Arginine-cysteine polymorphism at codon 264 of the human CYP19 gene does not affect aromatase activity.
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Animals↗
Biomedical subjects
J Watanabe
Publications and source records attributed to J Watanabe.
Antitumor activity of TZT-1027, a novel dolastatin 10 derivative.
Dolastatin 10, a pentapeptide isolated from the marine mollusk Dolabella auricularia, has antitumor activity. TZT-1027, a dolastatin 10 derivative, is a newly synthesized antitumor compound. We evaluated its antitumor activity against a variety of transplantable tumors in mice. Intermittent injections of TZT-1027 were more effective than single or repeated injections in mice with P388 leukemia and B16 melanoma. Consequently, TZT-1027 shows schedule dependency. TZT-1027 was effective against P388 leukemia not only when administered i.p., but also when given i.v. However, although TZT-1027 given i.v. was active against murine solid tumors, TZT-1027 administered i.p. was ineffective against all the tumors tested with the exception of colon 26 adenocarcinoma. The i.v. injection of TZT-1027 at a dose of 2.0 mg/kg remarkably inhibited the growth of three murine solid tumors; colon 26 adenocarcinoma, B16 melanoma and M5076 sarcoma, with T/C values of less than 6%. The antitumor activities of TZT-1027 against these tumors were superior or comparable to those of the reference agents; dolastatin 10, cisplatin, vincristine, 5-fluorouracil (5-FU) and E7010. In experiments with drug-resistant P388 leukemia, TZT-1027 showed good activity against cisplatin-resistant P388 and moderate activity against vincristine- and 5-fluorouracil-resistant P388, but no activity against adriamycin-resistant P388. TZT-1027 was also effective against human xenografts, that is, tumor regression was observed in mice bearing MX-1 breast and LX-1 lung carcinomas. TZT-1027 at 10 microM almost completely inhibited the assembly of porcine brain microtubules. Therefore, its mechanism of antitumor action seems to be, at least in part, ascribable to the inhibition of microtubule assembly. Because of its good preclinical activity, TZT-1027 has been entered into phase I clinical trials.
Animals↗
Comparative assessment of D-xylose absorption between small intestine and large intestine.
The present study aimed to evaluate the absorption of D-xylose, a passively absorbed five-carbon monosaccharide, from the large intestine compared with the small intestine, in order to explore the absorption potential of the large intestine. D-Xylose absorption was evaluated in the intestinal loop and everted sacs in rats and comparisons were made between small intestine (mid-gut) and large intestine (colon). The absorption of D-xylose was smaller, by an order of magnitude or more, after administration into the loop of large intestine than after administration into that of small intestine, based on appearance in plasma and disappearance from the intestinal loop. D-Xylose absorption was practically insignificant (nominal 4.9%) in 60 min in the large intestine, whereas it was moderate (57.0%) in the small intestine. Consistently, the uptake of D-xylose in everted sacs was about 20 times larger in the small intestine than in the large intestine. Thus the passive membrane permeability of D-xylose was demonstrated to be negligible in the large intestine, even though the small intestine was fairly permeable. This result helps rationalize kinetic modelling strategies assuming the small intestine as the sole absorption site for gastrointestinal absorption in-vivo. It also suggests that hydrophilic drugs with molecular size similar to or larger than D-xylose may not be good candidates for colonic drug delivery by controlled release.
Animals↗
Synergistic anti-influenza virus A (H1N1) activities of PM-523 (polyoxometalate) and ribavirin in vitro and in vivo.
