothelium-dependent vasodilatory effect in human peripheral vessels. Forearm blood flow during intra-arterial infusion of graded doses (12.5, 25, 50, 100, 200 micrograms/min) of amrinone was measured using plethysmography in 10 healthy subjects without organic vascular disease before and after nitric oxide synthase blocking with NG-monomethyl-L-arginine (L-NMMA, 400 mumol). The graded dose of amrinone produced progressive increases in amrinone plasma concentrations, and a dose over 100 micrograms/min caused amrinone plasma concentrations of more than 1.0 microgram/ml. The increase in forearm blood flow in response to amrinone was significantly depressed after L-NMMA doses of less than 100 micrograms/min, but the increase in forearm blood flow during infusion of higher doses (100, 200 micrograms/min) was not affected by L-NMMA. These results suggest that endothelial-derived nitric oxide may partially contribute to amrinone-induced vasodilation in humans. Thus, the vasodilatory effect of amrinone might be impaired in patients with endothelial dysfunction.

Adult↗
PubMed1999

Clinical significance of perfusion imaging of the left atrial wall and structures in its cavity by contrast echocardiography.

This study examined whether myocardial contrast echocardiography (MCE) can visualize left atrial appendage myocardial perfusion using transesophageal echocardiography (TEE) with intracoronary injection of sonicated albumin. We also evaluated blood flow into normal structures (i.e. muscular trabeculae) and abnormal masses (i.e. fresh thrombi and myxomas) within the left atrium by MCE. TEE images were obtained with a biplane or multiplane 5 MHz transducer in 16 patients without significant coronary artery occlusive disease. Left atrial appendage myocardium was divided into 4 segments in both the transverse and longitudinal planes, and contrast opacification of each segment during MCE was visually evaluated by 2 independent observers. Visual assessment of contrast opacification of prominent muscular trabeculae within the left atrial appendage (6 patients), and of left atrial or left atrial appendage thrombi (4 patients), was also performed. The ratio of background-subtracted peak videointensity from muscular trabeculae or thrombi versus left atrial appendage myocardium was determined as corrected peak videointensity. In 3 patients with myxomas, contrast opacification of the tumor was visually assessed. Ninety-six segments of left atrial appendage myocardium were visually analyzed. Contrast opacification of the left atrial appendage myocardium was identified in 92 of 96 segments (96%, 95% confidence interval 0.90-0.98) by Observer 1 and in 91 of 96 segments (95%, 95% confidence interval 0.88-0.98) by Observer 2. MCE also enhanced the imaging of left atrial appendage muscular trabeculae, but not of left atrial or left atrial appendage thrombi. Corrected peak videointensity from thrombi was significantly lower than that from muscular trabeculae (0.15 +/- 0.11 vs 0.95 +/- 0.18, p < 0.05). All myxomas were distinctly opacified by MCE. Transesophageal MCE with intracoronary injection of sonicated albumin can image left atrial appendage myocardial perfusion. MCE allows the evaluation of blood flow into normal structures and abnormal masses within the left atrium.

Adult↗
PubMed1999

[Left ventricular relaxation in lone atrial fibrillation and atrial fibrillation with heart disease].

Atrial fibrillation with organic heart disease shows a steady value for the time constant of left ventricular isovolumetric relaxation (TC), whereas left ventricular contractility varies from beat to beat. However, there is no report on left ventricular relaxation in lone atrial fibrillation. This study assessed left ventricular relaxation in 5 patients with lone atrial fibrillation, 3 with ischemic heart disease and one with hypertrophic cardiomyopathy. Left ventricular pressure was recorded at 3 msec intervals, with a high fidelity micromanometer-tipped catheter. Maximal positive dP/dt (dP/dtmax) and TC of isovolumetric left ventricular relaxation period [P(t) = (P0-P infinity) exp (-t/TC) + P infinity] were measured as indices of left ventricular contractility and left ventricular relaxation, respectively. Correlation coefficients of dP/dtmax and TC versus the ratio of the preceding to the pre-preceding RR-interval (RR2/RR1) were calculated. A good correlation was found between dP/dtmax and RR2/RR1 in all patients (r = 0.71-0.84, p < 0.0001). No correlation between TC and RR2/RR1 was found in patients with atrial fibrillation with organic heart disease, but a good correlation was found between TC and RR2/RR1 in patients with lone atrial fibrillation (r = 0.74-0.95, p < 0.0001). The correlation between TC and RR2/RR1 is well preserved in lone atrial fibrillation. The mechanism of the variation of TC with the RR2/RR1 interval in lone atrial fibrillation may be similar to the change of TC in postextrasystolic potentiation, which is attributed to the change of intracellular Ca2+ concentration. Absence of correlation between TC and RR2/RR1 interval may indicate that left ventricular relaxation is disturbed in patients with atrial fibrillation with organic heart disease.

