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Biomedical subjects

Y Kuroda

Publications and source records attributed to Y Kuroda.

At least 271 records · Page 15Linked to original sources
PubMed1998

NMDA receptors in the inferior colliculus are critically involved in audiogenic seizures in the adult rats with neonatal hypothyroidism.

The effects of N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists were compared on audiogenic seizures in the rats neonatally exposed to propylthiouracil (PTU). The rats treated with 0.02% PTU through mother's milk during days 0-19 after delivery showed a high incidence of audiogenic seizures consisting of running fit (RF) followed by generalized tonic-clonic seizure (GTCS) after matured. The systemic administration with MK-801, a NMDA receptor antagonist dose-dependently inhibited both RF and GTCS. NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione), a non-NMDA receptor antagonist, when systemically administered, failed to block audiogenic seizures. Audiogenic seizures caused a marked induction of c-fos messenger RNA (mRNA) in septal nucleus, bed nucleus of stria terminalis, amygdaloid nuclei, peripeduncular nucleus, and inferior colliculus, which was almost completely blocked by the pretreatment with MK-801. Bilateral microinjection of MK-801 into the inferior colliculus showed a tendency for inhibiting GTCS, but not RF, whereas CPP (3-(R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid), a competitive NMDA receptor antagonist produced a significant inhibition against both RF and GTCS. These NMDA receptor antagonists administered into cisterna ambience, the floor of which is composed of inferior colliculus and neighboring structures, have shown potent blocking effects on both RF and GTCS. The present results suggest that NMDA receptors in the inferior colliculus, presumably in the subnucleus of external cortex may play the critical role in the initiation of audiogenic seizures in PTU-treated rats.

Acoustic Stimulation↗
PubMed1998

Lactate-induced vascular relaxation in porcine coronary arteries is mediated by Ca2+-activated K+ channels.

Under ischemic conditions and during strenuous exercise, lactate concentrations increase in coronary artery smooth muscle cells. Although lactate causes pH-independent vasorelaxation, the mechanisms responsible for this effect are unclear. We investigated the effect of lactate on K+ channels in smooth muscle cells from porcine coronary arteries. Neutralized lactate (3-100 mm) induced vasorelaxation in ring segments of porcine coronary arteries precontracted with KCl in a dose-dependent manner. One millimolar tetraethylammonium (TEA), an inhibitor of Ca2+-activated K+ channels (KCa channels), reversed the lactate-induced relaxation, while 60 microM glibenclamide, an inhibitor of ATP-sensitive K+ channels (KATP channels), did not. In both inside-out and cell-attached patch clamp technique with cultured smooth muscle cells, the KCa channels were activated by lactate. In inside-out patches, lactate activated KCa channels, even under acidic conditions. This is in contrast to the effect of H+ which inactivated KCa channels. We conclude that vasodilation of porcine coronary arteries induced by lactate is, at least in part, mediated by activation of KCa channels. This effect may be self-protective by maintaining coronary blood flow during ischemia.

Animals↗
PubMed1998

Percutaneous isolated liver chemoperfusion for treatment of unresectable malignant liver tumors: technique, pharmacokinetics, clinical results.

