Biomedical subjects

T Uematsu

Publications and source records attributed to T Uematsu.

At least 37 records · Page 2Linked to original sources

PubMed2001

Measurement of flecainide in hair as an index of drug exposure.

We report a method for measuring the concentration of flecainide in hair. An animal study, in which flecainide (1, 5, and 10 mg/kg/day) was orally administered for 1, 2, and 3 weeks to pigmented rats, showed that flecainide concentration in rat hairs newly regrown after administration significantly correlated with both the daily dose and the dosing period. The part of hair containing flecainide continued to grow upward, retaining the drug within the hair structure that had been formed at the time of drug exposure. Flecainide was also determined in human scalp hairs collected from patients treated with flecainide. The drug content of white hairs was much less than that black hairs collected from the same rats and subjects, suggesting the determinant effect of hair pigment on flecainide accumulation in hair. These findings suggest that the analysis of flecainide in hair may be useful for assessing exposure to drug qualitatively.

Animals↗

PubMed2001

Staging of palpable T1-2 invasive breast cancer with helical CT.

BACKGROUND: The purpose of this study was to evaluate the accuracy of contrast-enhanced high resolution helical computed tomography (CT) for assessing locoregional staging of palpable T1-2 invasive breast cancer. METHODS: Helical CT studies of 156 lesions from 156 patients with invasive breast cancer before breast-conserving surgery were examined. A lesion was defined as positive if focal enhancement was detected by CT within 100 seconds after contrast material administration. After resection, tumors were histopathologically mapped and comparison made with the extent of contrast enhancement. RESULTS: Helical CT enabled detection of all 156 index tumors. CT enabled detection of 28 of 43 multifocal lesions (65%) and five of five multicentric lesions (100%). In 24 of 33 lesions (73%), CT revealed additional cancers not seen on mammography. The extent of tumor significantly correlated with CT measurements (r=0.76, p<0.0001). CONCLUSION: Helical CT of the breast is an accurate preoperative imaging modality for assessing the locoregional staging of T1-2 invasive breast cancer.

Adult↗

PubMed2001

Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilation.

A 52-year-old woman was found to have a liver tumor during treatment for a liver abscess. The tumor was diagnosed as intrahepatic cholangiocarcinoma by closer examinations, including a percutaneous needle biopsy. Ten years previously, she had undergone excision of a choledochal cyst, with reconstruction by Roux-en-Y hepaticojejunostomy, as treatment for Todani's type Ia congenital biliary dilation, which had been confined only to the extrahepatic bile duct. The significant association between congenital biliary dilation and hepatobiliary malignancies is well known. Some patients have been reported to develop biliary cancer long after the excision of the entire extrahepatic bile duct and hepaticoenterostomy. However, in these patients, the development mostly took place in the remnant choledochal cyst, the anastomotic site, or in the dilated intrahepatic bile duct of Todani's type IV-A congenital biliary dilation. The development of intrahepatic cholangiocarcinoma after operation has not been reported previously in a patient with Todani's type I congenital biliary dilation. This case suggests that the entire biliary tree may have a high risk of field cancerization, even in extrahepatic congenital biliary dilation.

Bile Duct Diseases↗

PubMed2001

Characterization of simple and reproducible vascular stenosis model in hypercholesterolemic hamsters.

