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Y Sawada

Publications and source records attributed to Y Sawada.

At least 37 records · Page 2Linked to original sources
PubMed2001

Possibility of the reversal of multidrug resistance and the avoidance of side effects by liposomes modified with MRK-16, a monoclonal antibody to P-glycoprotein.

For cancer chemotherapy, avoiding the side effects of chemotherapeutic agents is difficult. Multidrug resistance is one of the major obstacles to successful cancer chemotherapy. P-Glycoprotein (P-gp) serves as an efflux pump and plays a key role in the multidrug resistance. We examined the effect of MRK-16, a monoclonal antibody against P-gp, modified liposomes (MRK-Lip) on the human myelogenous leukemia K-562 cells and its adriamycin resistance cell line K-562/ADM cells to avoid the side effects and to reverse the multidrug resistance. The uptake of vincristine (VCR) by K-562/ADM cells was lower than that by K-562 cells. This low uptake was increased in the presence of verapamil and MRK-16, however, it was not increased in the presence of control antibody, IgG2A. The binding of MRK-Lip to K-562/ADM cells was higher than that of IgG2A-modified liposome (IgG-Lip) and liposome without modification (Cont-Lip). Moreover, the cytotoxicity of VCR-encapsulated MRK-Lip to K-562/ADM cells was higher than that of VCR-encapsulated IgG-Lip and Cont-Lip. These results suggest that the interaction between liposomes and multidrug resistance cells was increased by the modification of liposomes with MRK-16. Consequently, the usefulness of MRK-Lip in cancer chemotherapy as a potent carrier was suggested.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Significance of chymase-dependent angiotensin II-forming pathway in the development of vascular proliferation.

BACKGROUND: Vascular tissues of humans and dogs contain chymase as an angiotensin II-forming enzyme. In this study, we investigated whether chymase-dependent angiotensin II formation plays a crucial role in the development of vascular proliferation in dog grafted veins. METHODS AND RESULTS: The right external jugular vein of dogs was grafted to the ipsilateral carotid artery. As a control group, the right external jugular veins in dogs that had not received grafts were used. In the chymase inhibitor-treated group, the vein was infiltrated with 10 micromol/L Suc-Val-Pro-Phe(P)(OPh)(2) and was grafted to the carotid artery. In the placebo-treated group, ACE activity in the grafted veins was significantly lower than that in the control veins up to 7 days after the operation, whereas chymase activity was increased significantly. After 7 days, the mRNA levels of collagen I, collagen III, and fibronectin, all of which are induced by an increase of angiotensin II action, were significantly increased in the grafted veins, and the intima-media ratio of the grafted veins was also increased. In the chymase inhibitor-treated group, the chymase activity in the grafted veins 7 days after the operation was suppressed to 12.1%. The elevated mRNA levels of fibronectin, collagen I, and collagen III in the grafted veins were significantly suppressed by treatment with the chymase inhibitor, and the intima-media ratio was also decreased significantly. CONCLUSIONS: We demonstrate for the first time that chymase-dependent angiotensin II formation plays an important role in the development of vascular proliferation in the grafted veins.

Angiotensin II↗
PubMed2001

Effects of noise coherence on stochastic resonance enhancement in a bithreshold system.

We identify a method for optimizing the stochastic resonance (SR) in a symmetric bithreshold device: by varying the coherence of the added noise series. To show SR enhancement via this method, we compare the performance of the system using noise sources with different coherence at normalized amplitude. The normalization of the noise amplitude is based on the mean threshold crossing rate of the Gaussian white noise, which is considered as the standard noise in SR studies, at optimal variance. The amplitude for optimal performance of the Gaussian white noise is determined using a signal-to-noise ratio (Q). The Q measure is also used to compare and examine the system performance for different noise cases. This measure is used because it is particularly sensitive to the effects of coherence on the quality of the output power spectrum.

Journal Article↗
PubMed2001

Uptake mechanism of valproic acid in human placental choriocarcinoma cell line (BeWo).

