Biomedical subjects

M Kodama

Publications and source records attributed to M Kodama.

At least 37 records · Page 2Linked to original sources

PubMed2001

Protection against autoimmune myocarditis by gene transfer of interleukin-10 by electroporation.

BACKGROUND: Although immunosuppressive therapy for myocarditis has attracted a great deal of attention, its effectiveness is controversial. Interleukin (IL)-10 has a variety of immunomodulatory properties. Among the nonviral techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive, and safe. METHODS AND RESULTS: We examined the applicability of murine IL-10 (mIL-10) gene transfer to the treatment of rats with experimental autoimmune myocarditis. Nine-week-old Lewis rats were inoculated with pig myosin (day 0). A plasmid vector expressing mIL-10 cDNA (800 microgram per rat) was transferred into the tibialis anterior muscles by electroporation 3 times (5 days before immunization and at days 4 and 13); control rats received empty plasmid. Electroporation increased the serum mIL-10 levels to >250 pg/mL. The 21-day survival rate in rats treated with mIL-10 cDNA was higher (15 of 15; 100%) than that of the control group (9 of 15; 60%). Furthermore, mIL-10 treatment significantly attenuated myocardial lesions and improved hemodynamic parameters. CONCLUSIONS: These findings showed that gene transfer into muscle by electroporation in vivo is an effective means of delivery of IL-10 for the treatment of autoimmune myocarditis.

Animals↗

PubMed2001

Increased expression of synaptophysin and stathmin mRNAs after methamphetamine administration in rat brain.

The rearrangement of neural networks associated with the behavioral sensitization induced by psychostimulants is poorly understood. We have investigated the effect of methamphetamine (METH) administration on the mRNA levels of three different classes of plasticity-related genes in the rat brain. The expression of synaptophysin mRNA increased 20-40% in the nucleus accumbens, prefrontal and temporal cortices, 1-24 h after acute METH administration, and that of stathmin mRNA increased about 20% in the prefrontal cortex 1 h later. They did not change after subchronic administration. The level of alpha-tubulin mRNA was constant. Therefore, synaptophysin and stathmin play an important role in the neural plastic changes involved in the early induction process of METH-induced sensitization, but not in the later maintenance process.

Animals↗

PubMed2001

Association study of CAG repeats in the KCNN3 gene in Japanese patients with schizophrenia, schizoaffective disorder and bipolar disorder.

To investigate a possible involvement of expanded triplet repeats of genome in the genomes of patients with endogenous psychoses, we examined a CAG repeat polymorphism in the coding region of the KCNN3 gene in schizophrenia, schizoaffective disorder, bipolar disorder and controls of the Japanese population. There were no significant differences in the CAG repeat number of longer or shorter alleles among the four diagnostic groups or among the schizophrenia hebephrenic and paranoid subtypes.

Adenine↗

PubMed2001

Cellular distribution of thrombomodulin as an early marker for warm ischemic liver injury in porcine liver transplantation: protective effect of prostaglandin I2 analogue and tauroursodeoxycholic acid.

BACKGROUND: Warm ischemia of the graft from non-heart-beating donors is considered a risk factor for posttransplant graft dysfunction. The early administration of cytoprotective agents may help improve graft dysfunction. METHODS: Four groups of 10 pigs each underwent orthotopic liver transplantation. Prostaglandin I2 analogue, OP-41483, was administered intraportally 30 min before warm ischemic insult in donors and after reperfusion in recipients in one group. In the other study group, additional intravenous tauroursodeoxycholic acid (TUDC) was given before the warm ischemic insult in donors and after reperfusion, then maintained continuously until postoperative day (POD) 7. RESULTS: Exposure of liver grafts to warm ischemia resulted in severe congestion with the disappearance of thrombomodulin (Tm) from the sinusoidal endothelial cells (SECs) and smooth muscle cells (SMCs) around biliary epithelial cells (BEpCs) 2 hr after reperfusion, followed by positive immunoreactivity of Tm in BEpCs with hyperbilirubinemia, which was related to high mortality. Combined administration of OP-41483 and TUDC had a protective effect, demonstrated by sustained immunoreactivity of Tm from SECs and SMCs until POD 7, without that reactivity in BEpCs. This was associated with reduced congestion and hyperbilirubinemia, similar to the control group not subjected to warm ischemia. CONCLUSIONS: These findings suggest that negative immunoreactivity of Tm in SECs and SMCs surrounding BEpCs and positive in BEpCs may be an early marker for ischemic liver injury, and that OP-41483 and TUDC may protect against the microcirculatory and biliary derangement.