Aged↗
PubMed1998

Differential regulation of mouse uncoupling proteins among brown adipose tissue, white adipose tissue, and skeletal muscle in chronic beta 3 adrenergic receptor agonist treatment.

Uncoupling proteins (UCPs) are inner mitochondrial membrane transporters that dissipate the proton gradient, releasing stored energy as heat, without coupling to other energy-consuming processes. Therefore, the UCPs are thought to be important determinants of the metabolic efficiency. To elucidate relationships between the UCPs expressions and insulin sensitivity improvement, we treated KK-Ay mice with beta 3 adrenergic receptor agonist for 21 days and examined the changes of the UCPs mRNA expressions in various tissues. Chronic treatment of a specific beta 3 adrenergic receptor agonist, CL316,243 (0.2 mg/kg body weight/day s.c.) markedly increased the expressions of uncoupling protein 1 (UCP1), uncoupling protein 2 (UCP2), and uncoupling protein 3 (UCP3) by 14-fold, 6-fold, and 16-fold, respectively, in the brown adipose tissue (BAT). The UCP1 and UCP3 mRNA expressions in the white adipose tissue (WAT) were also increased by 12-fold and 9-fold, respectively, but the UCP2 mRNA expression was not changed in this tissue. Interestingly, the UCP2 and UCP3 mRNA expressions were strikingly decreased in the skeletal muscle and heart. Particularly, the UCP3 mRNA expression level in the skeletal muscle was dropped to 10% of that of the saline-treated control mice, indicating that the UCPs mRNA expressions are regulated in tissue-specific ways. The concentrations of plasma insulin and circulating free fatty acid (FFA) were significantly decreased, suggesting that they correlate with the reductions of the UCP2 and UCP3 mRNA expressions in the skeletal muscle and heart. It has been thought that the UCP1 and UCP3 mRNA expressions in the BAT and WAT are mainly controlled by the hypothalamus via the sympathetic nervous system, while the levels of insulin, FFA or both may play important roles in the control of the UCP2 and UCP3 mRNA expressions in the skeletal muscle an heart.

Adipose Tissue↗
PubMed1998

Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice.

ATP-sensitive K+ (KATP) channels regulate many cellular functions by linking cell metabolism to membrane potential. We have generated KATP channel-deficient mice by genetic disruption of Kir6.2, which forms the K+ ion-selective pore of the channel. The homozygous mice (Kir6.2(-/-)) lack KATP channel activity. Although the resting membrane potential and basal intracellular calcium concentrations ([Ca2+]i) of pancreatic beta cells in Kir6.2(-/-) are significantly higher than those in control mice (Kir6.2(+/+)), neither glucose at high concentrations nor the sulfonylurea tolbutamide elicits a rise in [Ca2+]i, and no significant insulin secretion in response to either glucose or tolbutamide is found in Kir6.2(-/-), as assessed by perifusion and batch incubation of pancreatic islets. Despite the defect in glucose-induced insulin secretion, Kir6.2(-/-) show only mild impairment in glucose tolerance. The glucose-lowering effect of insulin, as assessed by an insulin tolerance test, is increased significantly in Kir6.2(-/-), which could protect Kir6.2(-/-) from developing hyperglycemia. Our data indicate that the KATP channel in pancreatic beta cells is a key regulator of both glucose- and sulfonylurea-induced insulin secretion and suggest also that the KATP channel in skeletal muscle might be involved in insulin action.

