Biomedical subjects
Y Takeda
Publications and source records attributed to Y Takeda.
[Phase II study of paclitaxel (BMS-181339) in patients with ovarian cancer by 3-hour intravenous infusion].
A phase II study of Paclitaxel in patients with ovarian cancer by 3-hour intravenous infusion was undertaken by a cooperative study group of 30 institutes. Of 66 cases enrolled, 57 cases were evaluable for efficacy, and 63 cases were evaluable for safety. In spite of the fact that all cases for efficacy evaluation were previously treated with chemotherapy including platinum-based drugs, 2 cases of complete response (CR) and 15 cases of partial response (PR) were observed, with a response rate of 29.8% (The 95% confidence interval of response rate was 18.4-43.4%). Paclitaxel also showed 28.2% (11/39) response rate in patients refractory to treatment by platinum-based drugs. Histologically, the response rates were 28.9% (11/38) in serous adenocarcinoma, 40.0% (2/5) in clear cell adenocarcinoma and 25.0% (1/4) in mucinous adenocarcinoma. As the major laboratory abnormalities, leukopenia, neutropenia and decrease in hemoglobin were observed with incidence rates of 98.4% (62/63), 95.2% (59/62) and 85.7% (54/63), respectively. However, these abnormalities were clinically manageable by either withdrawal of medication, administration of antibiotics, G-CSF or metachysis etc. In addition, thrombocytopenia, elevation in GOT and GPT were seen with moderate incidence. Peripheral neuropathy was a major adverse symptom with an incidence of 79.4% (50/63), followed by alopecia, myalgia, arthralgia and fever. However, the majority of these adverse reactions were less than grade 3. From these findings, we confirmed that 3-hour intravenous infusion of Paclitaxel was a clinically useful chemotherapeutic agent in patients with ovarian cancer.
Medium-term effects of betaxolol monotherapy and combination therapy with nitrendipine on lipoprotein and apolipoprotein metabolism in patients with mild to moderate essential hypertension.
The objective of this study was to assess the medium-term effects of betaxolol, a long-acting, lipid-soluble, cardioselective, beta-adrenergic antagonist, alone and in combination with nitrendipine on blood pressure (BP) and metabolism of lipid, lipoprotein and apolipoprotein in patients with mild to moderate hypertension. Forty-seven patients (21 men, 26 women, average age 54 years) participated in an open controlled clinical trial. After a 4-week washout period, all of the patients received betaxolol monotherapy at a dose of 5-10 mg daily for 6 months (Phase I). From month 7 through month 12 (Phase II), half of the total patients (Group B, n = 23) with diastolic blood pressure (DBP) of 95 mm Hg or more at the end of Phase I were also given nitrendipine (10-20 mg, once daily), while the remaining patients (Group A, n = 24) continued to receive only betaxolol. Systolic blood pressure (SBP), DBP, and heart rate (HR) were monitored once monthly. Serum lipid profiles were measured at study entry and after 6 and 12 months of therapy. Betaxolol significantly reduced SBP, DBP, and HR in both groups during Phase I, and the reductions in SBP and DBP were markedly less in Group B than in Group A. During Phase II, the additional reduction of SBP and DBP to levels similar to those in Group A was achieved by betaxolol in combination with nitrendipine, and HR was slightly but significantly increased. Betaxolol monotherapy reduced serum levels of high density lipoprotein cholesterol (HDL-C) and increased levels of triglyceride, apolipoprotein (apo) C-II and apo C-III. Combination therapy with betaxolol and nitrendipine increased serum apo A-I but did not affect other lipid profiles. Our results indicate that betaxolol is an effective antihypertensive drug which has a preferable effect on HR and HDL profiles when combined with nitrendipine.
[T-kinin-induced increase in airway vascular permeability and its modulation by angiotensin-converting enzyme].