We have developed a single-catheter technique for percutaneous isolated liver chemoperfusion (PILP) with hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) for the treatment of malignant liver tumors. We report here the surgical technique, pharmacokinetics, and effectiveness of PILP in multiple advanced liver tumors. Twenty-eight patients with hepatocellular carcinoma (HCC) and 18 with metastatic liver tumors underwent a total of 61 PILPs with HVI-CHP. HVI-CHP was accomplished mainly by the single-catheter technique using a novel four-lumen, two-balloon catheter; it was used to isolate and capture total hepatic venous outflow and, at the same time, to direct the filtered blood to the right atrium. Under HVI-CHP, either doxorubicin 960-150 mg/m2) or cisplatin (150-200 mg/m2) was infused via the hepatic artery. The PILP was completed successfully in all 61 trials. Two of forty-six patients died early; one of necrotizing pancreatitis and the other of hepatic arterial thrombosis. Both deaths were related directly to the hepatic arterial catheter. Excluding these two deaths, the treatments were well tolerated. The major side effects were mild to moderate chemical hepatitis and reversible myelosuppression. Of the 27 evaluable HCC patients, 17 (63%) had an objective tumor response (5 complete and 12 partial responses). In 15 patients with colorectal hepatic metastases (CHM), 7 had a sharp decrease in serum carcinoembryonic antigen (CEA) levels (to < 50% of their pretreatment levels) after treatment. However, a single PILP had limited efficacy in terms of the durability of remission (< or = 6 months in most CHM patients, as assessed by CEA levels). These results indicate that PILP with HVI-CHP has high efficacy in most patients with multiple advanced liver tumors. In addition, the results suggest a role of multiple treatment courses of PILP in the induction of long-term remission, especially for patients responsive to the first treatment.

Antineoplastic Agents↗
PubMed1998

Hydrogen peroxide-induced vascular relaxation in porcine coronary arteries is mediated by Ca2+-activated K+ channels.

Hydrogen peroxide (H2O2) elicited concentration-dependent relaxation of endothelium-denuded rings of porcine coronary arteries. The relaxation induced by the H2O2 was markedly attenuated by 10 microM 1H-[1,2,4]oxadiazolo [4,3,a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase, or by 100 nM charybdotoxin, an inhibitor of large-conductance Ca2+-activated K+ (KCa) channels. A combination of the ODQ and charybdotoxin abolished the H2O2-induced relaxation. Pretreatment with 25 microM of an Rp stereoisomer of adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS), 20 microM glibenclamide, or 1 mM 4-aminopyridine did not affect the vascular response to H2O2. The presence of catalase at 1000 U/ml significantly attenuated the H2O2-induced relaxation. Exposure of cultured smooth muscle cells to H2O2 activated KCa channels in a concentration-dependent manner in cell-attached patches. Pretreatment with catalase significantly inhibited the activation of KCa channels. Rp-cAMPS did not inhibit the H2O2-induced activation of KCa channels. The activation of KCa channels by H2O2 was markedly decreased in the presence of ODQ. However, even in the presence of ODQ, H2O2 activated KCa channels in a concentration-dependent manner. In inside-out patches, H2O2 significantly activated KCa channels through a process independent of cyclic guanosine 3',5'-monophosphate (cGMP). In conclusion, H2O2 elicits vascular relaxation due to activation of KCa channels, which is mediated partly by a direct action on the channel and partly by activation of soluble guanylate cyclase, resulting in the generation of cGMP.

Animals↗
PubMed1998

Spinocerebellar ataxia type 6: MRI of three Japanese patients.

We describe the MRI findings in three Japanese patients with spinocerebellar ataxia type 6 (SCA6) in which a polymorphic CAG repeat was identified in the gene encoding the alpha 1A voltage-dependent P/Q-type Ca2+ channel subunit (CACNL1A4). All showed slowly progressive cerebellar ataxia and mild pyramidal signs. Neuroradiologically, they had moderate cerebellar atrophy, most prominently in the superior vermis, whereas the brain stem appeared to be spared. No abnormal signal intensity was identified.

Adult↗
PubMed1998

Effect of acidosis on Ca2+-activated K+ channels in cultured porcine coronary artery smooth muscle cells.