Animals↗
PubMed1998

Cloning of mouse uncoupling protein 3 cDNA and 5'-flanking region, and its genetic map.

Brown adipose tissue and skeletal muscle are important sites of non-shivering thermogenesis. It has been known that UCP1 and UCP2 function as the main effector of the thermogenesis: the former is expressed exclusively in brown adipose tissue, whereas the latter is distributed widely. Recently, the third UCP homologue was discovered in humans, which was designated as UCP3. We now report molecular cloning of full-length mouse UCP3 cDNA and its 5'-flanking genomic region. The mouse UCP3 cDNA sequence predicted a 308-amino acid protein, and the overall identity between the mouse and human UCP3 proteins was 85.6%. The mouse UCP3 amino acid sequence was 54.7% and 73.1% identical to the mouse UCP1 and UCP2, respectively. Expression of the mouse UCP3 was found to be abundant in skeletal muscle and somewhat less abundant in heart, but was minimally expressed in other critical organs. The sequences of 5'-flanking regions of the mouse UCP1 and UCP3 were very different, resulting in different distributions of putative transcriptional factor binding sites. The differences could reflect tissue-specific expression of the UCPs. The mouse Ucp3 gene was mapped near Ucp2 on chromosome 7, suggesting that the Ucp2 and Ucp3 are clustered genes. This region is boundary of synteny between human chromosome 11q13 and 11p15. As Solanes et al. reported that both human UCP2 and UCP3 genes are assigned to chromosome 11q13, the region where the mouse Ucp2 and Ucp3 are localized is syntenic to human chromosome 11q13.

Amino Acid Sequence↗
PubMed1998

Segments I and IV resection as a new approach for hepatic hilar cholangiocarcinoma.

Major hepatic resection for biliary tract carcinoma with obstructive jaundice has been reported on as bringing about high surgical morbidity and mortality rates. It has been also revealed that the extent of hepatic resection is closely associated with the occurrence of postoperative complications. Therefore, hepatic resection, limited as much as possible to what is necessary for curative resection, should be performed according to cancer extent. We performed a new surgical approach in 3 patients with hepatic hilar cholangiocarcinoma that included total resection of hepatic segments I and IV (by Couinaud's classification) and bile duct resection with hepaticojejunostomy of 4 to 6 intrahepatic bile duct stumps. All patients underwent curative surgical resections and were discharged within 6 weeks after surgery, without any serious complications. This limited resection of hepatic segments I and IV could be an effective radical surgical procedure for hepatic hilar cholangiocarcinoma, to avoid the occurrence of postoperative liver failure.

Cholangiocarcinoma↗
PubMed1998

Improved visualization of the left atrial appendage by transthoracic 2-dimensional tissue harmonic compared with fundamental echocardiographic imaging.

We compared fundamental and tissue harmonic transthoracic echocardiographic imaging for the delineation of the left atrial appendage (LAA) in 32 subjects. The LAA images recorded in the parasternal short-axis view were divided into 4 segments and 2 observers independently graded for each segment using a visual scoring system ranging from 0 to 3 (0 = no, 3 = clearly visible over the entire length of the segment). For the 128 segments, the averaged segment scores were significantly increased after switching to harmonic imaging (1.32 +/- 0.69 versus 1.60 +/- 0.81 for fundamental and tissue harmonic imaging, respectively; P <.0005 for observer 1, and 1.38 +/- 0.65 versus 1.61 +/- 0.82, respectively; P <.001 for observer 2). In a patient with LAA thrombus, the image contrast of the thrombus was improved in harmonic compared with fundamental imaging. These data suggest that tissue harmonic imaging significantly improves image quality of the LAA.

Adult↗
PubMed1998

Altered bcl-2 and bax expression and intracellular Ca2+ signaling in apoptosis of pancreatic cells and the impairment of glucose-induced insulin secretion.

