Biomedical subjects
Publications and source records attributed to M Toyoshima.
A series of indole alkaloids of the aspidofractinine-type was assessed for their potential in reversing MDR in vincristine-resistant KB cells. Of the compounds tested, kopsiflorine, kopsamine, pleiocarpine, 11-methoxykopsilongine, lahadinine A and N-methoxycarbonyl-11,12-methylenedioxy-delta 16,17-kopsinine were found to show appreciable activity.
Four new bisindoles of the vobasine-iboga type, conodiparines A-D were obtained from Tabernaemontana corymbosa which showed appreciable activity in reversing resistance in vincristine-resistant KB cells.
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by progressive ataxia, telangiectasia, sinopulmonary infections, hypersensitivity to ionizing radiation, and combined immunodeficiency. Recently, the AT gene (ATM) was cloned and shown to be mutated in AT patients. In this report, mutation analysis of ATM was performed in a 24-year-old AT patient without immunodeficiency. ATM amplified with reverse transcriptase-polymerase chain reaction (RT-PCR) was screened with a ribonuclease (RNase) cleavage assay and auto-sequenced. This patient, a compound heterozygote, showed two mutations in ATM: one missense mutation leading to a Leu2656Pro substitution and the other to the truncation at codon 3047 (Arg-->ter). The latter mutation is within the phosphatidylinositol 3-kinase (PI 3-kinase)-like domain and the former is outside but close to the domain. The particular phenotype in our patient, no immunodeficiency, suggests incomplete functional loss of ATM protein. The clinical spectrum of AT caused by ATM mutations may be broader than previously thought. Further analysis of patients with similar phenotypes will make the relation between ATM genotype and phenotype clear.
The EtOH extract of the leaves of Holarrhena curtisii yielded five new steroidal alkaloids: 17-epi-holacurtine (3), 17-epi-N-demethylholacurtine (4), holacurtinol (5), 3alpha-amino-14beta-hydroxypregnan-20-one (7), and 15alpha-hydroxyholamine (8), in addition to the known compounds, holacurtine (1), N-demethylholacurtine (2), and holamine (6). All eight compounds showed significant cytotoxic and leishmanicidal activities.
We have investigated the effect of calcium spirulan (Ca-SP) isolated from a blue-green alga, Spirulina platensis, which is a sulfated polysaccharide chelating calcium and mainly composed of rhamnose, on invasion of B16-BL6 melanoma, Colon 26 M3.1 carcinoma and HT-1080 fibrosarcoma cells through reconstituted basement membrane (Matrigel). Ca-SP significantly inhibited the invasion of these tumor cells through Matrigel/fibronectin-coated filters. Ca-SP also inhibited the haptotactic migration of tumor cells to laminin, but it had no effect on that to fibronectin. Ca-SP prevented the adhesion of B16-BL6 cells to Matrigel and laminin substrates but did not affect the adhesion to fibronectin. The pretreatment of tumor cells with Ca-SP inhibited the adhesion to laminin, while the pretreatment of laminin substrates did not. Ca-SP had no effect on the production and activation of type IV collagenase in gelatin zymography. In contrast, Ca-SP significantly inhibited degradation of heparan sulfate by purified heparanase. The experimental lung metastasis was significantly reduced by co-injection of B16-BL6 cells with Ca-SP. Seven intermittent i.v. injections of 100 microg of Ca-SP caused a marked decrease of lung tumor colonization of B16-BL6 cells in a spontaneous lung metastasis model. These results suggest that Ca-SP, a novel sulfated polysaccharide, could reduce the lung metastasis of B16-BL6 melanoma cells, by inhibiting the tumor invasion of basement membrane probably through the prevention of the adhesion and migration of tumor cells to laminin substrate and of the heparanase activity.