Although acidosis induces vasodilation, the vascular responses mediated by large-conductance Ca2+-activated K+ (KCa) channels have not been investigated in coronary artery smooth muscle cells. We therefore investigated the response of porcine coronary arteries and smooth muscle cells to acidosis, as well as the role of KCa channels in the regulation of muscular tone. Acidosis (pH 7.3–6.8), produced by adding HCl to the extravascular solution, elicited concentration-dependent relaxation of precontracted, endothelium-denuded arterial rings. Glibenclamide (20 µM) significantly inhibited the vasodilatory response to acidosis (pH 7.3-6.8). Charybdotoxin (100 nM) was effective only at pH 6.9–6.8. When we exposed porcine coronary artery smooth muscle cells to a low-pH solution, KCa channel activity in cell-attached patches increased. However, pretreatment of these cells with 10 or 30 µM O, O′-bis(2-aminophenyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl)ester (BAPTA-AM), a Ca2+ chelator for which the cell membrane is permeable, abolished the H+-mediated activation of KCa channels in cell-attached patches. Under these circumstances H+ actually inhibited KCa channel activity. When inside-out patches were exposed to a [Ca2+] of 10–6 M [adjusted with ethyleneglycolbis(β-aminoethylester)-N,N,N′,N′-tetraacetic acid (EGTA) at pH 7.3], KCa channels were activated by H+ concentration dependently. However, when these patches were exposed to a [Ca2+] of 10–6 M adjusted with BAPTA at pH 7.3, H+ inhibited KCa channel activity. Extracellular acidosis had no significant direct effect on KCa channels, suggesting that extracellular H+ exerts its effects after transport into the cell, and that KCa channels are regulated by intracellular H+ and by cytosolic free Ca2+ modulated by acute acidosis. These results indicate that the modulation of KCa channel kinetics by acidosis plays an important role in the determination of membrane potential and, hence, coronary arterial tone.

Acidosis↗
PubMed1998

Thiamine-responsive lactic acidaemia: role of pyruvate dehydrogenase complex.

UNLABELLED: Lactic acidaemia is sometimes associated with a defect of the pyruvate dehydrogenase complex (PDHC), catalysing the thiamine-dependent decarboxylation of pyruvate. The activity of PDHC for different thiamine pyrophosphate (TPP) concentrations was determined in 13 patients with lactic acidaemia, clinically responsive to thiamine treatment in order to assess the role of PDHC in the aetiology of thiamine-responsive lactic acidaemia. Culture of lymphoblastoid cells and skin fibroblasts and muscle biopsies were performed in these 13 patients. The activity of PDHC to sodium dichloroacetate (DCA), known as the activator of PDHC, was also examined. Three groups were identified according to PDHC activity. Group 1 (two patients) displayed very low PDHC activity, which was not increased by DCA. This PDHC activity increased at high TPP concentrations. Group 2 (five patients) displayed below normal PDHC activity at low TPP concentrations, increased by DCA. This PDHC activity became normal at high TPP concentrations. PDHC deficiency in these patients of groups 1 and 2 was due to a decreased affinity of PDHC for TPP. Group 3 included six patients with normal PDHC activity at low as well as high TPP concentrations. This PDHC activity was increased by DCA. CONCLUSION: High concentrations of TPP may be required for maximal activity of PDHC in some patients with lactic acidaemia. The assay of PDHC activity, performed at a low concentration of TPP (1 x 10(-4)mM) allows selection of patients with thiamine-responsive lactic acidaemia.

Acidosis, Lactic↗
PubMed1998

Surgery for abdominal aortic aneurysms associated with malignancy.

Of 148 patients treated for abdominal aortic aneurysms (AAA), 33 (22%) also had cancer. According to the classification of Szilagyi, there were 13 patients in group I, 19 in group II, and 1 in group IV. In group I, the mean interval between the cancer and AAA operations was 7 years (range 1-14 years). Aneurysmectomy was performed in 9 patients, wrapping in 2, and no operation in 2. In group II, a two-stage operation was performed in 8 patients, a single-stage operation in 4, only surgery for cancer in 4, and no operation in 3. Of 4 patients undergoing single-stage operations, 3 had colorectal cancer, and there were no postoperative complications such as graft infection or anastomotic breakdown. In group I, 6 of 13 patients died, but there were no cancer deaths. In group II, 9 of 19 patients died, 6 from progressive cancer. The group IV patient also died of cancer. These results suggest that if a patient can tolerate surgery for both diseases, a single-stage operation is preferable.

Abdominal Neoplasms↗
PubMed1998

Adrenocorticotropic hormone therapy for infantile spasms alters pyruvate metabolism in the central nervous system.