Animals↗

PubMed2001

NOTCH4 gene polymorphism and susceptibility to schizophrenia and schizoaffective disorder.

The NOTCH4 gene is located at 6p21.3, a site which several studies have shown to have significant linkage with schizophrenia. Recently, an exceptionally strong association was reported between NOTCH4 gene polymorphisms and schizophrenia in British patients. We re-examined their findings using a Japanese population. We genotyped three kinds of polymorphisms, SNP1 in the 5' flanking region, SNP2 in the promoter region and CTG repeats in exon 1 of the NOTCH4 gene of schizophrenics (N=188), patients with schizoaffective disorder (N=39) and controls (N=143). Genotypic distributions and allelic frequencies of SNP1, SNP2 and CTG repeats of the NOTCH4 gene did not show significant associations with schizophrenia or schizoaffective disorder. Neither they showed association with schizophrenia subcategories, hebephrenic and paranoid type schizophrenia, nor with subgroups of schizophrenia with and without positive family history of psychoses. The present study found that the NOTCH4 gene does not confer susceptibility to schizophrenia and schizoaffective disorders, at least in Japanese subjects, in contrast to the findings in British subjects.

Adult↗

PubMed2001

Lipopolysaccharide: neutralization by polymyxin B shuts down the signaling pathway of nuclear factor kappaB in peripheral blood mononuclear cells, even during activation.

BACKGROUND: There have been many studies on anti-lipopolysaccharide (LPS) agents and LPS-neutralizing agents; however, there have been no reports on the changes in clinical status and mediators that occur when these agents are used. Polymyxin (PMX) (treatment using a column containing polymyxin B-immobilized fiber) removed circulating endotoxin, and reduced various cytokines within 120 min, even in patients with high levels of plasma cytokines. Our purpose was examine the mechanisms of PMX treatment by which plasma cytokines are reduced by endotoxin neutralization with polymyxin B, even during therapy for sepsis and/or endotoxin shock. METHODS: We studied the interaction between nuclear factor kappaB (NF-kappaB) binding activity and tumor necrosis factor alpha (TNF-alpha) secretion in an experimental system using LPS-stimulated human peripheral blood mononuclear cells (PBMCs), after neutralization of LPS with polymyxin B. PBMCs were incubated with LPS in vitro, and TNF-alpha secretion and NF-kappaB activation were assessed. We then studied the changes in NF-kappaB activation and TNF-alpha secretion when both polymyxin B and LPS were added simultaneously and when polymyxin B was added after 30 or 120 min of incubation with LPS. RESULTS: Immediate inhibition of NF-kappaB binding activity and suppression of TNF-alpha secretion were observed after LPS neutralization with polymyxin B regardless of whether PBMCs were already producing TNF-alpha. CONCLUSIONS: These findings may indicate one of the mechanisms operating in the clinical changes that occur after circulating endotoxin removal, and are likely to have therapeutic value, even for patients with high proinflammatory cytokine levels.

Anti-Bacterial Agents↗

PubMed2001

Correlation between plasma endotoxin, plasma cytokines, and plasminogen activator inhibitor-1 activities in septic patients.

The objective of this study was to evaluate the relation between the clinical and plasma parameters and the changes in plasma endotoxin activity with 2 hours of endotoxin-adsorbing therapy using polymyxin B (PMX). A total of 88 consecutive patients were admitted for PMX treatment of severe sepsis or septic organ failure. Standard supportive care was continued without alteration during PMX treatment. Endotoxin, tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), IL-10, and plasminogen activator inhibitor-1 (PAI-1) activities and clinical parameters were measured before, immediately after, and the day after PMX treatment. The mean APACHE II and III scores were 24.2 +/- 1.0 and 85.8 +/- 3.0, respectively. The 2-week survival rate was 51.1%. In survivors, TNFalpha, IL-6, IL-10, and PAI-1 activities were significantly decreased during the 2-hour PMX treatment, the following day, or both times. There was no significant change in the parameters, except for TNFalpha, after PMX in nonsurvivors. In the subgroup whose plasma endotoxin decreased more than 30%, IL-6, TNFalpha, and PAI-1 significantly decreased after 2 hours of PMX or the following day (or both), but all four parameters in nonsurvivors showed no significant change. Hence PMX adsorbed plasma endotoxins and contributed to reductions in plasma proinflammatory cytokine levels and to improved clinical parameters during the 2-hour treatment. Changes in these parameters correlated with changes in plasma endotoxin activity in survivors whose plasma endotoxin levels were adequately reduced.