Apoptosis is the process of cellular self-destruction, and genes such as bcl-2 and bax are known to inhibit and promote apoptosis, respectively. In this study, we show that apoptosis can be induced in pancreatic beta-cell lines, and we investigate the apoptotic pathways through the bcl-2 and bax genes and intracellular Ca2+. Serum deprivation induces apoptosis in the MIN6 and RINm5F pancreatic beta-cell lines, and alters the bcl-2 messenger RNA (mRNA) and protein. KCl, BayK, A23187, and ionomycin elicit an elevation of cytosolic/nuclear Ca2+, which, however, is insufficient to evoke apoptosis or to alter bcl-2 or bax mRNA expression in MIN6 cells. The extracellular Ca2+ chelators, EGTA and 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetrapotassium salt, hydrate, evoke apoptosis and also alter the ratio of bcl-2 to bax mRNA and protein concomitantly with the depletion of cytosolic/nuclear Ca2+. This indicates that there are at least two apoptotic pathways in pancreatic beta-cells: through serum deprivation and through a decrease in cytosolic/nuclear Ca2+. MIN6 cells exhibit reduced insulin secretion induced by glucose regardless of the molecular pathway of apoptosis. Apoptosis in pancreatic beta-cells, therefore, may be closely related to the impairment of insulin secretion in certain pathological conditions such as diabetes mellitus.

Animals↗
PubMed1998

Urinary metabolites of valproic acid in epileptic patients.

The urinary excretion of valproic acid (VPA) and its metabolites (3-keto VPA, 3-OH VPA, and VPA-glucuronide) in 6 epileptic patients was studied using gas chromatography-mass spectrometry. The amount of VPA and 3-OH VPA excreted in the urine was low (0.1-0.5% of the dose of VPA and 0.6-1.5% of the dose of 3-OH administered). The amount of 3-keto VPA and glucuronide (VPA-Glu) excreted was marked (5.8-26.2% and 13.1-88.7% of the dose of VPA administered, respectively). The urinary excretion of VPA and its metabolites by patients who have taken a normal amount of a VPA preparation was almost the same as that of healthy volunteers. Two epileptic patients who took a large amount of the VPA preparation showed a high excretion of VPA-Glu without an increase in their plasma VPA-Glu.

Adolescent↗
PubMed1997

Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel.

ATP-sensitive K+ (KATP) channels are known to play important roles in various cellular functions, but the direct consequences of disruption of KATP channel function are largely unknown. We have generated transgenic mice expressing a dominant-negative form of the KATP channel subunit Kir6.2 (Kir6.2G132S, substitution of glycine with serine at position 132) in pancreatic beta cells. Kir6.2G132S transgenic mice develop hypoglycemia with hyperinsulinemia in neonates and hyperglycemia with hypoinsulinemia and decreased beta cell population in adults. KATP channel function is found to be impaired in the beta cells of transgenic mice with hyperglycemia. In addition, both resting membrane potential and basal calcium concentrations are shown to be significantly elevated in the beta cells of transgenic mice. We also found a high frequency of apoptotic beta cells before the appearance of hyperglycemia in the transgenic mice, suggesting that the KATP channel might play a significant role in beta cell survival in addition to its role in the regulation of insulin secretion.

Adenosine Triphosphate↗
PubMed1997

Relationship between progressive microvascular damage and intramyocardial hemorrhage in patients with reperfused anterior myocardial infarction: myocardial contrast echocardiographic study.