To clarify the mechanism of action of adrenocorticotropic hormone (ACTH) in treating infantile spasms, we evaluated the effects of ACTH on the metabolism of pyruvate in the central nervous system (CNS) of children with infantile spasms. We measured the levels of lactate and pyruvate in cerebrospinal fluid (CSF) and serum, before and during ACTH treatment in 12 children with infantile spasms. We evaluated statistically any correlation between the observed metabolic changes and the clinical response of ACTH. ACTH therapy significantly elevated the levels of lactate and pyruvate in the CSF and serum. The effect was not dose-dependent. During ACTH therapy, the serum levels of lactate and pyruvate and the ratio of lactate to pyruvate (L:P ratio) were unrelated to these levels in CSF. Patients who showed a good initial response to treatment had a significantly higher CSF level of pyruvate and a lower L:P ratio during therapy than did those with a poor initial response. This is the first report that ACTH therapy administered for infantile spasms alters pyruvate metabolism in the CNS. This metabolic change may be involved in part in the action of ACTH in relieving infantile spasms.

Adrenocorticotropic Hormone↗
PubMed1998

Proton magnetic resonance spectroscopy of the brain in patients with Prader-Willi syndrome.

Five patients with Prader-Willi syndrome underwent magnetic resonance imaging and proton magnetic resonance spectroscopy. Magnetic resonance images revealed mild abnormalities, including slight ventriculomegaly, cortical atrophy, and a small brainstem, in all cases. The N-acetylaspartate/Choline (NAA/Cho) and N-acetylaspartate/Creatine (NAA/Cr) ratios were decreased in one (Case 1) and two (Cases 1 and 4) patients, respectively. The Choline/Creatine (Cho/Cr) ratio did not differ from those in control subjects. Thus, in patients with Prader-Willi syndrome, it is thought that there may be neuron loss or a neuron dysfunction caused by a chromosome abnormality. Statistically significant relationships were observed between IQ (DQ) and the NAA/Cho and Cho/Cr ratios: r = 0.895 (P < .05, NAA/Cho ratio) and r = -0.898 (P < .05, Cho/Cr ratio). This suggests that the parietal lobe pathology detected on 1H-magnetic resonance spectroscopy may be associated with more global brain damage and with loss of cognitive functions.

Adolescent↗
PubMed1998

Mutational analyses in four Japanese families with X-linked liver phosphorylase kinase deficiency type 1.

We analysed the gene of the human alpha-subunit of liver phosphorylase kinase (PHKA2) in four Japanese families with X-linked liver phosphorylase kinase deficiency type 1 by RT-PCR followed by PCR-single-strand conformation polymorphism and direct DNA sequencing. In this study, two novel mutations (Y116D and 2675A-->G) and one mutation previously reported (P1205L) were identified, revealing molecular heterogeneity in Japanese patients. Considering the dissimilarity in phenotype among our patients even with an identical mutation in the PHKA2 gene, it seems that each genetic deficiency in this gene may not be the only factor to determine the clinical heterogeneity in this disease.

Base Sequence↗
PubMed1998

New consecutive high-dose chemotherapy modality with fractionated blood stem cell support in the treatment of high-risk pediatric solid tumors: a feasibility study.