APACHE↗

PubMed2001

Spontaneous loss of a conditionally dispensable chromosome from the Alternaria alternata apple pathotype leads to loss of toxin production and pathogenicity.

The Alternaria alternata apple pathotype causes Alternaria blotch of susceptible apple cultivars through the production of a cyclic peptide, host-specific toxin, AM-toxin. We recently cloned a cyclic peptide synthetase gene, AMT, whose product catalyzes the production of AM-toxin and showed that it resides on chromosomes of 1.8 Mb or less, depending on the A. alternata apple pathotype strain. Reverse transcriptase (RT)-PCR, using primers specific to AMT, on laboratory sub-cultured strains previously shown to produce AM-toxin, identified one isolate that did not express the gene. A leaf necrosis bioassay confirmed an AM-toxin-minus phenotype. However, an original isolate of this strain which had not undergone sub-culture gave a positive result by both RTPCR and bioassay. Contour-clamped homogeneous electric field electrophoresis and Southern hybridization demonstrated the loss of a 1.1-Mb chromosome in the non-toxin-producing isolate. Since this chromosome can be entirely lost without affecting growth, but is necessary for pathogenicity, we propose it is a conditionally dispensable chromosome.

Alternaria↗

PubMed2001

Techniques available for the management of massive sacrococcygeal teratomas.

An infant born in the 34th week of gestation weighing 5,355 g with a massive sacrococcygeal (SC) tumor was delivered by elective cesarean section. An ultrasonographic examination showed solid and cystic components in the tumor. Resection was successfully undertaken with insertion of a Nélaton catheter into the rectum to avoid unnecessary impairment of the viscera. The tumor weighed 2,380 g, measured 25 x 14 x 11 cm, and was clinicopathologically diagnosed to be a SC teratoma. This experience and other publications show that several considerations including control of hemorrhage and coagulopathies, visceral protection, and avoidance of wound infection are necessary to facilitate the surgical management of massive SC tumors. Several suggestions are made concerning the pre- and intraoperative management of this rare tumor.

Female↗

PubMed2001

The insular but not the perirhinal cortex is involved in the expression of fully-kindled amygdaloid seizures in rats.

We have previously reported an important excitatory role of the perirhinal cortex (PRC) in rat kindling development using an immunohistochemistry technique. In this study, we investigated the roles of the PRC and the insular cortex (INS) located rostral to the PRC, in fully-kindled amygdaloid seizures, using a microinjection technique in the rat kindling model of epilepsy. Following the establishment of daily kindling, we investigated the effects of microinjections of procaine hydrochloride, 2-amino-5-phosphonovalerate (APV; an N-methyl-D-aspartate (NMDA) receptor antagonist) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)-quinoxaline (NBQX; an alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor antagonist). Microinjections of these drugs into the ipsilateral PRC did not suppress kindled seizures. The possibility is that the process of kindling development forms novel seizure-generalization pathways that do not require further activation of the PRC. On the other hand, procaine and APV injected into the ipsilateral INS significantly suppressed kindled seizures. The manner of suppression appeared to be 'all or none'. It is therefore possible that at least the activation of NMDA receptors in the INS is necessary to express generalized kindled amygdaloid seizures.

Amygdala↗

PubMed2001

Enhanced expression and production of monocyte chemoattractant protein-1 in myocarditis.

Monocyte chemoattractant protein-1 (MCP-1) is a member of the C-C chemokine family that has been shown to play a major role in the migration of monocytes and T cells to an inflammatory focus. To clarify the role of MCP-1 in the pathogenesis of myocarditis, we have examined the expression of MCP-1 in rat hearts with experimental autoimmune myocarditis (EAM), and have also measured serum levels of MCP-1 in patients with histology-proven acute myocarditis. Lewis rats were immunized with cardiac myosin and were killed 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 42 and 56 days after immunization. Large mononuclear cells in the myocardial interstitium were stained with an anti-MCP-1 antibody. mRNA of MCP-1 increased in the hearts of EAM rats from days 15--27 as shown by quantitative reverse transcription-polymerase chain reaction. Serum MCP-1 levels of the rats with EAM were significantly elevated from days 15--24. In the clinical study, serum levels of MCP-1 in 24 patients with acute myocarditis at the time of admission (165.2 +/- 55.8 pg/ml) were significantly (P = 0.0301) elevated compared with those of 20 healthy volunteers (61.8 +/- 10.7 pg/ml). Serum MCP-1 levels of 8 fatal cases (371.8 +/- 145.2 pg/ml) were significantly (P = 0.0058) higher than those of 16 cases who survived (65.5 +/- 12.8 pg/ml). In conclusions, MCP-1 may play an important role in the pathogenesis of human acute myocarditis as well as in the progression of rat EAM.

