Biomedical subjects

M Tominaga

Publications and source records attributed to M Tominaga.

At least 73 records · Page 4Linked to original sources

PubMed2000

Insulin activates p38 mitogen-activated protein (MAP) kinase via a MAP kinase kinase (MKK) 3/MKK 6 pathway in vascular smooth muscle cells.

BACKGROUND: Induction of stress-activated mitogen-activated protein (MAP) kinases such as p38 could be important for the development of cardiovascular diseases since p38 MAP kinase activation stimulates apoptosis, cell growth, prostanoid formation and other cellular dysfunctions when induced by oxidants, hyperosmolarity, or pro-inflammatory cytokines. On the other hand, insulin resistance is one of the most important factors promoting atherogenesis, including cardiovascular diseases, but it is not clear how these different factors transmit their signals intracellularly at the cytosolic and nuclear levels. In this study, we investigated the effect of insulin on p38 mitogen-activated protein (MAP) kinase activation in cultured rat vascular smooth muscle cells (VSMC). MATERIALS AND METHODS: VSMC were obtained from the aortas of male Wistar rats by the media explant technique. After being stimulated by insulin with SB-203580, PD-98059, or GF109203X, the cells were solubilized and the expressions of MAP kinases, MAP kinase kinases and p70 S6 kinase were examined by immunoblot analysis. The amount of DNA synthesis was measured by [3H]thymidine incorporation. RESULTS: Insulin activated p38 MAP kinase phosphorylation in a dose-dependent manner, and the phosphorylation was specifically inhibited by SB-203580, a p38 MAP kinase-specific inhibitor, but not by PD-98059, a specific inhibitor of upstream kinase (MEK), of extracellular signal-regulated kinase (ERK), or GF209203X, a protein kinase C-specific inhibitor. Insulin also activated MAP kinase kinase (MKK) 3/MKK 6 phosphorylation, the upstream kinase of p38 MAP kinase, but neither stress-activated protein kinase (SAPK)/ERK kinase (SEK1/MKK4) nor SAPK/c-jun NH2-terminal protein kinase. Surprisingly, phosphorylation of p70 S6 kinase and an increase of DNA synthesis by insulin were suppressed dose dependently by SB-203580. CONCLUSION: These results have established that insulin activates the p38 MAP kinase cascade via an MKK 3/6 pathway in rat VSMC, independently of a MEK-ERK cascade, and partly regulates cell growth.

Animals↗

PubMed2000

Gastric mucosal damage caused by monochloramine in the rat and protective effect of taurine: endoscopic observation through gastric fistula.

BACKGROUND AND STUDY AIMS: The mechanism of Helicobacter pylori-induced gastric mucosal injury is unknown, but H. pylori infection is conducive to accumulation in the stomach of monochloramine, a cytotoxic substance. The present study involved morphological investigation of the damaging effects of monochloramine on rat gastric mucosa, using endoscopic observations through a gastric fistula. The study also examined the protective effect of taurine against monochloramine-induced gastric mucosal lesions in rats. MATERIALS AND METHODS: The effects of monochloramine in rats were studied by administering the substance via a gastrostomy, which was then used to conduct a series of endoscopic observations. Local blood flow was measured using a laser Doppler method. Histological examination was carried out after 24 hours. Various monochloramine concentrations were used, and some animals were pretreated with taurine, a monochloramine scavenger, via the gastrostomy. RESULTS: Endoscopically, monochloramine was found to produce hemorrhagic mucosal erosions, mainly in the gastric body, in a time-dependent and concentration-dependent manner. Blood flow was decreased in advance of mucosal erosion. Taurine prevented mucosal injury by 30 mM monochloramine, the highest concentration tested. CONCLUSIONS: Although only the first 24 hours of mucosal injury were observed in the present study, the most likely mechanisms by which monochloramine caused injury to the gastric mucosa appeared to be both oxidative damage and a reduction in blood flow, impairing the mucosal defense mechanism.

Analysis of Variance↗

PubMed2000

Relationship between Sjögren's syndrome and human T-lymphotropic virus type I infection: follow-up study of 83 patients.