The importance of low-density lipoprotein (LDL) in the etiology of atherosclerosis is well recognized. We have established a reproducible stenosis model in hypercholesterolemic hamsters, and the process of arterial stenosis by thrombus or neointima was studied and compared with that in normal hamsters. The level of plasma LDL was 4.6 times higher in hamsters fed a high-cholesterol diet than in hamsters fed normal food. Endothelial injury in right common carotid arteries was induced using a modified catheter. Arterial blood flow was monitored continuously using a Doppler flow probe. Arterial patency after the initiation of injury in high-cholesterol hamsters was significantly changed as compared with that of normal hamsters. Neointima was observed 2 wk after the vascular injury. The neointimal area of high-cholesterol hamsters was significantly larger than that of normal hamsters. To characterize the stenosis in hypercholesterolemic hamsters, we measured platelet aggregation, thrombin time, activated partial thromboplastin time, and proliferating smooth muscle cells (SMC) in vitro and in vivo. The half-maximal inhibitory concentration value for platelet aggregation induced by thrombin or collagen, the DNA synthesis stimulated by platelet-derived growth factor (PDGF)-BB, and 5-bromo-2-deoxy-uridine labeling indices (proliferating index of SMC in vivo) in high-cholesterol hamsters were each significantly higher than the comparable value from normal hamsters. However, specific binding of PDGF-BB in SMC was not different between the two types of hamsters. Furthermore, we investigated the inhibitory effects of probucol or losartan on neointima formation using this model. Probucol, but not losartan, significantly reduced the neointimal area in hypercholesterolemic hamsters. These findings indicated that high levels of plasma LDL strongly contributed to the development of thrombus and neointima formation via both up-regulation of platelet aggregation and the enhancement of SMC proliferation. This stenosis model may be useful for the investigation of hypercholesterolemia-associated cardiovascular diseases.

Animals↗

PubMed2001

P-glycoprotein expression in human major and minor salivary glands.

Sodium pump and carbonic anhydrase activity have been described in the salivary glands. However, it remains to be elucidated whether these energy sources are used for secretion, excretion or both. In addition, the differences in the function of excretion and the role of the excretory duct cells are currently unknown in salivary glands. Expression of P-glycoprotein (P-gp), which is an ATPase-binding efflux pump, was tested in normal major and minor salivary glands from humans. P-gp was distributed on the basolateral membrane of serous acinar cells in the major salivary glands and the minor salivary glands. In particular, it was found to be present on the basolateral membrane and cytoplasm of acinar demilunar cells in the anterior lingual gland. Intense expression was identified in the basolateral membrane of the striated duct cells of the major salivary glands. P-gp was distinctly positive in the basolateral and/or luminal membranes of the initial part and in the luminal membrane of the terminal part of the excretory duct cells of the major salivary glands, whereas it was positive in the luminal membranes of both the initial part and the terminal part of the excretory duct cells of the minor salivary glands. These disparate distributions between the major and the minor salivary glands suggest different physiological excretions in the striated duct. P-gp may be physiologically involved in an important part of the transporter system, not only in the acinar serous cells and the striated duct cells, but also in the excretory duct cells in the salivary glands.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Development of a 1.0 T MR microscope using a Nd-Fe-B permanent magnet.

A compact 1.0 T MR microscope was developed using a permanent magnet made of high performance Nd-Fe-B magnetic material and a compact MRI console (54 cm (W) x 77 cm (H) x 60 cm (D), 80 kg weight). Since the magnetic field of the permanent magnet had a large temperature coefficient (-1200 ppm/deg), an internal NMR locking technique was developed for the imaging sequences. The performance of the system was evaluated using several biological specimens. As a result, good SNR 3D images at (50 microm)(3)-(200 microm)(3) voxel dimensions were obtained in practical imaging times (0.5-7.5 hours). Thus we have concluded that the permanent-magnet compact MR microscope has great promise as a research or analytical tool.

Animals↗

PubMed2001

Mechanism of prostaglandin D(2)-stimulated heat shock protein 27 induction in osteoblasts.