Acute Disease↗

PubMed2001

Sleep-wake rhythm during stay in an intensive care unit: a week's long-term recording of skin potentials.

To monitor the sleep-wake cycle of patients during their stay in the intensive care unit (ICU), we tried continuous and long-term recording of skin potential (SP) levels in patients after surgery. A graph of the week-long SP showed the sleep-wake pattern to be evident until the fourth day. It disappeared beginning on the fifth day, resulting finally in delirium with a relatively high mean SP level. In another record, the administration of sedative agents to calm the excitement lowered the mean SP level and suppressed SP responses evoked by frequent day and night treatment or nursing care. Continuous monitoring of arousal level by SP will be of help in prevention of ICU syndrome.

Aged↗

PubMed2001

Two kinds of mitogen-activated protein kinase phosphatases, MKP-1 and MKP-3, are differentially activated by acute and chronic methamphetamine treatment in the rat brain.

Two functionally different MAP kinase phosphatases (MKPs) were investigated to clarify their roles in behavioral sensitization to methamphetamine (METH). MKP-1 mRNA levels increased substantially by about 60-300% in a range of brain regions, including several cortices, the striatum and thalamus 0.5-1 h after acute METH administration. After chronic METH administration its increase was less pronounced, but a more than 50% increase was still seen in the frontal cortex. MKP-1 protein levels also increased 3 h after acute or chronic METH administration. MKP-3 mRNA levels increased by about 30-50% in several cortices, the striatum and hippocampus 1 h after acute METH administration, but only in the hippocampus CA1 after chronic METH administration. Pre-treatment with the D(1) dopamine receptor antagonist, SCH23390, attenuated the METH-induced increase of MKP-1 and MKP-3 mRNA in every brain region, while pre-treatment with the NMDA receptor antagonist, MK-801, attenuated it in some regions. These findings suggest that in METH-induced sensitization, MKP-1 and MKP-3 play important roles in the neural plastic modification in widespread brain regions in the earlier induction process, but in the later maintenance process, they do so only in restricted brain regions such as MKP-1 in the frontal cortices and MKP-3 in the hippocampus.

Acute Disease↗

PubMed2001

Mechanical alternans in patients with chronic heart failure.

BACKGROUND: Clinical implications of mechanical alternans in patients with chronic heart failure have remained uncertain. In this study, prevalence, characteristics, and prognostic implications of mechanical alternans were investigated. METHODS AND RESULTS: Consecutive 51 patients with dilated cardiomyopathy underwent diagnostic cardiac catheterization using a micromanometer-tipped catheter. Under basal conditions, 7 of 35 patients with sinus rhythm showed mechanical alternans. Physiologic tachycardia (110 bpm) induced mechanical alternans in another 15 patients with sinus rhythm and in another 10 of 16 patients with atrial fibrillation. Low doses of dobutamine also induced mechanical alternans in another 8 patients, but a high dose of dobutamine eliminated mechanical alternans. Consequently, 40 patients (78%) showed mechanical alternans. Mechanical alternans was always accompanied by alternating changes of positive dP/dt, a parameter of contractility during isovolumetric contraction time, but negative dP/dt was occasionally constant. Concordant mechanical alternans between both ventricles was more prevalent than discordant alternans. The left ventricular end-diastolic volume indices and end-systolic volume indices of patients with mechanical alternans were larger than those of patients without. The left ventricular ejection fraction of patients with alternans was significantly lower than that of patients without. CONCLUSIONS: Mechanical alternans was highly prevalent in patients with chronic heart failure. The origin of mechanical alternans seems to exist before or at the isovolumetric contraction time.

Adult↗

PubMed2001

The PU.1 and NF-EM5 binding motifs in the Igkappa 3' enhancer are responsible for directing somatic hypermutations to the intrinsic hotspots in the transgenic Vkappa gene.

Somatic hypermutation is a key mechanism in generating Ig with higher affinities to antigen, a process known as affinity maturation. Using Igkappa transgenes, the 3' enhancer (kappaE3') has been shown to play an important role in introducing hypermutations. In order to identify the cis-acting elements that regulate hypermutagenesis, we have generated transgenic substrates containing mutations/deletions in the kappaE3' region. Here, we report that base substitutions in the kappaE3', either in the PU.1 or in the NF-EM5 binding motif, not only reduce the mutation rate but also disrupt the directed mutagenesis in the intrinsic hotspots of the Igkappa transgene.