We have previously demonstrated a high prevalence of Sjögren's syndrome (SS) in patients with human T-lymphotropic virus type I-associated myelopathy (HAM) in Nagasaki prefecture. The present follow-up study compared the clinical and laboratory findings of SS with or without human T-lymphotropic virus type I (HTLV-I) antibody in this endemic area for HTLV-I infection. We investigated the clinical and laboratory manifestations in 83 patients with SS and HAM, including histologic examination of labial salivary glands and the prevalence of SS in patients with HAM. Definite SS was diagnosed in 13 out of 20 patients with HAM when the European Community criteria were used. The density of mononuclear cell infiltration in labial salivary glands was higher in HTLV-I-seropositive patients with SS (including patients with HAM) than in HTLV-I-seronegative patients. The volume of saliva and lacrima determined by the Schirmer or Saxon test was lower than normal but was not different among SS-HTLV-I-seronegative patients, HTLV-I-seropositive patients without HAM, and HTLV-I-seropositive patients with HAM. The proportions of patients positive for antinuclear antibody (ANA) and anti-SS-A (Ro) antibody or anti-SS-B (La) antibody were similar in the three groups. However, the low volume of saliva and the frequency of ANA in SS correlated with the degree of mononuclear cell infiltration in labial salivary glands. Our results suggested that HTLV-I infection is related to SS and that laboratory and clinical findings in SS closely correlate with the degree of mononuclear cell infiltration in the salivary glands.

Adult↗

PubMed2000

Regulation of root growth by gibberellin in Lemna minor.

Hormonal control of root growth was studied in Lemna minor. Although addition of gibberellic acid (GA3) to the culture medium did not promote the root growth, a gibberellin biosynthesis inhibitor, uniconazole P (Un-P), significantly inhibited root growth. Both length and diameter of roots in Un-P-treated plants were significantly smaller than those in control plants, mainly caused by inhibition of cell division. In epidermal cells, the length was slightly decreased and the width increased by Un-P treatment, indicating inhibition of elongation growth. GA3 completely nullified the inhibition caused by Un-P. Transverse cortical microtubules (CMTs) of epidermal cells in the elongation zone were significantly fragmented by treatment with Un-P, but not by that in the presence of GA3. The cellulose microfibril array in the Un-P-treated cells was more random and more oblique than that in the control cells. These results suggested that root growth in L. minor is regulated by endogenous gibberellin.

Gibberellins↗

PubMed2000

Superiority of mild hypothermic (20 degrees C) preservation for pancreatic microvasculature using the two-layer storage method.

Hypothermia causes vascular endothelial damage that leads to graft microcirculation disorder and eventually thrombosis after reperfusion. The two-layer cold storage method (TL) was previously demonstrated to supply oxygen to the pancreas graft and maintain high adenosine triphosphate tissue concentration. In this study, we evaluated whether mild hypothermic (20 degrees C) preservation using the TL method could reduce endothelial damage while maintaining parenchymal viability. Graft survival by 20 degrees C preservation was investigated using a dog segmental pancreas autotransplantation model (simple storage in University of Wisconsin solution (UW) for 5 and 8 hours or TL for 5, 8, 12, and 24 hrs. respectively). Subsequently, the grafts were preserved in four different conditions (4 and 20 degrees C UW. 4 and 20 degrees C TL) for 8 hours to evaluate microvascular endothelial damage. Trypan blue uptake of vascular endothelium and pancreatic tissue perfusion were evaluated. No graft preserved by 20 degrees C UW for 5 and 8 hours survived (0/7 and 0/4). In contrast, the graft survival rates by 20 degrees C TL for 5, 8, 12, and 24 hours were 100% (5/5), 80% (4/5), 20% (1/5), and 0% (0/4), respectively. In trypan blue uptake analysis, there were significant differences between 4 and 20 degrees C in both UW and TL (4 degrees C UW, 37% [n = 5) vs. 20 degrees C UW, 13% [n = 4] [p < 0.01]; 4 degrees C TL, 29% [n = 5] vs. 20 degrees C TL, 10% [n = 5] [p < 0.011). The perfusion values in 20 degrees C TL were significantly higher than those in other groups at least for up to 120 minutes after reperfusion (p < 0.01 ). In short-term pancreas preservation, mild hypothermic TL reduced vascular endothelial cell damage and ameliorated graft microcirculation while maintaining parenchymal viability. Mild hypothermic TL may lessen vascular complications in clinical pancreas transplantation when used for several-hour preservation.