We studied the effect of T-kinin on airway vascular permeability and its modulation by endogenous peptidases in anesthetized rats in vivo, Vascular permeability was assessed by photometric measurement of extravasated Evans blue dye after formamide extraction. Intravenous injection of T-kinin increased dye extravasation in the trachea and main bronchi in a dose-dependent manner. Plasma extravasation evoked by T-kinin was inhibited by Hoe 140, a B2 receptor but-not by des Arg9-Leu8-bradykinin, a B1 receptor antagonist. Treatment with captopril, an angiotensin-converting enzyme inhibitor, potentiated the T-kinin-induced plasma extravasation, whereas phosphoramidon, a neutral endopeptidase inhibitor, had no effect. These results suggest that T-kinin increases airway vascular permeability via stimulation of B2 receptors, and that this effect is modulated by endogenous angiotensin-converting enzyme.
[TNF/TNFR gene and apoptosis].
Intracellular signal transduction pathways induced by in the reaction of TNF and TNF receptors has been clarified through finding of various TNF receptor associated intracytoplasmic molecules. The possible role of these signal transduction pathways for apoptosis induced by TNF is discussed.
Short-term effects of a high-sucrose diet on plasma lipid, lipoprotein cholesterol, tissue lipoprotein lipase and hepatic triglyceride lipase in rats.
Short-term (2 weeks) effects of a high-sucrose diet on plasma lipids, lipoproteins, tissue lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities were investigated in rats. Three days of sucrose feeding significantly increased plasma TG (42 +/- 3 mg/dl vs. 56 +/- 2 mg/dl, p = 0.032), while TC increased significantly after 10 days of the diet (50 +/- 2 mg/dl vs. 62 +/- 2 mg/dl, p = 0.0001). HDL-C increased significantly after 3 days of sucrose feeding (36.2 +/- 0.9 mg/dl vs. 42.4 +/- 2.7 mg/dl, p = 0.011). Although LDL-C tended to decrease on days 3, 7 and 10, these changes were not significant. The plasma glucose level did not change during the study. Increased LPL activity in adipose tissue and decreased enzyme activities in skeletal and heart muscles were observed. Adipose tissue LPL returned to the baseline value after 14 days of the diet treatment, while LPL in skeletal and heart muscles remained at the decreased level. HTGL and HTGL/total liver lipase activities were significantly increased after 14 days of the diet. The different responses of lipase activities in various tissues may help to regulate serum lipid and lipoprotein levels in sucrose-fed rats.
Comparison of the sensitivity & specificity of a polyclonal versus monoclonal capture antibody based Bead ELISA for direct detection of cholera toxin from stool specimens.
This study was conducted to examine whether substitution of polyclonal anti-CT IgG (PAb) coated beads with monoclonal anti-CT IgG, (MAb) coated beads would enhance the sensitivity and specificity of the Bead ELISA for direct detection of CT in stool samples of cholera patients. Sensitivity of MAb Bead ELISA was found to be more efficient (92.7%) than the PAb Bead ELISA (88.2%) in comparison to the 'gold standard' method of conventional culture method (CM). However, the MAb based Bead ELISA had lower specificity (45%) than that of PAb Bead ELISA (51.8%). Further, the positive predictive value was also lower in MAb Bead ELISA (69.9%) as compared to PAb Bead ELISA (82.1%). Generally, all the statistical evaluation demonstrated better agreement between PAb (77.9%) and MAb (72.6%) Bead ELISAs in direct detection of free CT and culture method in confirming the causative organism i.e., Vibrio cholerae in stool specimens. When the two assay systems, viz., PAb and MAb Bead ELISAs were compared, the superiority of the PAb Bead ELISA over MAb Bead ELISA was clearly evident as it had 82.4 per cent of agreement value.
Comparative analysis of factors promoting optimal production of cholera toxin by Vibrio cholerae O1 (classical & E1Tor biotypes) & O139.