We previously showed that prostaglandin D(2) (PGD(2)) stimulates activation of protein kinase C (PKC). We investigated whether PGD(2) stimulates the induction of heat shock protein (HSP) 27 and HSP70 in osteoblast-like MC3T3-E1 cells and the mechanism underlying the induction. PGD(2) increased the levels of HSP27 while having little effect on HSP70 levels. PGD(2) stimulated the accumulation of HSP27 dose dependently in the range between 10 nM and 10 microM. PGD(2) induced an increase in the levels of mRNA for HSP27. The PGD(2)-stimulated accumulation of HSP27 was reduced by staurosporine or calphostin C, inhibitors of PKC. PGD(2) induced the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. The HSP27 accumulation induced by PGD(2) was significantly suppressed by PD98059, an inhibitor of the upstream kinase of p44/p42 MAP kinase, or SB203580, an inhibitor of p38 MAP kinase. Calphostin C suppressed the PGD(2)-induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase. PD98059 or SB203580 suppressed the PGD(2)-increased levels of mRNA for HSP27. These results strongly suggest that PGD(2) stimulates HSP27 induction through p44/p42 MAP kinase activation and p38 MAP kinase activation in osteoblasts and that PKC acts at a point upstream from both the MAP kinases.

Animals↗

PubMed2001

Three-dimensional helical CT of the breast: accuracy for measuring extent of breast cancer candidates for breast conserving surgery.

OBJECTIVE: To evaluate the accuracy of three-dimensional (3D) helical computed tomography (CT) for assessing the extent of breast cancer of candidates for breast conserving surgery. METHODS: Results of helical CT were studied in 144 lesions of 144 patients with breast cancer before breast-conserving surgery. A lesion was defined as positive if focal enhancement was detected by CT within 100 s after contrast material administration. After resection, tumors were histopathologically mapped and correlated with the extent of 3D images. RESULTS: Helical CT enabled detection of 143 tumors but not of one ductal carcinoma in situ (DCIS). The median deviation of the tumor extension revealed by 3D helical CT images from pathological assessment was 7.7 mm (range 0-60 mm). The extent of tumors was significantly correlated with CT measurements (r = 0.714, p < 0.0001). By multivariate analysis, the presence of invasive tumors with intraductal extensions beyond the edge of the invasive tumor and histologic type (DCIS) were significant risk factors for deviation of the tumor extension revealed by 3D helical CT images from pathological assessment. CONCLUSION: Three dimensional helical CT of the breast is an accurate preoperative imaging modality for assessing the extent of breast cancer candidates for breast conserving surgery.

Adult↗

PubMed2001

Mechanism of retarded liver regeneration in plasminogen activator-deficient mice: impaired activation of hepatocyte growth factor after Fas-mediated massive hepatic apoptosis.

Urokinase-type plasminogen activator (uPA) is implicated in the regulation of hepatic regeneration by activating hepatocyte growth factor (HGF). Here, we investigated its role in the hepatic regeneration after Fas-mediated massive hepatocyte death employing mice deficient in either uPA or its inhibitor, plasminogen activator inhibitor-1 (PAI-1). We measured kinetics of hepatic levels of proliferating cell nuclear antigen (PCNA)-labeling index, plasmin activity, mature HGF, and its phosphorylated receptor, c-Met. In the genetically targeted and wild-type mice, hepatocytes fell into the same extent of apoptosis 6 to 12 hours after an intraperitoneal injection with anti-Fas antibody, as judged from histologic analysis and a histon-DNA enzyme-linked immunosorbent assay (ELISA). In the wild-type mice, mature HGF emerged in the liver 6 hours following anti-Fas injection, and hepatic PCNA-labeling index started to increase following 24 hours and peaked at 48 hours. In the uPA(-/-) mice, emergence of mature HGF was delayed 12 hours and hepatic regeneration peaked at 96 hours. Supplementation with the uPA gene to the uPA(-/-) mice by in vivo lipofection restored hepatic plasmin levels, and improved a delay in the expression of both mature HGF and phosphorylated c-Met, accompanying a normal rate of liver regeneration. In contrast, PAI-1(-/-) mice showed accelerated liver regeneration; mature HGF emerged as early as 3 hours, and PCNA-labeling index increased at 24 hours. This accelerated regeneration was abolished by administration with anti-HGF antibody. These results strongly suggest a physiologic role of uPA in the proteolytic maturation of HGF, and thereby in hepatic regeneration after Fas-mediated massive hepatocyte death.

Animals↗

PubMed2001

Pharmacokinetics of a new parenteral oligosaccharide antibiotic, SCH27899 (Ziracin), in healthy subjects.