3' Untranslated Regions↗

PubMed2001

Inhibition of progression of heart failure and expression of TGF-beta 1 mRNA in rats with heart failure by the ACE inhibitor quinapril.

The cardioprotective effects of quinapril, an angiotensin-converting enzyme inhibitor, were studied in a rat model of heart failure. Twenty-six rats were divided into two groups: one given 20 mg/kg/day quinapril (n = 11), and controls given 0.5% methylcellulose (n = 15). After oral administration for 1 month, quinapril reduced heart weight (from 1.28+/-0.05 to 0.87+/-0.02 g; p < 0.05) without changing body weight. Quinapril lowered left ventricular end-diastolic pressure (from 14.1+/-2.0 to 6.6+/-1.5 mmHg; p < 0.05) and central venous pressure (from 2.7+/-0.9 to 0.7+/-0.4 mmHg), and increased +/- dP/dt (from +2409+/-50 to +3569+/-169 mmHg/s, and from -2318+/-235 to -3960+/-203 mmHg/s; both p < 0.01). The area of myocardial fibrosis was markedly reduced by quinapril (6+/-3%) as compared with controls (29+/-6%; p < 0.01). Expression of transforming growth factor (TGF)-beta1 mRNA was markedly increased in controls as compared with age-matched normal rats. The increase in level of TGF-beta1 mRNA was significantly suppressed by quinapril (from 17.1+/-6.2 to 9.00+/-2.40; p < 0.05). These observations indicated that quinapril has cardioprotective effects on heart failure, and that the beneficial effects may be partly explained by attenuation of fibrotic response through suppression of TGF-beta1 mRNA expression.

Administration, Oral↗

PubMed2001

Bisoprolol improves survival in rats with heart failure.

The cardioprotective effects of bisoprolol were studied in a rat model of severe heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization, Lewis rats were divided into four groups: 0.1 mg/kg/day bisoprolol (Group 0.1), 1.0 mg/kg/day bisoprolol (Group 1) and 10 mg/kg/day bisoprolol (Group 10), and vehicle (0.5% methylcellulose; Group V) (all groups, n = 13). After oral administration for 1 month, heart weight, mean blood pressure, heart rate, central venous pressure, peak left ventricular pressure, left ventricular end-diastolic pressure, +/- dP/dt, and area of fibrosis were measured. Although bisoprolol reduced heart rate (399+/-11/min in Group V, 382+/-10/min in Group 0.1, 348+/-8/min in Group 1 and 302+/-9/min in Group 10) and increased survival (62% in Group V, 69% in Group 0.1, and 100% in Group 1 and Group 10) in a dose-dependent manner, this drug did not change heart weight, the area of myocardial fibrosis or hemodynamic parameters. These observations suggested that bisoprolol may improve survival independently of its effect on left ventricular function by reducing sudden death in patients with severe heart failure.

Adrenergic beta-Antagonists↗

PubMed2001

The role of bacterial translocation on neutrophil activation during hemorrhagic shock in rats.

Some biological responses to hemorrhage have been reported to be associated with bacterial translocation (BT). While the relationship between peripheral blood neutrophils and BT in the late phase of hemorrhagic shock or burn injury has been reported, this relationship in the early phase has not been fully elucidated. We investigate the role of BT in neutrophil activation and priming during hemorrhagic shock. The experimental rats were divided into three groups: a group with normal intestinal flora (NF group), an antibiotic-decontaminated group (AD group), and a sham shock group with normal intestinal flora (sham group). Hemorrhagic shock was induced in the NF and AD groups (MAP 30 mm Hg for 30-90 min). The rats were sacrificed at 30, 60, or 90 min following the shock induction. Cultures were taken from the liver, spleen, mesenteric lymph nodes (MLNs), and systemic blood to assess the occurrence of BT. Hydrogen peroxide generation and CD11b/c expression were assayed by flow cytometry to evaluate peripheral blood neutrophil activation and priming, respectively. In the NF group, significant BT to the MLNs and spleen was noted from 30 min after the shock induction, and significant hydrogen peroxide generation was also noted from 30 min. The expression of CD11b/c on neutrophils was significantly up-regulated at 90 min after the shock induction. Furthermore, BT, as also the aforementioned parameters of neutrophil function, was significantly suppressed in the AD group. We, therefore, concluded that neutrophil activation and priming during hemorrhagic shock might be closely related to BT, and that infectious factors possibly influence the host responses starting from the early phase of damage, even in noninfectious stress-inducing conditions.

Animals↗