Animals↗

PubMed2000

[Three cases of tuberculosis complicating acute respiratory distress syndrome].

In this report, we describe three patients with pulmonary tuberculosis with acute respiratory failure with an extensive tuberculous consolidation in bilateral lung fields. Disseminated intravascular coagulation (DIC) was present in one patient and miliary tuberculosis in two patients. They all developed acute respiratory distress syndrome (ARDS), nessecitating management by mechanical ventilation with a combination therapy of antituberculous agents and methylprednisolone (m-PSL) pulse therapy. Only one patient survived in whom the PaO2/FiO2 ratio recovered rapidly after the initiation of therapy. Two patients whose systemic condition upon admission was critically ill eventually died of hepatic failure and bacterial pneumonia, even though ARDS and pulmonary tuberculosis were successfully treated. Prognosis of pulmonary tuberculosis complicating ARDS and DIC is poor, and these patients need systemic intensive treatment, in which m-PSL therapy may be beneficial.

Aged↗

PubMed2000

Goosecoid suppresses cell growth and enhances neuronal differentiation of PC12 cells.

In all vertebrate species, the homeobox gene goosecoid serves as a marker of the Spemann organizer tissue. One function of the organizer is the induction of neural tissue. To investigate the role of goosecoid in neuronal differentiation of mammalian cells, we have introduced goosecoid into PC12 cells. Expression of goosecoid resulted in reduced cell proliferation and enhanced neurite outgrowth in response to NGF. Expression of goosecoid led to a decrease in the percentage of S-phase cells and to upregulation of the expression of the neuron-specific markers MAP-1b and neurofilament-L. Analysis of goosecoid mutants revealed that these effects were independent of either DNA binding or homodimerization of Goosecoid. Coexpression of the N-terminal portion of the ets transcription factor PU.1, a protein that can bind to Goosecoid, repressed neurite outgrowth and rescued the proliferation of PC12 cultures. In contrast, expression of the bHLH transcription factor HES-1 repressed goosecoid-mediated neurite outgrowth without changing the proportion of S-phase cells. These results suggest that goosecoid is involved in neuronal differentiation in two ways, by slowing the cell cycle and stimulating neurite outgrowth, and that these two events are separately regulated.

Animals↗

PubMed2000

Capsaicin receptor in the pain pathway.

Capsaicin, the main pungent ingredient in 'hot' chili peppers, elicits burning pain by activating specific (vanilloid) receptors on sensory nerve endings. The cloned capsaicin receptor (VR1) is a nonselective cation channel with six transmembrane domains that is structurally related to a member of the TRP (transient receptor potential) channel family. VR1 is activated not only by capsaicin but also by increases in temperature that reach the noxious range (>43 degrees C). Protons potentiate the effects of capsaicin or heat on VR1 activity by markedly decreasing the capsaicin concentration or temperature at which the channel is activated. Furthermore, a significant increase in proton concentration (pH <5.9) can evoke channel activity at room temperature. The analysis of single-channel currents in excised membrane patches suggests that capsaicin, heat or protons gate VR1 directly. VR1 can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit pain. VRL-1, a VR1 homologue, is not activated by vanilloids or protons, but can be activated by elevation in ambient temperature exceeding 52 degrees C. These findings indicate that related ion channels may account for thermal responsiveness over a range of noxious temperature.

Animals↗

PubMed2000

Thiazolidinediones exert different effects on insulin resistance between dexamethasone-treated rats and wistar fatty rats.