A Kegin-type polyoxometalate, PM-523, in combination with ribavirin, was tested for its therapeutic effectiveness against influenza virus (FluV) A (H1N1) infection in tissue culture and in mice. PM-523 [(PriNH3)6H [PTi2W10O38(O2)2] x H2O, where Pri is isopropanol] and ribavirin individually inhibited FluV A-induced cytopathic effects in Madin-Darby canine kidney (MDCK) cells at median effective concentrations (EC50s) of 30 and 34 microM, respectively, and at 70% effective concentrations (EC70s) of 48 and 72 microM, respectively. On the other hand, a combination of PM-523 and ribavirin at a ratio of 1:16 exhibited lower EC50s and EC70s than each compound used singly, and combination indices were less than 1. A wide range of combinations of PM-523 and ribavirin at ratios of from 1:128 to 1:1 exhibited additive or synergistic anti-FluV effects in MDCK cells. When these compounds were tested for their anti-FluV A activities in vivo by aerosol exposure of mice which had been infected with a lethal dose of FluV A by an intranasal route, a 1:16 combination of PM-523 and ribavirin was found to have a significantly better therapeutic effect than a single dose of either compound used singly with respect to both the survival rate of the mice and the virus titer in the lungs of the infected mice. PM-523 was effective for the treatment of experimental FluV infection, and in combination with ribavirin, PM-523 exhibited enhanced anti-FluV effects in vitro and in vivo compared with the effect of PM-523 alone.
Animals↗
Role of cytosolic Ca2+ and protein kinase C in developing myogenic contraction in isolated rat small arteries.
Cytosolic Ca2+ and protein kinase C (PKC) may regulate the myogenic contraction of arterial myocytes. The role of these second messengers is examined in skeletal muscle small arteries, which have strong myogenic activity, and mesenteric small arteries, which have weak myogenic activity. The vessels were isolated and cannulated. The inner diameter was measured with a video-digitizing system. Cytosolic Ca2+ concentration was assessed by fura 2. Skeletal muscle small arteries dilated from 122 +/- 6 to 153 +/- 6 microm immediately after the transmural pressure change from 40 to 100 mmHg and constricted to 121 +/- 5 microm (myogenic contraction) with an increase in the 340/380 fluorescence ratio (by approximately 33%) in control vessels. Nifedipine abolished myogenic contraction and the increase in the fluorescence ratio. PKC inhibitors (H7 and staurosporine) abolished myogenic contraction but did not depress the increase in the fluorescence ratio. In mesenteric small arteries, myogenic contraction was insignificant in control vessels. A relatively low dose of PKC activator (4.4 +/- 1.4 nmol/l) elicited myogenic contraction, but a higher dose (21 +/- 6 nmol/l) depressed it. Thus the cytosolic Ca2+ increase and PKC activity may cooperatively act on the myogenic contraction of skeletal muscle small arteries. The activity of PKC should play an important role in myogenic contraction of rat small arteries.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Effect of aging on the intestinal transport of hydrophilic drugs in the rat small intestine.
The effect of aging on the intestinal transport of hydrophilic drugs (and probe compounds) was investigated in the rat small intestine. Passive transport was suggested to be unchanged with aging from 8 (young) to 54 (old) and further to 101 (very old) weeks old, as shown for D-xylose and urea in single-pass intestinal perfusion (under urethane anesthesia), where steady-state transport across the intestinal membrane into the blood stream was evaluated. The passive transports of cephradine, 5-fluorouracil (5-FU) and L-glucose were also unchanged, though they were compared only between the young and the old. Consistently, the passive uptake in the intestinal everted sacs, where the entry process into the membrane was evaluated for 5-FU, D-xylose, urea and polyethylene glycol (PEG) 900, was unchanged with aging from the young to the very old. The carrier-mediated transport of cephradine was also unchanged with aging from the young to the old in perfusion under anesthesia, though that of D-glucose was declined by about 50% with aging from the young to the old and thereafter remained constant in the very old. In perfusion in unanesthetized rats, age independency in passive transport (examined for cephradine, L-glucose and D-xylose) and an age-dependent decline in D-glucose transport were also observed, suggesting that the findings under anesthesia are not qualitatively distorted. These results suggest that, although carrier-mediated transport may moderately decline with aging, the barrier function of the intestinal membrane to passive permeation of hydrophilic drugs (with molecular weight below 1000) may be unaffected by aging, supporting the suggestion from our previous in vivo studies that age-dependent increases in the orally absorbed fraction may be predicted for incompletely absorbed drugs because of delayed intestinal transit rather than increased intestinal transport (membrane permeability).
Aging↗
Kinetic characterization of binding and internalization of fractionated [3H]heparin in rat liver parenchymal cells in primary culture.