The pharmacokinetic properties of an everninomicin antibiotic (SCH27899; Ziracin) were studied with healthy Japanese male volunteers by single (1, 3, 6, and 9 mg/kg of body weight) and multiple 60-min intravenous infusions (3, 6, and 9 mg/kg once daily for 10 consecutive days following a 2-day interval after the initial dose). At single doses the peak serum concentration and the area under the serum concentration-time curve linearly increased with the dose. While total body clearance (CL; 31.2 to 45.6 ml/kg/h) and percent cumulative urinary recovery as unchanged drug (4.9 to 7.1%) were rather constant irrespective of doses, the terminal half-life of gamma phase (t(1/2 gamma); 14.2 to 19.6 h) were slightly prolonged at the higher two doses compared with the lower two doses. With repeated doses of SCH27899, a statistically significant decrease and increase were found in CL and t(1/2 gamma) of about 36 and 21%, respectively, although these changes may be clinically irrelevant. The most commonly reported adverse events were local reactions such as erythema, pain, and palpable venous cord of mild to moderate degree around the injection site, which could be managed by changing the injection sites.

Adult↗

PubMed2001

Inhibition by adenylyl cyclase-cAMP system of ET-1-induced HSP27 in osteoblasts.

We have previously reported that endothelin-1 (ET-1) stimulates heat shock protein (HSP) 27 induction in osteoblast-like MC3T3-E1 cells and that p38 mitogen-activated protein (MAP) kinase acts at a point downstream from protein kinase C (PKC) in HSP27 induction. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on ET-1-stimulated induction of HSP27 in MC3T3-E1 cells. Dibutyryl-cAMP (DBcAMP) dose dependently inhibited the HSP27 accumulation stimulated by ET-1. Forskolin and cholera toxin significantly suppressed the ET-1-stimulated accumulation of HSP27. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the ET-1-induced HSP27 accumulation. Forskolin reduced the p38 MAP kinase phosphorylation induced by ET-1 or 12-O-tetradecanoylphorbol-13-acetate (TPA). PGE(1), an extracellular agonist that activates cAMP production, reduced the ET-1-induced HSP27 accumulation. In addition, the phosphorylation of p38 MAP kinase induced by ET-1 or TPA was suppressed by PGE(1). Forskolin, DBcAMP, and PGE(1) suppressed the ET-1-stimulated increase in the mRNA level for HSP27. These results indicate that the adenylyl cyclase-cAMP system has an inhibitory role in ET-1-stimulated HSP27 induction in osteoblasts and that the effect is exerted at the point between PKC and p38 MAP kinase in osteoblasts.

Adenylyl Cyclase Inhibitors↗

PubMed2001

Photochemically induced equilibrium dysfunction in the hamster model with evaluation by means of a new globe rotatory test system.

Thrombosis in the inner ear is regarded as one of the causes of equilibrium dysfunction. We have established an experimental thrombosis model by producing a photochemical reaction between rose bengal and green light, and have evaluated the dysfunction with a new rotatory test system. Hamsters were treated with tissue-type plasminogen activator (tPA) in doses of 0, 0.13, 0.26, and 0.52 mg/kg. The equilibrium dysfunction of the hamsters was evaluated by scoring their behavior according to visual observation and by measuring their time on the rotatory test system. Treatment of animals with sufficient tPA (> or = 0.26 mg/kg) caused a significant amelioration of the behavior and a concomitant significant prolongation of time on the rotating globe. These findings suggest that the equilibrium dysfunction induced by the photochemical reaction was due to the thrombi formed, and that our test system may provide a useful tool for evaluating equilibrium dysfunction in hamsters.

Animals↗

PubMed2001

Trifluoromethyl ketone-based inhibitors of apoptosis in cerebellar granule neurons.