Various culture media [AKI, Brain heart infusion broth (BHI), Casamino acid-yeast extract broth (CAYE), Casamino acid-yeast extract broth supplemented with 90 micrograms/ml of lincomycin (CAYE-L), Tryptic soy broth (TSB) and Yeast extract peptone (YEP)], cultural conditions (stationary and shaking) and incubation temperatures (30 degrees C and 37 degrees C) were evaluated to determine optimal conditions for production of cholera toxin (CT) by different biotypes (classical and E1Tor) and serogroups (O1 and O139) of V. cholerae. It was found that V. cholerae O1 E1Tor grown in CAYE-L and incubated at 30 degrees C with constant shaking was optimal for production of CT, while for the classical biotype and for the O139 serogroup, CT was maximally produced when grown in YEP and incubated at 30 degrees C in a shaker. Temperature appeared to be a prominent factor affecting the production of CT by the O1 E1Tor biotype when the media used were AKI, CAYE-L and YEP and also for the classical biotype when the media used were the AKI, BHI, CAYE and YEP. In the case of the O1 E1Tor biotype, CAYE-L was the best medium for CT production whereas for the classical biotype, CAYE-L was a poor medium as far as CT production was concerned. Irrespective of the media used, 30 degrees C shake culture condition seemed to be more favourable for supporting CT production except in CAYE medium for the O1 E1Tor biotype where incubation at 37 degrees C in a shaker was as good as incubation at 30 degrees C.
[Sarcoidosis representing multiple splenic nodules in a patient with IgA nephropathy].
We have encountered a 49-year-old female with persistent proteinuria and hematuria. Blood pressure, renal function, physical findings and chest X-p showed no abnormality, but blood tests disclosed mild thrombocytopenia, elevated serum ACE activity, serum lysozyme activity and serum IgA concentration. Abdominal echography and CT revealed multiple nodules in her spleen. In order to make a definite diagnosis and exclude the possibilities of malignant lymphoma or metastatic malignant tumor, splenectomy, and open renal biopsy were performed at the same time. On histological examinations, light microscopic appearance of the spleen was characterized by non-caseating granulomas compatible with sarcoidosis. Renal biopsy specimen showed diffuse proliferative glomerulonephritis with positive staining of IgA predominantly located in the mesangial area, compatible with IgA nephropathy. The present case may provide suggestive evidence for a link between sarcoidosis and IgA nephropathy in the pathogenesis. IgA nephropathy complicated by sarcoidosis is rare, and thus is of particular interest because common immunological abnormalities might be considered in the disease process of both diseases. We feel that despite a low index of suspicion, physicians must be alert to the possibility of IgA nephritis associated with sarcoidosis. The literature is reviewed regarding the relationship between IgA nephropathy and sarcoidosis.
[Effect of sodium cromoglycate on airway vascular leakage caused by hypertonic saline in the rat trachea].
The action of the anti-asthmatic drug sodium cromoglycate (SCG) on airway inflammation remains uncertain. Using Evans blue dye as a maker of plasma leakage, we studied the effect of SCG on neurogenic vascular extravasation evoked by hypertonic saline (HTS) in the rat trachea. Inhalation of HTS (5-15%) caused a concentration-dependent increase in plasma leakage, but inhaled 0.9% NaCl had no effect. Inhalation of SCG did not affect the baseline level of vascular permeability, but it inhibited the effect of HTS in a dose-dependent manner: plasma extravasation induced by 10% NaCl was significantly reduced by 2 minutes of inhalation of SCG at concentrations of 10 and 50 mg/ml (p < 0.05 and p < 0.01, respectively). SCG (10 mg/ml), also inhibited the changes in microvascular permeability caused by aerosols of substance P (10(-4) M), whereas it did not affect the responses to aerosols of platelet-activating factor (3 x 10(-4) M). A similar dose of SCG did not significantly alter microvascular leakage caused by 5% NaCl. However, phosphoramidon, a selective inhibitor of neutral endopeptidase, potentiated the response to 5% NaCl, an effect that was inhibited by SCG (p < 0.05). These results suggest that SCG inhibits HTS-induced airway vascular permeability, presumably through a tachykinin-antagonist-like property, and that this inhibition is exaggerated when the activity of endogenous neutral endopeptidase is low.