BACKGROUND: Recent studies indicated that ischemic microvascular damage may be reversible or progressive after coronary reflow. Intramyocardial hemorrhage is a phenomenon that reflects severe microvascular injury. We examined the relationship between temporal changes in microvascular perfusion patterns detected by myocardial contrast echocardiography (MCE) and intramyocardial hemorrhage detected by magnetic resonance imaging (MRI) in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The study population consisted of 24 patients with anterior AMI. All patients underwent MCE shortly after reflow and in the chronic stage (a mean of 31 days after reflow). Wall motion score (WMS) was determined as the sum of 16 segmental scores (dyskinetic/akinetic=3 to normal=0) at days 1 and 31. Gradient-echo acquisition and gadolinium-DTPA-enhanced spin-echo MRI were performed within 10 days after reflow. In MCE shortly after reflow, 16 patients (67%) showed contrast enhancement and the other 8 patients (33%) showed a sizable contrast defect. In the chronic stage, a persistent contrast defect was observed in 7 of 8 patients with a contrast defect shortly after reflow. Consistent contrast enhancement was observed in 12 of 16 patients (75%) with contrast enhancement shortly after reflow, indicating that a contrast defect newly appeared in 4 patients (25%). Intramyocardial hemorrhage was detected in 9 patients (38%): 5 of 7 patients with a persistent contrast defect and in all 4 patients with a new appearance of a contrast defect during the chronic stage. The patients without hemorrhage showed a significant improvement in WMS compared with patients with hemorrhage at day 31 (5+/-5 versus 19+/-6, P<.0005). CONCLUSIONS: These results suggest that irreversible microvascular damage to the ischemic myocardium may cause intramyocardial hemorrhage after reflow, associated with impaired recovery of left ventricular function. Contrast enhancement within the risk area shortly after reflow does not necessarily indicate long-term microvascular salvage.

Aged↗
PubMed1997

Megakaryocytopoietic activity of a truncated variant of mouse thrombopoietin.

Thrombopoietin (TPO) is a hemopoietic cytokine that specifically stimulates the growth and development of megakaryocytes. In addition to full-length TPO (corresponding to TPO-1), cDNAs of three truncated variants (TPO-2 to 4) have been isolated. However, whether or not these variants have biological activities has not been clarified presumably because of poor secretion into extracellular milieu. To examine the biological significance of the shortest variants, TPO-4, we prepared two fusion cDNAs of TPO-1 and TPO-4, each of which was combined with the finger-growth factor-kringle 1 (FGK1) domains of tissue plasminogen activator (tPA) as a tag and transfected them into baby hamster kidney (BHK) cells. An immunodetection assay for FGK1 antigen revealed that the amount of secreted TPO-4-FGK1 fusion protein was about 2% of that of TPO-1-FGK1. These fusion proteins after affinity purification had comparable activities on a molar basis in both megakaryocyte colony stimulating activity towards mouse bone marrow cells and growth promotion activity towards the TPO-responsive cell line UT-7/GM. These results indicate that the TPO-4 is biologically active in vitro, although its primary structure of the C-terminal half after the 111th amino acid residues is completely different from authentic TPO-1 due to frame shift.

Animals↗
PubMed1997

Pulmonary blood flow regulates plasma tissue plasminogen activator concentrations in patients with congenital heart defects.

OBJECTIVE: The wall shear stress generated by blood flow regulates the expression of fibrinolytic proteins by endothelial cells in vitro. In the present study, the effects of pulmonary blood flow on fibrinolytic activity were studied in patients with congenital heart defects and pulmonary hypertension. METHODS: Twenty-seven patients who underwent cardiac operation because of congenital heart defects were divided into four groups according to the severity of pulmonary hypertension. Group I consisted of seven patients with normal pulmonary artery pressure, group II consisted of nine patients with pulmonary hypertension caused by increased pulmonary blood flow, group III consisted of six patients with pulmonary hypertension caused by increased pulmonary vascular resistance, and group IV consisted of five patients with tetralogy of Fallot. Plasma concentrations of tissue plasminogen activator, plasmin, and thrombin were assayed as the inhibitor-bound forms. RESULTS: The preoperative concentration of tissue plasminogen activator was higher in group II than in all other groups (p = 0.0003). However, the postoperative concentration decreased only in patients in group II when compared with the preoperative value (p = 0.01). By Pearson's correlation analysis, pulmonary blood flow was found to correlate with the preoperative concentration of tissue plasminogen activator (95% confidence interval = 3.99 to 10.58, p = 0.0001). No definite conclusion was found for the relationship between tissue plasminogen activator and plasmin concentration. Further, the preoperative thrombin concentration was similar in all groups. CONCLUSIONS: These findings suggest that pulmonary blood flow may regulate the plasma concentration of tissue plasminogen activator in patients with congenital heart defects.

Child, Preschool↗