We determined the in vivo effects of thiazolidinediones on insulin resistance induced by dexamethasone (Dx), as well as that observed in Wistar fatty (WF) rats, using glucose clamp technique to measure glucose uptake (Gu) and percent suppression of hepatic glucose output (HGOsup) to evaluate insulin resistance. Male Wistar rats were treated with Dx (0.5 mg/kg/day) for 7 days. Pioglitazone (P) or troglitazone (T) was coadministered orally for the same period at 10 and 200 mg/kg/day, respectively. Two, 5 and 20 mU/kg/min. of insulin infusion rates (IIR) were used. The Gu levels at clamp steady-state at IIR20 in rats treated with Dx (16.4 +/- 4.7 mg/kg/min.) were significantly lower than those in control rats (36.3 +/- 2.4). The Gu levels at the same IIR in rats coadminstered with P (19.6 +/- 3.2) and T (21.3 +/- 6.3) were slightly but significantly higher than that in rat treated with Dx. HGOsup at IIR5 in control rats (97.5 +/- 6.2%) was decreased by Dx treatment (52.1+/- 31.3). This decrease was slightly but significantly ameliorated by addition of T (78.3 +/- 12.2). The Gu levels at IIR20 in WF rats (6.6 +/- 0.9) were decreased significantly from that in lean littermates of WF (WL) rats (25.8 +/- 2.1). This attenuation of Gu increase was completely ameliorated with administration of P (20.9+/-2.8) or T (22.2+/-3.9). The HGOsup at IIR20 in WF rats (17.4 +/- 11.2) was significantly decreased from that in WL rats. Administration of P or T ameliorated this decrease completely. These results indicate that Dx induces insulin resistance by mechanisms different from those in WF rat, hence thiazolidinedione administration can be only partially useful to treat insulin resistance induced by Dx.

Animals↗

PubMed2000

Successful combined therapy of cyclophosphamide and cyclosporine for acute exacerbated interstitial pneumonia associated with dermatomyositis.

Interstitial pneumonia of polymyositis and dermatomyositis (PM/DM), especially the rapid progressive type, is a serious complication. We report a case of acute exacerbated interstitial pneumonia associated with DM. The respiratory distress condition was refractory to steroid pulse therapy and cyclosporine, however, there was a good response to additional intravenous cyclophosphamide pulse therapy (IVCY). We propose the possibility that the combination of these immunosuppressants might be useful for interstitial pneumonia with DM which is resistant to conventional steroid therapies.

Acute Disease↗

PubMed2000

Current practice of management of bacteremic sepsis: a study in a tertiary care teaching hospital in Japan.

OBJECTIVE: To investigate how patients with bacteremic sepsis are managed in a tertiary care teaching hospital. PATIENTS AND METHODS: Prospective observational study on patients with bacteremic sepsis. Clinical and microbiological characteristics of bacteremic sepsis were analyzed in relation to prognosis. Severity of the illness was quantitatively analyzed by the APACHE (Acute Physiology, Age, Chronic Health Evaluation) III scoring system. Also investigated was how closely physicians paid attention to acute physiological alterations in patients. RESULTS: The 28-day mortalities in fifty hemodynamically stable patients and in twenty-three septic shock patients were 26% and 52%, respectively (p=0.028). Gram-positive organisms accounted for 54% of all organisms, with the mortality and incidence of septic shock being the same as with Gram-negative infections. The mean APACHE III score was 42.9 in survivors, and 76.5 in non-survivors (p < 0.001). Although serum levels of C-reactive protein and acute physiology score (APS) was significantly higher in non-survivors than in survivors, the correlation with APACHE III score was more prominent in APS. The number of vital signs recorded was 1.67 in physicians and 3.6 in nurses (p < 0.001). CONCLUSIONS: The present study proved that the APACHE III score accurately discriminates between survivors and non-survivors of patients with sepsis. By addressing the need for an objective evaluation of severity of illness, it strongly recommends that physicians should be made aware of physiologically defined sepsis and that they should pay closer attention to patients' physiological alterations to identify the development of sepsis in critically ill patients.

APACHE↗

PubMed2000

Antidiuretic effects of a nonpeptide vasopressin V(2)-receptor agonist, OPC-51803, administered orally to rats.