In the course of our screening for compounds that reverse multidrug resistance, we found that the cytotoxicity of vincristine was enhanced 1.5-20-fold depending on the concentration of andrastin A in vincristine-resistant KB cells (VJ-300). Andrastin A alone had no effect on the growth of drug sensitive KB cells and VJ-300 cells. On the other hand, andrastin A (25 and 50 micrograms/ml) significantly enhanced accumulation of [3H]vincristine in VJ-300 cells. Andrastin A (50 micrograms/ml) completely inhibited the binding of [3H]azidopine to the P-glycoprotein in VJ-300 cells. The result suggests that andrastin A directly interacts with P-glycoprotein and inhibits the efflux of antitumor agents in drug resistant cells.
Pharmacist's instruction is provided to asthmatic patients who received an inhaled steroid in Hamamatsu University Hospital. We studied influences of pharmacist's instruction on the repeutic effects of an inhaled steroid, beclomethasone dipropionate (BDP). In 29 patients who had been treated with inhaled BDP under the physician's instruction for more than 3 months, we examined drug compliance, correctness of inhalation procedure and treatment score, symptom score, peak expiratory flow (PEF) values, and compared these before and after the instruction. The instruction was repeatedly provided at an interval of about one month. Patients who followed the indicated regimen were 55.2 and 93.1% before and after the instruction, respectively. An appropriate inhalation maneuver was respectively. An appropriate inhalation maneuver was performed in 24.1 and 93.1% of patients before and after the instruction, respectively. PEF values increased by 12.9 +/- 9.3% (mean +/- standard deviation, p < 0.01) after the instruction. In conclusion, pharmacist's repeated instruction enhanced the therapeutic effects of inhaled BDP in patients with asthma.
We describe a 57-year-old man with interstitial pneumonia associated with systemic sclerosis. About 3 years prior to the appearance of distinctive signs of systemic sclerosis, he was admitted to our hospital with a chronic dry cough. A chest roentgenogram on admission revealed reticulonodular shadows in both lung fields. There were no abnormal laboratory findings. Open lung biopsy specimens revealed patterns indicative of usual interstitial pneumonia, and myxomatous connective tissue within the lumen of the airways. Skin biopsy specimens showed heightened levels of collagen in the dermis, a finding consistent with systemic sclerosis. The patient was given a diagnosis of lung involvement preceding systemic sclerosis despite the absence of concurrent skin symptoms.
Cardiopulmonary bypass (CPB) is associated with a whole body inflammatory response which may have detrimental consequence resulting in post perfusion syndrome. Adhesion molecule E-selectin plays a pivotal role in the inflammatory response, especially in the interaction of endothelium and neutrophils. Soluble form of E-selectin (sE-selectin) is thought to be a marker of endothelial activation. To evaluate the activation of endothelium during CPB with heparin coated and un-coated extracorporeal circuits, we measured plasma levels of sE-selectin, tumor necrosis factor alpha (TNF alpha), and neutrophil elastase in 16 patients having coronary artery bypass grafting. sE-selectin plasma concentration increased during or after CPB. Significantly lower maximum levels of sE-selectin are observed in patients perfused with heparin coated extracorporeal circuits. Maximum values of sE-selectin correlated with plasma levels of TNF alpha and neutrophil elastase in each patient. These observations suggest that endothelium is activated by extracorporeal circulation in cardiac surgery, and this activation was attenuated by heparin coating of extracorporeal circuits.
We studied clinicopathological characteristics of interstitial pneumonia associated with amyopathic dermatomyositis. The subjects comprised two men and three women, and their mean age was 58.2 years. All subjects had cruptions specific for dermatomyositis, but had no signs of myositis. They all presented with acutely or subacutely developed coughing and dyspnea. Results of tests for anti-Jo-1 antibody were negative in all cases. Chest X-ray films showed infiltrations or streaky shadows, or both in the middle and lower lung fields. Analysis of bronchoalveolar lavage fluid revealed abnormally high percentages of lymphocytes and neutrophils. In one patients a specimen obtained by open lung biopsy showed homogeneous cell infiltrations in alveolar septa and regional alveolar damage. That patient was successfully treated with cyclosporin and corticosteroids in early phase of the disease. The other four patients received immunosuppressive agents after respiratory failure developed. All four died despite having received high-dose corticosteroid and immunosuppressive therapy. Examination of autopsy specimens showed diffuse alveolar damage.