The binding and internalization of fractionated [3H]heparin (FH) was kinetically analyzed in rat liver parenchymal cells to clarify its cellular uptake mechanism. The binding of FH to the cell surface was saturable with the dissociation constant (Kd) of 53.5 nM and a maximum binding capacity (Bmax) of 19.9 pmol/mg protein. The binding of FH to the cell surface was competitively inhibited not only by heparan sulfate, a polyanion analogous to heparin, but also by rose bengal, an organic anion, suggesting the binding is based on an electric interaction requiring an anionic charge for substrates and consistent with the earlier suggestion of the involvement of the scavenger-like receptor. According to kinetic model analysis, the rate constants of association (K(on)), dissociation (k(off)), and internalization (k(int).app) were estimated to be 0.0005 nM-1 min-1, 0.0112 min-1, and 0.0056 min-1, respectively. Although both Kd and Bmax were larger than those reported in Kupffer cells, suggesting lower affinity and higher capacity in liver parenchymal cells, the apparent internalization rate constant was similar to that in Kupffer cells. We thus provided additional evidence suggesting that a scavenger-like receptor exists in rat liver parenchymal cells, and then kinetically characterized the surface binding and internalization of fractionated heparin by this receptor.
Animals↗
The rise time of the monophasic action potential--a new index of local use-dependent conductivity by sodium channel blockers in human myocardium.
The kinetics of global use-dependent conduction slowing produced by sodium channel blockers in the human heart, estimated as a change in the QRS width, are known to be similar to those of use-dependent block of the maximum rate of depolarization in in vitro studies. However, the kinetics of the regional use-dependent decrease in conductivity have not been investigated. We examined whether the rise time of the monophasic action potential would be clinically useful as a marker of the local use-dependent decrease in conductivity by sodium channel blockers. In 12 patients without organic heart disease, monophasic action potentials (MAPs) were recorded at the right ventricular endocardium using a contact electrode before and after the administration of disopyramide (n = 6, 2 mg/kg, i.v.) or pilsicainide (class Ic agents, n = 4, 1 mg/kg, i.v., and n = 2, 150 mg, po) while the stimulus frequency was abruptly increased from 100/min to 150/min. The rise time, defined as the interval from the pacing pulse to the first peak deflection of the monophasic action potential, and the ORS width were measured simultaneously. In the absence of the sodium channel blockers, the abrupt increase in heart rate did not alter the QRS width or the rise time. In the presence of the agents, both variables were lengthened exponentially. The rate constants of onset changes in the QRS width and the rise time were 2.1 +/- 0.5 beats and 2.1 +/- 0.4 beats after the administration of disopyramide, and 7.5 +/- 3.0 beats and 8.2 +/- 4.0 beats after pilsicainide, respectively. The rate constant of the rise time was closely correlated with that of the QRS width. The present results are very closely comparable with the onset rate constants of use-dependent block of the maximum rate of depolarization in in vitro studies. These results suggest that (1) the rise time is a good indicator of local use-dependent decrease in conductivity by sodium channel blockers in human hearts and (2) the local use-dependent decrease in conductivity has kinetics similar to those of use-dependent sodium channel blocks.
Action Potentials↗
[Work intensity during working hours and different types of care done by special nursing home workers].
This study was done to estimated work intensity during working hours and different types of care to obtain basic data for making a care program. The subjects were care workers in good health (n = 8, 24-45 years) who worked in a special nursing home. The estimated maximal oxygen intake level, which is the maximal aerobic capacity, of each subject was assessed as normal to very good. The energy expenditure was 1787 +/- 534kcal during working hours. The work intensity was 0.061 +/- 0.011kcal/kg/min, 2.7 +/- 0.7RMR, 98 +/- 6beats/min, and 30.3 +/- 2.0% VO2max. Among the duties assessed for work intensity, bathing had the highest intensity, followed by transferring, changing diapers, feeding, and dressing. The work intensity of bathing was 0.081 +/- 0.31kcal/kg/min, 3.9 +/- 1.0RMR, and 40.0 +/- 6.1 VO2 max, which was significantly higher than feeding, dressing, and transferring(p < 0.05). Care giving at the time of bathing was significantly longer than the other care types (p < 0.05). Feeding and transferring by inexperienced care workers were significantly low intensity (p < 0.05). Work intensity of care was at high levels within the maximal permissible level in which fatigue doesn't make an appearance during working hours and in five types of care. Furthermore, care work intensity increased according to a decrease in the ADL level among the elderly. It is concluded that when making a care program, it is important to consider the ADL level of the elderly, work intensity and the amount of care-giving time, not only to maintain the health of care workers, but, also, to give superior quality care to the elderly.