OPC-51803 is the first nonpeptide vasopressin (AVP) V(2)-receptor-selective agonist. Its pharmacological profile, including antidiuretic action and receptor binding, was characterized using conscious Brattleboro rats with hereditary diabetes insipidus and Sprague-Dawley rats. In membrane preparations from the liver and kidney, OPC-51803 displaced the [(3)H]AVP binding to V(2)-receptors (K(i) = 49.8 +/- 8.1 nM) more greatly than that to V(1a)-receptors (K(i) = 1061 +/- 60 nM), showing a 21 times higher affinity for V(2)-receptors. At single oral doses of 0.003 to 0.3 mg/kg in female Brattleboro rats, OPC-51803 decreased urine volume (from 10.8 +/- 1.1 to 0.5 +/- 0.2 ml during 0-2 h postdosing) and increased urinary osmolality (from 114 +/- 9 to 432 +/- 114 mOsm/kg) in a dose-dependent manner. During the period of 4-week treatment with OPC-51803, significant and constant antidiuresis was observed. In male Sprague-Dawley rats with normal plasma AVP levels, OPC-51803 at 0.03 to 0.3 mg/kg also produced a dose-dependent antidiuretic action (urine volume: from 2.6 +/- 0.6 to 1.1 +/- 0.2 ml at 0-4 h postdosing). Few changes in urinary parameters, serum parameters, or plasma hormone levels were observed. OPC-51803 did not change blood pressure or heart rate, or inhibit AVP-induced pressor response even at 30 mg/kg p.o. These results demonstrate that OPC-51803 is a V(2)-selective agonist that produces a significant antidiuretic action after single and multiple oral dosing in AVP-deficient and normal AVP states. The data suggest that OPC-51803 is a useful therapeutic drug in the treatment of hypothalamic diabetes insipidus, nocturnal enuresis, and some kinds of urinary incontinence.

Administration, Oral↗

PubMed2000

[Phase I study of super high-dose chemotherapy for liver cancer with percutaneous isolated hepatic perfusion (PIHP) and peripheral blood stem cell transplantation (PBSCT)].

The aim of this study was to evaluate the phase I aspects of super high-dose chemotherapy for advanced liver cancer with combined use of PIHP and PBSCT. In 4 patients with HCC and 1 patient with colonic liver metastases, peripheral blood stem cells (PBSC) were mobilized by either i.v. infusion of ETP (180 mg/m2/day for 3 days) or i.a. infusion of doxorubicin (100-120 mg/m2). In 3 (60%) of 5 patients, PBSC for PBSCT were harvested in effective quantities (CFU-GM > or = 2 x 10(5)/kg or CD 34 positive cells > or = 2 x 10(6)/kg). In these 3 patients, a repeated PIHP with either doxorubicin, 5-fluorouracil, or CDDP was carried out 4 weeks after the 1st PIHP. Thereafter, auto-PBSCT was intravenously administered 2 days after PIHP. In the repeated PIHP treatments, although anti-cancer drugs were administered at doses equivalent to or even higher than those administered at the 1st PIHP, bone marrow suppressions were transient and well tolerated. Fatal complications were not observed in any patients. These results indicate that with the combined use of PIHP and PBSCT, high-dose regional chemotherapy of the liver can be safely repeated without systemic toxicities.

Adolescent↗

PubMed2000

[A case of renovascular hypertension with normalized blood pressure despite interval progression of stenosis of the bilateral renal arteries].

We report here a unique case of renovascular hypertension(RVH) showing spontaneously normalized blood pressure(BP) after progression of a stenosis of the renal arteries for 16 years. The patient was a 41-year-old man. At the age of 25, he developed drug-resistant hypertension with hypokalemia, hyperreninemia and severe stenosis of the right renal artery, and was diagnosed with RVH. He soon discontinued medication without medical advice. At age 40, he developed pons infarction and his aortography showed progression of the stenosis to the bilateral renal arteries. However, his BP along with the levels of plasma potassium and renin activity were normalized and his renal function was preserved. Renal scintigraphy revealed a significant size difference between the bilateral kidneys. We assume that the hypotrophic changes in the ischemic kidneys counterbalanced the reduction in renal blood flow.

Adult↗

PubMed2000

[The examinations for diffuse lung diseases].