Effects of K(+)-channel blockers on epithelium-derived relaxing factor (EpDRF)-mediated modulation of airway smooth muscle contractility.
Airway epithelium plays a role in the regulation of bronchial smooth muscle tone releasing cyclooxygenase products and epithelium-derived relaxing factor (EpDRF). To test possible involvement of K+ channels in the action of EpDRF, we studied rabbit tracheal segments in the presence of indomethacin under isometric conditions in vitro. Mechanical removal of the epithelium increased the contractile responses to acetylcholine, so that negative logarithm of the concentration required to produce 50% of maximal effect (pD2) increased from 5.0 +/- 0.4 to 5.7 +/- 0.3 (P < 0.01). Addition of charybdotoxin per se caused a leftward shift of acetylcholine concentration-response curves in epithelium-intact tissues, but the subsequent removal of the epithelium did not further potentiated the contractile responses. In contrast, apamin or glibenclamide had no effect on the epithelium-removal-induced potentiation of the contraction. The responses to electrical field stimulation were likewise potentiated by epithelial removal, an effect that was abolished by charybdotoxin. These results suggest that Ca(2+)-activated K+ channels are involved in the EpDRF modulation of airway smooth muscle responsiveness.
[The usefulness of induced sputum in the diagnosis of pulmonary tuberculosis].
This study was designed to compare the results of culture for tubercle bacilli using induced sputum by an ultrasonic nebulizer and gastric aspirates from same patients who were suspected of having active tuberculosis with little or no sputum and had received no prior chemotherapy. 22 patients included in this series were either culture positive for tubercle bacilli or showed unequivocal radiographic improvement after three months of therapy with three anti-tuberculosis drugs. Induced sputum from 17 patients and gastric aspirates from seven patients were culture positive for M.tuberculosis. This difference is significant (p < 0.01). Paired induced sputum and gastric aspirates were both positive for tubercle bacilli in seven patients. The finding of acid-fast bacilli on microscopy or tubercle bacilli in culture in four of the seven patients were available much earlier with induced sputum than with gastric aspirates. Positive gastric aspirates and negative induced sputum for tubercle bacilli was not seen. These results suggest that induced sputum by an ultrasonic nebulizer is superior to gastric aspirates in terms of high sensitivity and early finding for tubercle bacilli and induced sputum and gastric aspirates do not supplement each other.
Growth of hepatitis A virus in murine cells.
In order to investigate the growth of hepatitis A virus (HAV) in murine cells, L929 cells of the established mouse cell line were transfected with the virion RNA or infected with the virions and examined for the formation of negative-strand RNA and the rise of the viral infectivity titer. In both the transfected and infected cells, the formation of negative-strand HAV RNA was assayed by the reverse transcription-polymerase chain reaction (RT-PCR). In the transfected cells, infectious HAV of an average titer of 10(1.8) TCID50/dish was obtained. The experiment with the virion infection was further extended by using other mouse cell lines, namely Balb/3T3 clone A31, NIH/3T3, and Swiss/3T3. Here, only NIH/3T3 cells were found capable to support the formation of negative-strand HAV RNA. Thus some murine cell lines are considered to have a complete cellular machinery for supporting the growth of HAV, though the efficiency of virus growth therein was considerably lower as compared to that in the susceptible primate cells.
Cell-adhesion proteins of the immunoglobulin superfamily in the nervous system.
The unique groups of cell-adhesion proteins, such as IgSF, play essential parts in the formation and maintenance of the nervous system. Recent crystallographic studies have revealed a possible common structure of cell-adhesion proteins. The IgSF proteins are sub-grouped into simple, complex and mixed types. Accumulating evidence reveals the importance of cell-adhesion proteins in neural morphogenesis, maintenance and regeneration. They play key roles in neuronal migration, neurite outgrowth promotion, neurite fasciculation, pathfinding, target recognition, synaptogenesis and myelination. Mutations of cell-adhesion proteins result in neurological disease; for example, mutations of PO in hereditary neuropathy and mutations of L1 in hereditary hydrocephalus, MASA syndrome and spastic paraplegia type 1. Perspectives of the studies of neural cell-adhesion proteins are discussed.