Valproic acid is an anticonvulsant widely used for the treatment of epilepsy. However, valproic acid is known to show fetal toxicity, including teratogenicity. In the present study, to elucidate the mechanisms of valproic acid transport across the blood-placental barrier, we carried out transcellular transport and uptake experiments with human placental choriocarcinoma epithelial cells (BeWo cells) in culture. The permeability coefficient of [3H]valproic acid in BeWo cells for the apical-to-basolateral flux was greater than that for the opposite flux, suggesting a higher unidirectional transport in the fetal direction. The uptake of [3H]valproic acid from the apical side was temperature-dependent and enhanced under acidic pH. In the presence of 50 microM carbonyl cyanide p-trifluoromethoxylhydrazone, the uptake of [3H]valproic acid was significantly reduced. A metabolic inhibitor, 10 mM sodium azide, also significantly reduced the uptake of [3H]valproic acid. Therefore, valproic acid is actively transported in a pH-dependent manner on the brush-border membrane of BeWo cells. Kinetic analysis of valproic acid uptake revealed the involvement of a non-saturable component and a saturable component. The Michaelis constant for the saturable transport (K(t)) was smaller under acidic pH, suggesting a proton-linked active transport mechanism for valproic acid in BeWo cells. In the inhibitory experiments, some short-chain fatty acids, such as acetic acid, lactic acid, propanoic acid and butyric acid, and medium-chain fatty acids, such as hexanoic acid and octanoic acid, inhibited the uptake of [3H]valproic acid. The uptake of [3H]valproic acid was also significantly decreased in the presence of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, salicylic acid and furosemide, which are well-known inhibitors of the anion exchange system. Moreover, p-aminohippuric acid significantly reduced the uptake of [3H]valproic acid. These results suggest that an active transport mechanism for valproic acid exists on the brush-border membrane of placental trophoblast cells and operates in a proton-linked manner.

3-O-Methylglucose↗
PubMed2001

Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation.

Cells differentiate in response to various extracellular stimuli. This cellular response requires intracellular signaling pathways. The mitogen-activated protein (MAP) kinase cascade is a core signal transduction pathway that determines the fate of many kinds of cell. MAP kinase kinase kinase activates MAP kinase kinase, which in turn activates MAP kinase. Apoptosis signal-regulating kinase (ASK1) was identified as a MAP kinase kinase kinase involved in the stress-induced apoptosis-signaling cascade that activates the SEK1-JNK and MKK3/MKK6-p38 MAP kinase cascades. Expression of the constitutively active form of ASK1 (ASK1-DeltaN) in keratinocytes induced significant morphological changes and differentiation markers, transglutaminase-1, loricrin, and involucrin. A transient increase in p21(Cip1/WAF1) reduced DNA synthesis, and cell cycle analysis verified the differentiation. p38 MAP kinase inhibitors, SB202190 and SB203580, abolished the induction of differentiation markers, transglutaminase-1, loricrin, and involucrin. In turn, the induction of differentiation with ceramide in keratinocytes caused an increase in ASK1 expression and activity. Furthermore, normal human skin expresses ASK1 protein in the upper epidermis, implicating ASK1 in in vivo keratinocyte differentiation. We propose that the ASK1-p38 MAP kinase cascade is a new intracellular regulator of keratinocyte differentiation.

Cell Differentiation↗
PubMed2001

Serum levels of fluconazole in patients after cytotoxic chemotherapy for hematological malignancy.