Activities of Daily Living↗
Isolation and identification of alpha-glucosidase inhibitors from tochu-cha (Eucommia ulmoides).
alpha-Glucosidase inhibitory activity was found in aqueous methanol extracts of tochu-cha, dried leaves of Eucommia ulmoides (Eucommiaceae). Five active principles against yeast enzyme were isolated and characterized. Among them, quercetin (1, Ki: 8.5 x 10(-6) M) was considered to contribute mostly to the activity of the tochu leaves. In regard to an animal alpha-glucosidase, rat intestinal sucrase activity was also inhibited by 1.
Animals↗
Cytotoxicity of some oxysterols on human vascular smooth muscle cells was mediated by apoptosis.
A decrease in smooth muscle cells is observed in advanced atherosclerotic lesion. To understand this mechanism, we selected oxysterols as candidates for toxic lipid, and examined their cytotoxicity on human cultured vascular smooth muscle cells, together with the manner of cell death. In the presence of 7-ketocholesterol or 7 beta-hydroxycholesterol (50 mumol/L), the percentage of detached cells increased significantly with dose dependency, and an increase in detached cell number and DNA nick detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling study (TUNEL) preceded an increase in lactate dehydrogenase released into the medium. DNA extracted from smooth muscle cells incubated with 7-ketocholesterol or 7 beta-hydroxycholesterol showed a laddering pattern on agarose electrophoresis. In the presence of 7-ketocholesterol or 7 beta-hydroxycholesterol, fragmented DNA quantified by the quantitative sandwich enzyme immunoassay was significantly increased. From these results, it is proposed that 7-ketocholesterol and 7 beta-hydroxycholesterol are toxic to smooth muscle cells, and that this cytotoxicity is mediated by apoptosis.
Apoptosis↗
Cyclothialidine analogs, novel DNA gyrase inhibitors.
DNA gyrase inhibitors, cyclothialidines B, C, D and E were isolated from four Streptomycete strains (NR 0659, NR 0660, NR 0661 and NR 0662). Their structures have been elucidated based on the amino acid analysis of the hydrolysates, NMR and HRFAB-MS experiments and shown to be cyclothialidine analogs. The absolute stereochemistry has been determined by the chiral HPLC analysis of the hydrolysates. Cyclothialidines B, D and E are novel and potent inhibitors of DNA gyrase.
Chromatography, High Pressure Liquid↗
[Posterior iris bowing after accommodation--elucidation of the etiology of pigment dispersion syndrome].
Recent advancements in imaging the anterior segment structures using the ultrasound biomicro scope (UBM) have proven the involvement of posterior iris bowing due to reverse pupillary block as the cause of pigment dispersion syndrome. In this report, we examined whether the posterior iris bowing occurs even in normal eyes following accommodation, and whether the degree of iris concavity tends to be greater in myopic eyes than in emmetropic eyes. The subjects were normal eyes with sufficient accommodation power, i.e. 5 myopic eyes with less than-5 diopter reflection, 5 emmetropic eyes within +/- 1 dioptor reflection, respectively. We obtained UBM images of the iris at 4 portions before and after accommodation, and measured the degree of posterior iris bowing. We found that almost all data shift posteriorly after accommodation, and that the iris concavity is more distinct in myopic eyes than in emmetropic eyes both before and after accommodation (before: p = 0.0004, after: p < 0.0001). From these results, we confirmed that iris concavity after accommodation occurs in normal eyes but not enough for iridozonular contact, and that pigment dispersion syndrome results from augmented iris concavity owing to pre-existing factors such as iris flexibility, myopia, and sufficient accommodation power.