Adenomatoid odontogenic tumor with extensive formation of tubular dentin.
Although the adenomatoid odontogenic tumor (AOT) is categorized as an odontogenic epithelial tumor with odontogenic ectomesenchyme, AOT with induction of true tubular dentin with or without concomitant formation of enamel is exceedingly rare. This paper reports a case of AOT showing evidence of extensive induction of tubular dentin, but without concomitant formation of enamel. The patient was a 20-year-old female with a rather well-circumscribed intraosseous lesion of the maxillary incisor-premolar area without an embedded tooth. Histologically, extensive induction of a dysplastic form of tubular dentin with globular calcification was evident, in addition to the characteristic histological features of AOT. The present case lends support to the categorization of AOT as an odontogenic tumor consisting of a disorderly mixture of odontogenic epithelium and odontogenic ectomesenchyme with or without dental hard tissue formation.
Regulation of neutrophil apoptosis--its biological significance in inflammation and the immune response.
Neutrophils play a pivotal role in host defence against bacterial infection. Their life span is short compared with that of leukocytes of other lineages. Neutrophils are programmed to die by apoptosis at the time of differentiation. However, recent studies have demonstrated that environment also has a great influence on apoptosis of these cells. Based on our recent experimental results, we present here a review of studies on the regulation of neutrophil apoptosis and discuss its biological significance in inflammation and the immune response.
Phorbol ester and okadaic acid-resistant cells: the crossroads of signal transduction and drug resistance.
Many factors are involved in the development of drug resistance for anticancer drugs. The drugs should pharmacokinetically attain the appropriate concentration. They should be metabolized to the active forms. Tumor cells should have sensitivity to them. Several molecular and biochemical mechanisms that may explain cellular drug resistance have been identified. The contribution of protein phosphorylation and dephosphorylation for drug resistance is demonstrated in phorbol ester and okadaic-acid-resistant cells. The modulation of drug resistance by substances that affect the signal transduction pathway is an important issue in the development of an effective method for overcoming drug resistance.
Effects of estrogen and parathyroid hormone on osteoblastic activity via regulating the binding activity of insulin-like growth factor binding protein-4 in SaOS-2 cells: implications for the pathogenesis of postmenopausal osteoporosis.
The cellular mechanisms involved in the accelerated bone loss occurring in association with estrogen deprivation as seen following the menopause have not been fully understood. Insulin-like growth factor-I (IGF-I) is the local regulator of osteoblasts and one of its binding protein, insulin-like growth factor binding protein-4 (IGFBP-4), binds to IGF-I and suppresses its biological activity. We have therefore studied the effects of 17 beta-estradiol and parathyroid hormone (PTH) on binding activity of IGFBP-4 and osteoblastic activity using SaOS-2 osteoblastic cells. DNA and collagen synthesis were enhanced by IGF-I or 17 beta-estradiol and suppressed by PTH in a concentration dependent manner. The inhibitory effect of PTH on DNA and collagen synthesis was abolished by the presence of IGF-I or 17 beta-estradiol. The binding activity of IGFBP-4 was stimulated 2-fold by 10 nM PTH, while this PTH-induced IGFBP-4 production was completely inhibited by the addition of 17 beta-estradiol. The stimulated DNA and collagen synthesis by IGF-I or 17 beta-estradiol were inhibited by IGFBP-4 in a concentration dependent manner. The simplest explanation is that 17 beta-estradiol suppressed the inhibitory effect of PTH on osteoblastic activity by inhibiting the PTH-induced increment of IGFBP-4 binding activity in SaOS-2 cells.