We performed a prospective evaluation of pharmacokinetics of fluconazole administered for prophylactic purposes to 19 patients after cytotoxic chemotherapy for hematological malignancies. On days 7 and 15, we obtained 5 ml of blood from each patient. If fluconazole was administered orally, blood samples were drawn 2, 8, and 24 hr after ingestion of the drug. If it was administered intravenously, blood samples were drawn 1, 8, and 24 hr post-injection. Serum fluconazole levels were analyzed by HPLC with ultraviolet light detection. In patients receiving 200 or 400 mg of fluconazole per day, maximal serum levels were 7.9 and 15.6 mg/l and minimum levels were 5.0 and 10.3 mg/l, respectively. There was no significant difference in serum fluconazole levels comparing the levels after oral and intravenous administration, and pharmacokinetic parameters of fluconazole were comparable at each time point within one dose level. However, considerable variation in serum fluconazole levels was noted in this study, as the maximal serum levels ranged from 4.0 to 13.3 mg/l and from 8.7 to 26.9 mg/l in patients receiving 200 and 400 mg of fluconazole orally, respectively. These variations may be associated with prophylactic failures for patients with insufficient fluconazole concentrations. Multiple regression analysis showed significant correlation between serum fluconazole levels and some variables including dose of fluconazole, age, serum aspartate aminotransferase levels and blood urea nitrogen levels. These variations may be associated with disturbance of body water balance, such as massive hemorrhage and dehydration.

Adult↗
PubMed2001

Transcellular transport of genistein, a soybean-derived isoflavone, across human colon carcinoma cell line (Caco-2).

Genistein, a soybean-derived isoflavone, is thought to have an anticarcinogenic action, but little is known about the cellular mechanisms of its intestinal absorption. This study was designed to investigate the absorption mechanisms of genistein using human colon carcinoma cell line, Caco-2 cells. The apical-to-basolateral transcellular transport of genistein across a Caco-2 cell monolayer was significantly greater than that in the opposite direction. An uptake experiment revealed that cellular uptake of genistein by Caco-2 cells was concentrative. The transcellular transport of genistein was saturable and temperature-dependent, and was inhibited by other flavonoids such as rutin, quercetin, (+)-catechin and (-)-epicatechin. These results suggest that genistein is transported across Caco-2 cells by a carrier-mediated system, located on the apical membrane.

Antineoplastic Agents↗
PubMed2001

Normalized pulse volume (NPV) derived photo-plethysmographically as a more valid measure of the finger vascular tone.

Normalized pulse volume (NPV) was advocated as a more valid measure for the assessment of finger vascular tone. Based on the optical model in the finger tip expressed by Lambert--Beer's law, NPV is expressed as Delta I(a)/I. Here, Delta I(a) is the intensity of pulsatile component superimposed on the transmitted light (I). Theoretically, NPV seems to be superior to the conventional pulse volume (PV; corresponding to Delta I(a)). Firstly, NPV is in direct proportion to Delta V(a), which is the pulsatile component of the arterial blood volume, in a more exact manner. Relatedly, NPV can be processed as if it is an absolute value. Secondly, the sensitivity of NPV during stressful stimulations is expected to be higher. These expectations were supported experimentally using 13 male students. Firstly, the correlation between cutaneous vascular resistance in the finger tip (CVR) and NPV was higher than that between CVR and PV among all the subjects, although there was not much difference between these correlations within each subject. Secondly, NPV decreased much more than PV during mental stress. Some limitations of the present study were addressed, including the point that certain factors can violate the direct proportional relationship of NPV and PV to Delta V(a).

Adult↗
PubMed2001

PTHrP increases pancreatic beta-cell-specific functions in well-differentiated cells.

Parathyroid hormone-related protein (PTHrP) is reportedly produced in normal islets and insulinomas. PTHrP induces differentiation in some cell-types and growth in others. We examined whether PTHrP production is greater in well-differentiated or growing beta cells and whether PTHrP induces differentiation or growth in beta cells. We used four groups of the well-differentiated mouse beta cell line MIN6 with 17, 25, 31 and 41 passages, and mouse pancreatic islets. With passage, insulin content diminished, whereas the expression of PTHrP, its activating enzyme furin and cell growth gradually increased. PTHrP increased insulin content and mRNA levels more in MIN6-17 cells than in MIN6-41 cells. In contrast, PTHrP increased DNA synthesis more extensively in MIN6-41 cells than in MIN6-17 cells. Dibutyryl cAMP reproduced PTHrP's effect on insulin content and DNA synthesis. We conclude that PTHrP increases insulin expression in well-differentiated beta cells through the cAMP pathway and stimulates growth in growing beta cells.