A variety of aromatic trifluoromethyl ketone derivatives has been studied as inhibitors of apoptosis in cerebellar granule neurons (CGNs). Among them, alpha-trifluoromethyl diketone (2) and benzyl trifluoromethyl ketone (11) were found to be apoptosis inhibitors which can prevent a neurodegenerative disease. Compounds 2 and 11 showed neuroprotection effect on low K+-induced apoptosis in CGNs. Furthermore, these compounds effectively suppressed DNA fragmentation accompanied with apoptosis. The neuroprotection mode of 2 and 11 was not related to inhibition of caspase-3.

Acetic Anhydrides↗

PubMed2001

AlphaB-crystallin, a low-molecular-weight heat shock protein, acts as a regulator of platelet function.

It has recently been reported that alphaB-crystallin, a low-molecular-weight heat shock protein, may be released from cells by mechanical stretch. We investigated a physiological role of alphaB-crystallin in platelet function. AlphaB-crystallin inhibited platelet aggregation induced by thrombin or botrocetin in hamsters and humans. These platelets had specific binding sites for alphaB-crystallin. Moreover, alphaB-crystallin significantly reduced thrombin-induced Ca2+ influx and phosphoinositide hydrolysis by phospholipase C in human platelets. Additionally, plasma levels of alphaB-crystallin were markedly elevated in cardiomyopathic hamsters. Levels of alphaB-crystallin in vessel walls after endothelial injury were markedly reduced. Therefore, our results suggest that alphaB-crystallin, which is discharged from vessel walls in response to endothelial injury, acts intercellularly as a regulator of platelet function.

Animals↗

PubMed2001

p38 mitogen-activated protein (MAP) kinase but not p44/p42 MAP kinase is involved in prostaglandin E1-induced vascular endothelial growth factor synthesis in osteoblasts.

We investigated the mechanism underlying vascular endothelial growth factor (VEGF) synthesis stimulated by prostaglandin E1 (PGE1) in osteoblast-like MC3T3-E1 cells. PGE1 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. SB203580, a specific inhibitor of p38 MAP kinase, inhibited the PGE1-stimulated VEGF synthesis as well as PGE1-induced phosphorylation of p38 MAP kinase. PD98059, an inhibitor of the upstream kinase that activates p44/p42 MAP kinase, which reduced the PGE1-induced phosphorylation of p44/p42 MAP kinase, had little effect on the VEGF synthesis stimulated by PGE1. AH-6809, an antagonist of the subtypes of the PGE receptor, EP1 and EP2, or SC-19220, an antagonist of EP1 receptor, did not inhibit the PGE1-induced VEGF synthesis. H-89, an inhibitor of cAMP-dependent protein kinase, and SQ22536, an inhibitor of adenylate cyclase, reduced the VEGF synthesis induced by PGE1. Cholera toxin, an activator of G(s), and forskolin, an activator of adenylate cyclase, induced VEGF synthesis. SB203580 and PD169316, another specific inhibitor of p38 MAP kinase, reduced the cholera toxin-, forskolin- or 8bromo-cAMP-stimulated VEGF synthesis. However, PD98059 failed to affect the VEGF synthesis stimulated by cholera toxin, forskolin or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP). SB203580 reduced the phosphorylation of p38 MAP kinase induced by forskolin or 8bromo-cAMP. These results strongly suggest that p44/p42 MAP kinase activation is not involved in the PGE1-stimulated VEGF synthesis in osteoblasts but that p38 MAP kinase activation is involved.

Alprostadil↗

PubMed2001

Therapeutic effect of balloon-occluded retrograde transvenous obliteration on portal-systemic encephalopathy in patients with liver cirrhosis.