For the treatment of childhood solid tumors, we performed a pilot feasibility study of consecutive high-dose therapies, in which each course was followed by transplantation with granulocyte colony-stimulating factor-mobilized peripheral blood cells which had been separated into CD34-positive and -negative fractions by an Isolex system (Baxter). Positive selection of CD34+ cells has been associated with inevitable cell loss. To overcome this loss, CD34+ cells that had migrated into the negative fraction were saved and used for the first transplant, which was followed by a second transplant after a 3- to 5-month interval. In this phase I feasibility study, the results in six children were evaluated for safety and engraftment. Multi-drug cytoreductive regimens using ranimustine (MCNU), melphalan, thiotepa, carboplatin, cyclophosphamide or VP-16 were comparable between the two transplant procedures in terms of their intensity. The number of CD34+ cells in the 'CD34(+) fraction' was 3.31 x 10(6)/kg (0.63-4.3 x 10(6)/kg), while this number in the 'CD34(-) fraction' could not be evaluated correctly due their scarcity (<0.1%). The median numbers of infused MNC and CFU-GM were, respectively, 4.2 x 10(6)/kg and 1.75 x 10(5)/kg in the CD34(+) fraction, and 4.8 x 10(8)/kg and 3.35 x 10(5)/kg in the CD34(-) fraction. The number of days required to achieve an ANC >0.5 x 10(9)/l and a platelet count >20 x 10(9)/l and >50 x 10(9)/l were, respectively, 14.5, 15.0 and 19.5 in the first transplant with CD34- cells, and 13.5, 18.0 and 25.0 in the second transplant with CD34+ cells, with no essential difference between the two treatments. Although the small number of patients, the variation in clinical status and treatment, and the short follow-up invalidate any evaluation of the therapeutic benefit of this strategy, the encouraging results support the feasibility of this strategy, which enables an escalation of dose intensity with an improved cost/benefit ratio.

Adolescent↗
PubMed1998

Clinically applicable bulk isolation of blood CD34+ cells for autografting in children.

CD34+ cells were purified in bulk from apheresis-collected cells of children with cancer using monoclonal antibody (MoAb) and magnetic beads (Baxter ISOLEX system). To improve the purity of the final product for possibly better tumor cell purging and to make the manufacturer's original procedure more cost-effective, we incubated the cells for 30 min with l-phenylalanine methylester hydrochloride (PME) to reduce the cell number by removing contaminating granulocytes and monocytes in the initial step before incubation with MoAb. Our modification prevented nonspecific interactions between MoAb and magnetic beads, and thereby saved expensive materials for purification. A total of 40 purifications were performed with samples containing a mean of 3.1 x 10(9) blood cells mobilized from 15 children by chemotherapy plus granulocyte colony-stimulating factor (G-CSF). The entire purification procedure, from the end of apheresis to storage, was completed within 5h. After incubation with PME and double-layered (40/60%) Percoll separation, the number of CD34+ cells was reduced to 48+/-29%, which suggests the possibility that half of the CD34+ cells in the inoculum were nonclonogenic in the hematopoietic progenitor assay. PME/Percoll-treated cells were then subjected to a final isolation procedure with MoAb according to the manufacturer's suggestions, and 52+/-42% and 32+/-22%, respectively, of the CFU-GM and CD34+ cells present in the initial bag inoculums were recovered. The recovery rates were, respectively, 54% and 67%, when the calculation was limited to the isolation procedure with MNoAb. The purity of isolated CD34+ cells and the plating efficiency in methylcellulose culture were, respectively, 77+/-24% and 33+/-13%. Fourteen children were subsequently autografted with purified CD34+ cells after marrow ablative chemotherapy. The median number of days to achieve an ANC of 0.5 x 10(9)/l was 12 and that to achieve a platelet count of 50 x 10(9)/l was 22.5, which were comparable to those in our historical group of 55 patients who underwent transplant with unmanipulated blood cells (13 and 16 days). These results suggest that our modified purification procedure with PME is useful for the initial reduction of cell numbers to save costly materials, and that cells isolated by this procedure can be directly used in clinical transplantation procedures.

Adolescent↗
PubMed1998

Modification of parallel activity elicited by propagating bursts in developing networks of rat cortical neurones.

Networks of cultured cortical neurones exhibit regular, synchronized, propagating bursts which are synaptically mediated, and which are hypothesized to play a part in activity-dependent formation of connections during development in vivo. The relationship between the strength of synaptic connections and the characteristics of synchronized propagating bursting, however, is unclear. Modification of synchronized activity in cortical cultures in response to electrical stimulation was examined using multisite electrode array recording. By measuring the response of the network to weak, localized, test stimulation (TS), we observed a potentiation of activity following a relatively stronger inducing stimulation (IS). This potentiation was evident as an increased probability of eliciting bursts by TS, an increased frequency of spontaneous bursts and number of spikes per burst, and increased speed of burst propagation, and it lasted for at least 20 min. Changing the parameters of IS revealed that high frequency tetanic stimulation is not necessary to induce potentiation, while it is essential for IS to produce a regeneratively propagating burst. The results provide a direct demonstration of modification of both the spatial and temporal characteristics of synchronized network activity, and suggest an important physiological role for propagating synchronized bursting, as a mechanism for inducing plastic modifications in the developing cortex.