Animals↗
PubMed2001

Quantitative relationship between myocardial concentration of tacrolimus and QT prolongation in guinea pigs: pharmacokinetic/pharmacodynamic model incorporating a site of adverse effect.

Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration-response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (Emax) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The Emax model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QTprolongation. Such a hysteresis pattern for QTprolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.

Animals↗
PubMed2001

Cell type proportioning in Dictyostelium slugs: lack of regulation within a 2.5-fold tolerance range.

The proportion of prestalk and prespore cells in Dictyostelium discoideum slugs is often cited as an example of "almost perfect" regulation. The pattern is similar over a very wide range of cell number; furthermore, removal of either of the cell types leads to compensatory transdifferentiation. Several studies of Dictyostelium fruiting bodies, however, have suggested that proportioning in Dictyostelium differs systematically from true constancy. We have confirmed this in the slug stage using a short-lived beta-galactosidase as a reporter of the prestalk specific ecmA gene expression: the prestalk proportion decreases from 24+/-5% in slugs of 10(3) cells to 10+/-3% when 10(5) cells are present. Regeneration experiments suggest that this difference is not due to a modulation of the proportioning set-point by size, as one might have expected; instead there appears to be a regulatory "tolerance zone" at all sizes. After amputation of the whole posterior region, transdifferentiation stops after the fraction of prestalk has been reduced from 100% to 28+/-20%, well above the initial value of 10+/-3%, while after anterior removal the transdifferentiation endpoint is about 10%. Most strikingly, we find no regulation at all after partial amputations of the prespore region. It seems that any prestalk proportion is stable between a approximately 10% lower threshold and a approximately 30% upper threshold. To explain this, we propose a regulation mechanism based on a negative feedback plus cell type bistability. In both intact and regenerating slugs we find that the slug morphology is regulated so that the length-to-width ratio of the anterior region is constant.

Amputation, Surgical↗
PubMed2001

Primary retroperitoneal ganglioneuroblastoma in an adult.

A case of retroperitoneal ganglioneuroblastoma in a 60-year-old man is reported. This retroperitoneal tumor was surgically removed and pathologic diagnosis was ganglioneuroblastoma. Ganglioneuroblastoma usually occurs in children and is extremely rare in adults. The characteristics are described of an unusual tumor based on the published reports.

Ganglioneuroblastoma↗
PubMed2001

A new operative method of correcting cryptotia using large Z-plasty.

A large Z-plasty on the postauricular surface of the ear has been used for successful reconstruction of cryptotia. This technique provides extensive skin coverage of the posterior auricle without skin grafting. The technique is easy and simple. The natural hairline is not disturbed and the temporoauricular sulcus is emphasised. Almost all of the scar is hidden behind the auricle. It has been performed on 17 patients with no recurrence of the cryptotia. One patient had partial congestion in the cranial-flap tip, which improved within 1 week. There were no other complications.

Child↗
PubMed2001

Retroauricular flap: its clinical application and safety.

We report the application and safety of the retroauricular flap in 38 cases. The flap was used on the anterior auricular surface in 21 cases, in the peri-auricular region in five cases, in the region of the preauricular sideburn area in two cases, in the malar region in six cases, in the eyelid in three cases and in the intraorbital region in one case. When this flap was used in the auricular or periauricular region, the blood circulation was safe and the appearance was aesthetically good in flaps pedicled by the postauricular vessels or by the superficial temporal vessels. However, when the defect was more remote from the auricle, the blood circulation of the flaps pedicled by superficial temporal vessels, whether subcutaneous pedicle flaps or free flaps, was unstable. In some cases there was extensive or partial necrosis of the distal area of the flap. On the other hand, the free flaps pedicled by the postauricular vessels had satisfactory blood circulation, but the vessels were sometimes short, narrow and difficult to find, especially the veins. In these cases, we were obliged to use the superficial temporal vessels. A further problem is that some of the patients, especially younger women, were dissatisfied when the retroauricular flap was used in the malar region because of the reddish colour of the flap.