We studied the clinical characteristics of pneumonitis induced by Sho-saiko-to (SST). Of 94 cases reported to a drug maker, 72 were judged to be SST-induced pneumonitis (52 men and 20 women, mean age 63.7 years). Most patients took SST for chronic liver diseases due to infection with the hepatitis C virus. The mean duration of SST therapy before the onset of pneumonitis was 50.2 +/- 42.1 days. Most patients presented with coughing, dyspnea, and fever of acute onset. Chest X-ray films showed diffuse ground-glass shadows and infiltration. Abnormally high levels of C-reactive protein and lactate dehydrogenase were common, as was hypoxia. Analysis of bronchoalveolar lavage fluid revealed abnormally high percentages of lymphocytes and neutrophils and a low CD4/CD8 ratio. Although 64 of 72 patients survived after cessation of SST only or steroid therapy, 8 died of respiratory failure despite high-dose steroid therapy. Compared with patients who survived those who died were more likely to have an underlying lung disease, had been taking SST longer after the onset of pneumonitis, and had more severe hypoxemia.
For 120 young patients who had undergone reconstruction of anterior cruciate ligament of the knee, we investigated the effect of epidural administration of buprenorphine on the incidence of nausea or vomiting, and the anti-emetic effect of epidural administration of droperidol. In the group who had received bolus injection of buprenorphine 0.1 mg, nausea or vomiting occurred early most often, and the injection was not useful to prolong analgesic effect. In the another group who had received continuous epidural infusion of buprenorphine 0.3 mg, nausea or vomiting occurred late. Bolus injection of droperidol 2.5 mg was not useful to prevent nausea or vomiting caused by continuous epidural infusion of buprenorphine. While, continuous infusion of droperidol 5 mg was effective in decreasing nausea or vomiting caused by continuous epidural infusion of buprenorphine. In conclusion, continuous epidural administration of droperidol is useful to prevent nausea or vomiting.
OBJECTIVE: To compare values measured by a continuous intra-arterial blood gas monitoring system with those measured by conventional blood gas analyzer for the assessment of the clinical performance of a new device for measurement of PaO2, PaCO2, and arterial pH. METHODS: Forty-six patients undergoing cardiopulmonary bypass were enrolled in this study. All patients had a continuous intra-arterial sensor (PB 3300) placed into the radial artery through a 20-gauge catheter. A total of 319 arterial blood gas and pH values were obtained for comparison with a conventional blood gas analyzer. The measurements were performed every 12 hrs after the initial in vitro calibration of the sensor for each patient. RESULTS: Measurements were made over a range of 12 to 192 hrs. The overall bias and precision determined by the two methods were 4.5 and 17.1 mmHg for PaO2; 4.5 and 6.2 mmHg for PaCO2; and 0.009 and 0.035 for pH, respectively. For the range of PO2 less than 150 mmHg, the bias and precision improved to 4.2 and 9.5 mmHg. The sensor-derived PCO2 value, PCO2 (IABG), increased significantly more than the conventional blood gas analysis value, PCO2(ABG), even within 72 hrs (2.8 and 4.1 mmHg). The relationship between the two measurements can be described as: PCO2(IABG)/PCO2(ABG) = 1 + 0.0026.t where t is the time period of use (in hours). By correcting the PCO2(IABG) value using this formula, the overall bias and precision of the values measured by two methods decreases to -0.4 and 3.6 mmHg. CONCLUSIONS: The PO2 and pH values derived from an intra-arterial blood gas monitoring system agreed well with the values measured by a conventional blood gas analyzer. However, the PCO2 value must be corrected due to an increase of drift, especially with extended use for more than 72 hours.