Diffuse lung diseases show an abnormal shadow that is widely scattered on the bilateral lung fields in the chest X ray view and includes many respiratory diseases such as the infectious or the non-infectious disease; neoplasms. Among these, idiopathic pulmonary fibrosis(IPF) has been studied extensively because of its high frequency and difficulty of treatment. IPF is defined by the respiratory functions, the radiological findings, which depend on HRCT, and the histopathological evaluation by surgical lung biopsy. In particular, the histopathological appearance of usual interstitial pneumonia(UIP) is essential for the diagnosis of IPF. Most serum examinations such as angiotensin-converting enzyme, anti-nuclear antibodies are applied to rule out other diffuse lung diseases. SP-D or KL-6, which is the marker of the type II epithelial cells, is thought to be very useful for revealing the disease activity, but since it is not increased in the early stages of IPF, it is not applied in the diagnosis of IPF. The definitive serum examinations for the diagnosis or determinations of the therapeutic effect or prognosis of IPF have not been established. Easier, more useful and critical examinations including genetic diagnosis are required to manage patients with IPF.

Aged↗

PubMed1999

Roxithromycin and clarithromycin, 14-membered ring macrolides, potentiate the antitumor activity of cytotoxic agents against mouse B16 melanoma cells.

We previously reported antiangiogenic activity of roxithromycin and clarithromycin, 14-membered ring macrolide antibiotics. In the present study, we examined the antitumor effects of roxithromycin and clarithromycin, alone and in combination with several cytotoxic drugs, on mouse B16BL6 melanoma cells in vivo and in vitro. Both roxithromycin and clarithromycin potentiated the inhibition of tumor growth induced by cyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin and vindesine in vivo. However, neither roxithromycin nor clarithromycin, altered the cytotoxicity of 4-hydroperoxycyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin or vindesine in an in vitro cell proliferation assay. These results suggest that the antiangiogenic activity of roxithromycin and clarithromycin may provide beneficial effects in combination with cytotoxic therapies against solid tumors.

Animals↗

PubMed1999

GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1 binding in murine cells.

Misexpression of the dorsal mesodermal patterning factor goosecoid on the ventral side of amphibian embryos results in inhibition of blood formation in early embryogenesis. To investigate the mechanism of this inhibition, we ectopically expressed goosecoid in erythroleukemia cells. While erythroid differentiation of these cells can be induced by activin, goosecoid expressing cells were unresponsive to activin. We demonstrate an in vitro interaction between the oncogene PU.1, an ets family transcription factor thought to play a role in erythropoiesis, and the goosecoid protein (GSC). Interaction with PU.1 was specific as GSC did not bind to the ets family members, Fli-1 or Ets-2. The ability of goosecoid expressing erythroleukemia cells to differentiate in response to activin was rescued by coexpression of the GSC-binding N-terminal portion of PU.1. The N-terminal portion of PU.1 was co-immunoprecipitated with anti-GSC antibodies as well. The N-terminal domain of PU.1 is the region recognized by the retinoblastoma protein (Rb), a tumor suppressor gene presumably involved in erythroid differentiation. We show that GSC competitively inhibits binding of Rb to PU.1. Our data suggest that the suppression of blood formation by GSC could, at least in part, be mediated by binding to PU.1.

Activins↗

PubMed1999

Nitric oxide production is decreased in the brain of the seizure susceptible EL mouse.

To investigate nitric oxide production in the brain of the EL mouse, an inbred mutant strain of the ddY mouse that is susceptible to convulsive seizures, we measured whole brain nitric oxide metabolites, and counted the number of nitric oxide-producing cells in the parietal cortex and striatum. Nitric oxide metabolites in the brain and serum were determined by measuring levels of nitrite plus nitrate. Nitric oxide-producing cells were demonstrated histochemically by staining for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase. Levels of nitrite plus nitrate in the whole brain were significantly lower than those of the control mice, although levels of nitrite plus nitrate in the serum did not differ between groups. There were significantly fewer NADPH-diaphorase-positive cells in the parietal cortex and striatum of the EL mouse compared to the ddY controls. These results suggest that lower nitric oxide production in the brain may be related to the susceptibility of the EL mouse to convulsive seizures.

Animals↗