Adolescent↗
PubMed2001

Chymase-dependent angiotensin II formation in the saphenous vein versus the internal thoracic artery.

OBJECTIVES: The great saphenous vein graft is known to be less patent than the internal thoracic artery graft. Recently, we reported that chymase-dependent angiotensin II formation plays an important role in the development of intimal hyperplasia in dog grafted veins. In this study we investigated the levels of angiotensin II-forming enzymes, angiotensin-converting enzyme, and chymase in human saphenous veins and internal thoracic arteries. METHODS: The saphenous vein and internal thoracic artery specimens were obtained from coronary artery bypass grafts of patients during surgical procedures (saphenous vein, n = 16; internal thoracic artery, n = 16). Activities of angiotensin-converting enzyme and chymase were determined by using the extract from the saphenous vein or internal thoracic artery. Sections of the saphenous vein or internal thoracic artery were stained with van Gieson's elastin stain and were immunostained with anti-human chymase antibody. RESULTS: The activities of angiotensin-converting enzyme in the saphenous vein and internal thoracic artery were 0.34 +/- 0.12 and 0.32 +/- 0.17 mU/mg protein, respectively, and the difference was not significant. The chymase activity in the saphenous vein was significantly higher than that in the internal thoracic artery (saphenous vein, 10.1 +/- 0.81 mU/mg protein; internal thoracic artery, 6.21 +/- 1.86 mU/mg protein). Chymase-positive cells in the saphenous vein were located in both the media and adventitia, and those in the internal thoracic artery were located only in the adventitia. The number of chymase-positive cells in the saphenous vein was about 2.6 times that in the internal thoracic artery. CONCLUSION: The chymase activity, but not the angiotensin-converting enzyme activity, was significantly higher in the saphenous vein, suggesting that the high levels of chymase activity may be related to the poorer performance of the saphenous vein for use as a bypass conduit.

Aged↗
PubMed2001

Reconstruction of a subtotally amputated auricle: a case report.

A 42-year-old woman presented with a subtotal amputation of the left auricle except for the helical skin. The treatment was by primary suture with debridement of some margins, and the auricle healed well. The fact that the treatment was successful without microvascular anastomoses is important, considering the anatomical features of the auricular vascular networks.

Adult↗
PubMed2001

Assessment of systemic adverse reactions induced by ophthalmic beta-adrenergic receptor antagonists.

To assess quantitatively the risks of ophthalmic beta-blocking agents for cardiovascular and respiratory adverse reactions, we analyzed the binding kinetics of beta-blocking agents to the beta-1 and beta-2 adrenoceptors. The relationship between the occupancies for beta-1 and beta-2 adrenoceptors and the effects on the exercise pulse rate or the forced expiratory volume in one second (FEV1) after topical administration of carteolol, befunolol, timolol and betaxolol was analyzed using a ternary complex model. The beta-1 and beta-2 receptor occupancies after ophthalmic administration were calculated to be quite high as well as those after oral administration. The maximum occupancies for beta-1 and beta-2 receptors after ordinary ophthalmic administration were 52% and 88% for carteolol, 52% and 61% for befunolol, 62% and 82% for timolol, and 44% and 3% for betaxolol, respectively. Concave relationships were obtained between a decrease in exercise pulse rate and the beta-1 receptor occupancy and between a decrease in FEV1 and beta-2 receptor occupancy, respectively. Nasolacrimal occlusion was estimated to decrease the exercise pulse rate and FEV1 by 65% and 50%, respectively. The beta-1 and beta-2 adrenoceptor occupancies were proved to be the most appropriate indicators for cardiac and pulmonary adverse reactions evoked by ophthalmic beta-blocking agents.

Administration, Oral↗