Animals↗
PubMed1998

Intra-apheresis recruitment of blood progenitor cells in children.

BACKGROUND: Determination of the optimal duration of apheresis requires a careful examination of blood progenitor cell (BPC) kinetics during apheresis. Intra-apheresis recruitment of BPCs should be evaluated. STUDY DESIGN AND METHODS: Twenty-six apheresis procedures were performed in 13 children with various malignant disorders (ages, 10 months to 17 years; median, 7 years) to collect BPCs for autologous transplant, using a blood cell separator with 2 to 5.2 blood volumes processed. The subjects were divided into three groups according to age: below 1 year (n = 4), 2 to 10 years (n = 5), and 11 to 20 years (n = 4). BPCs were mobilized by a combination of chemotherapy and granulocyte-colony-stimulating factor (G-CSF; 2-7.5 micrograms/kg/day intravenous drip). The levels of circulating CD34+ cells and colony-forming units-granulocyte-macrophage (CFU-GM) were monitored to examine intra-apheresis recruitment. For every 50 mL per kg or 2 L of processed blood, 5-mL blood samples were collected via a central line. RESULTS: In the first apheresis procedure, more CD34+ cells were mobilized by the procedure itself in the infant group than in the older groups, and the number of cells decreased with the subject's age. When the same analysis was made during the second apheresis procedure, performed 1 day later, the levels of both CD34+ cells and CFU-GM had decreased to below the preapheresis values in all of the populations. Cell yields in the second apheresis procedure were significantly lower than those in the first. CONCLUSION: Although several factors prevent a reliable analysis, the data suggest that the intra-apheresis recruitment of BPCs may be age-specific; the continuous and prolonged supply of cells from the bone marrow to peripheral blood that occurs during apheresis is more predominant in infants, which leads to the collection of proportionately more BPCs in younger children than in their older counterparts.

Adolescent↗
PubMed1998

Continuous monitoring of hematocrit values during apheresis for allogeneic peripheral blood stem cell collection.

Rapid changes in the circulating blood volume or hemoglobin level during apheresis may pose a risk for healthy individuals donating allogeneic PBSC. In this study, a real-time noninvasive monitor CRIT-LINE was used for continuous monitoring of hematocrit values in a total of 16 aphereses performed in 4 adult (median age 30 years) and 4 pediatric donors (4 years). Donors received recombinant G-CSF (10 microg/kg s.c. for 5 days) for mobilization of PBSC. A CS3000 plus blood cell separator (Baxter) was used in two different procedures. Adults donors were subjected to modified program 1-120 using a combination of the granulocyte chamber and the small volume collection chamber (SVCC), and pediatric donors were subjected to specialized program 4 with a combination of the newly developed small volume separation chamber holder (SVSCH) and SVCC. In all of the procedures for children, the extracorporeal line was primed with 400 ml leukocyte-depleted allogeneic RBC or 200 ml autologous RBC after regular priming with normal saline, whereas none of the adult donors received this treatment. We found a marked contrast in the hematocrit kinetics during apheresis in the two cohorts/procedures. In adults, the initiation of apheresis was followed by an immediate decline in the hematocrit value over the initial 10 min until a stable plateau level was reached (7% decrease). In children, the values decreased slowly but progressively throughout the entire procedure to finally reach a 9% decrease at the completion of apheresis. These data may suggest that the use of SVSCH plus SVCC or priming with RBC can eliminate the abrupt decline in blood hemoglobin levels that occurs during apheresis.

Adult↗