BACKGROUND: Although the pathogenesis of acute eosinophilic pneumonia remains largely unknown, it has been suggested that it may include a hypersensitivity phenomenon induced by inhaled environmental antigens. METHODS: To investigate this possibility, we studied the effect of environmental challenges in three patients with acute eosinophilic pneumonia. Symptoms and laboratory findings were evaluated before and after the challenge tests in the patient's homes and their places of work. RESULTS: After the provocation challenges to their homes, all three patients developed fever, cough, and fatigue and two of them presented with dyspnea. Inspiratory crackles became audible in all cases, and there was a decreased Pao2 level in two. Similar challenges at their workplaces were negative. After moving out of their homes, the patients engaged in their usual work but had no recurrent episodes. CONCLUSIONS: These results suggest that environmental factors in the home can be the cause of acute eosinophilic pneumonia. In order to elucidate the pathogenesis of the disease, it is important to further investigate environmental factors.
BACKGROUND: Cardiopulmonary bypass (CPB) causes a systemic inflammatory response. TNF alpha, which is a major inflammatory mediator, has been found in the circulation during and after CPB. Although previous studies have shown that heparin coating of the extracorporeal circuits reduces complement and granulocyte activation, and the inflammatory response, the possible effect of heparin coating on TNF alpha formation and the inflammatory response has not been fully investigated. METHODS: Eighteen patients scheduled for coronary artery bypass grafting were divided randomly into two groups. One group of patients had extracorporeal perfusion using heparin coated circuits (HC group, n = 9). The other group had extra-corporeal perfusion using an identical circuit that was not coated (UC group, n = 9). Blood samples were drawn before, during, and after CPB for measurement of plasma TNF alpha, plasma IL-8, neutrophil count, and neutrophil elastase. RESULTS: Plasma levels of TNF alpha increased during CPB in the UC group but not in the HC group. Plasma concentrations of IL-8 increased similarly during and after CPB in both groups. Coating the circuits with heparin did not affect the levels of IL-8. In both groups, the neutrophil count increased after the release of the aortic cross clamp and remained elevated for three days. In the HC group, however, the increase of neutrophil count was significantly lower compared with the UC group. Plasma concentrations of neutrophil elastase were significantly increased during and after CPB in both groups. However, the levels of elastase were significantly lower at certain time points in the HC group. CONCLUSION: From these observations, we conclude that heparin coating of the extracorporeal circuits reduces the TNF alpha formation during CPB, which may reduce neutrophil activation.
The pulmonary manifestations of rheumatoid arthritis (RA) include bronchiolar diseases such as follicular bronchiolitis (FB) and bronchiolitis obliterans (BO). In this study, we investigated the clinical and pathologic features of FB and BO, as well as the effect of erythromycin (EM) on these diseases. The subjects included 15 RA patients with biopsy-proven bronchiolar disease (eight with FB, seven with BO). None of the patients had Sjögren's syndrome. Eleven patients (73%) had chronic sinusitis, and 14 (93%) had a chronic cough with sputum. Bacterial culture of sputum was positive in 50% and 71% of the FB and BO patients, respectively. High-resolution computed tomography (HRCT) revealed small nodular shadows in the centrilobular regions (FB and BO), patchy areas of low attenuation (BO), and peribronchial thickening (FB and BO). Eleven patients who received EM therapy showed a significant improvement of symptoms. In addition, none of the 15 patients died of the bronchiolar disease during follow-up. In conclusion, RA patients with FB or BO basically have a chronic clinical course with main complaint of productive cough, and EM may be useful for the management of these diseases.
We studied the clinical features of minocycline-induced pneumonitis in seven patients. Acute symptoms included fever, dry cough and dyspnea, indicating acute respiratory failure. Diffuse ground glass shadows with Kerley's B lines, bronchial wall thickening, swelling of vascular bundles and pleural effusion were visible on radiography. Bronchoalveolar lavage or transbronchial lung biopsy confirmed pulmonary eosinophilia. Cessation of minocycline led to rapid remission with no treatment or only short-term steroid therapy. The lymphocyte stimulation test for minocycline with peripheral blood lymphocytes was not found to be useful for diagnosis.
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