OBJECTIVE: Balloon-occluded retrograde transvenous obliteration (B-RTO) has recently been introduced as a new interventional modality to prevent fatal bleeding from solitary gastric varices. A large portal-systemic shunt including gastric varices also causes severe encephalopathy in some cirrhotic patients. In this study, we evaluated the effect of B-RTO as a candidate therapeutic method to treat chronic recurrent hepatic encephalopathy due mainly to a portal-systemic shunt. PATIENTS AND METHODS: Since July 1995, we experienced 43 cirrhotic patients with chronic reccurent hepatic encephalopathy. Among them, six patients had anigographically proven large (>1 cm in diameter) portal-systemic shunt, and received B-RTO. B-RTO was carried out only once using 5% ethanolamine oleate with iopamidole to obliterate the portal-systemic shunt for 30 minutes. The median observation period after B-RTO was 29 months (range 23-46 months). RESULTS: In all 6 patients, encephalopathy had disappeared after B-RTO, and the patients were free of encephalopathy during the following 6 months. B-RTO significantly reduced blood ammonia levels at one month, 3 months, and 6 months later, without affecting serum aspartate aminotransferase activity, total bilirubin and albumin concentrations, and plasma prothrombin time. Encephalopathy relapsed in 4 patients between 6 and 30 months. Additional B-RTO was required and effective in 2 of them. CONCLUSION: B-RTO is an effective treatment for chronic recurrent hepatic encephalopathy with an angiographically proven portal-systemic shunt.

Aged↗

PubMed2001

In vitro high-resolution helical CT of small axillary lymph nodes in patients with breast cancer: correlation of CT and histology.

OBJECTIVE: This study seeks to determine whether high-resolution in vitro helical CT can show the internal structure of small axillary nodes and to establish the CT characteristics of benign versus metastatic axillary nodes in patients with breast cancer. SUBJECTS AND METHODS: We obtained in vitro helical CT images of 212 nodes excised from 19 patients with breast cancer. The longest mean size was 5.9 mm, and the range was 0.5 to 26.5 mm. The hilar and cortical characteristics, the size, and the ratio of the longest axis to the shortest axis were evaluated. CT findings were correlated with histologic findings. RESULTS: Pathologic assessment of excised nodes with a central low-density hilum visualized on CT showed arteries, veins, lymphatic sinuses, and fatty tissue. A peripheral high-density cortex on CT contained mostly lymphatic tissue. Abnormal (eccentric, irregular) cortices were observed in malignant nodes (p<0.0001). Marked differences were observed among the proportions of benign and malignant nodes when the ratio of the longest axis to the shortest axis was less than 2 and an abnormal cortex was observed. CT could also detect extracapsular lymph node extension. CONCLUSION: In vitro high-resolution helical CT can detect the internal structure of small nodes. Morphologic changes detected on helical CT help distinguish benign from malignant nodes.

Adult↗

PubMed2000

Nuclear factor-kappaB activates dual inhibition sites in the regulation of tumor necrosis factor-alpha-induced neutrophil apoptosis.

The objective of this study was to elucidate the role of the nuclear factor-kappaB (NF-kappaB) pathway in tumor necrosis factor-alpha (TNF-alpha)-induced neutrophil apoptosis. A single treatment with TNF-alpha produced significant caspase-3 activation in a time- and concentration-dependent manner, while no significant morphological change in neutrophils was observed. After pretreatment of neutrophils with cycloheximide or actinomycin D, TNF-alpha produced morphologically typical apoptosis in a time- and concentration-dependent manner. Similarly, following pretreatment of neutrophils with the specific NF-kappaB inhibitors, pyrrolidine dithiocarbamate or SN50, TNF-alpha also produced neutrophil apoptosis (assessed morphologically). Caspase-3 activation by TNF-alpha was significantly enhanced by pretreatment with both cycloheximide and pyrrolidine dithiocarbamate. TNF-alpha-induced a rapid phosphorylation and degradation of IkappaB-alpha in neutrophils. Furthermore, TNF-alpha increased NF-kappaB DNA binding, which was abolished by pretreatment with pyrrolidine dithiocarbamate. These results indicate that the NF-kappaB pathway is crucial for neutrophil survival against TNF-alpha cell toxicity. Furthermore, it is proposed that NF-kappaB-induced proteins act on dual inhibitory sites, both upstream and downstream of caspase-3, to protect against apoptosis.

Apoptosis↗