Accommodation, Ocular↗
Localization of parathyroid glands using technetium-99m-tetrofosmin imaging.
UNLABELLED: Preoperative localization of hyperactive parathyroid glands is useful to minimize operative time and reduce patient morbidity. This investigation compared the sensitivity of radionuclide imaging with 99mTc tetrofosmin with that of ultrasonography and magnetic resonance (MR) imaging in patients with hyperparathyroidism. METHODS: Twenty-six patients with primary (n = 7) or secondary (n = 19) hyperparathyroidism were imaged with 99mTc tetrofosmin, ultrasound and MR imaging of the neck and thorax to localize the lesions. The presence of hyperparathyroidism was identified by an intact parathyroid hormone in vitro assay. The parathyroid/normal thyroid tissue activity ratio was calculated for all patients with evidence of an abnormality on tetrofosmin images. Pathological findings were compared with the results of imaging in 18 of the 26 patients who underwent parathyroidectomy. RESULTS: Technetium-99m tetrofosmin scans demonstrated focal uptake in 46 glands of 26 patients. The uptake was categorized as slight in 78.3% (36/46) and intense (parathyroid/normal thyroid tissue activity ratio, > 1.4) in 21.7% (10/46). Ultrasonography and MR imaging identified 44 and 47 glands, respectively, in these patients. Eleven of the 18 patients who underwent parathyroidectomy within 1 mo after tetrofosmin imaging had hyperplastic glands, while 7 had parathyroid adenomas. Tetrofosmin imaging successfully localized 7 of 7 (100%) adenomas and 27 of 37 (73.0%) hyperplastic glands. The sensitivities of each technique for localizing abnormal parathyroid glands were 77.3% (34/44) for tetrofosmin imaging: 68.2% (20/44) for ultrasonography: and 68.2% (30/44) for MR imaging. Technetium-99m tetrofosmin uptake ratio in the 18 patients with surgical exploration was not proportional to several oxyphil cells. CONCLUSION: Technetium-99m tetrofosmin parathyroid imaging may be useful for localizing abnormal glands in patients with primary and secondary hyperparathyroidism. The sensitivity of 99mTc tetrofosmin parathyroid imaging was high as compared to ultrasonography or MR imaging. The prolonged retention of tetrofosmin may not depend on the number of mitochondria-rich oxyphil cells.
Adenoma↗
[Significance and limit of the tests for prevention of transfusion-associated infectious diseases].
To prevent virus infectious associated with transfusion the excellent screening tests should be implemented. The blood screening tests should comply with five "S" requirements, in other words it should be sensitive, specific, simple, speedy and safe. In the very first stage of the virus infection, a term called "window period", during which infectious agents, are undetectable by current assays. So the possibility of viral transmission is still remain. Therefore, after due consideration of the benefits and the risks of blood transfusion and only in the case of its efficacy is expected enough, minimal volume of blood should be transfused. Furthermore, the transfusion should be into practice after thorough informed consent.
Antibodies, Viral↗
Quantitative analysis of endoplasmic reticulum and cytochrome P-450 in hepatocytes from rats injected with methylcholanthrene.
To examine whether the smooth endoplasmic reticulum (SER) proliferates in hepatocytes from animals treated with methylcholanthrene (MC) frequently used as an inducer for the enzymes of the microsomal mono-oxygenase system, we estimated the area of (smooth and rough) ER per unit cytoplasmic volume by morphometry in periportal, midzonal and perivenular hepatocytes from rats injected with 25 mg/kg MC once a day for 3 days. In addition, immunostaining intensity of major MC-inducible cytochrome P-450 (P-450) forms (1A1/1A2) and total P-450 content in the cytoplasm of hepatocytes in the three zones were measured by microphotometry to ascertain whether P-450 is sufficiently induced in each sublobular zone by the administration. In spite of significant increase in the staining intensity of P-450 1A1/1A2 and amount of total P-450, the proliferation of SER (and RER) did not occur in the three-zone hepatocytes from rats injected with MC. In perivenular hepatocytes, constitutive forms of P-450 other than 1A1/1A2 decreased (to 10%) instead of marked increase in P-450 1A1/1A2 (about 20 times), while the constitutive forms decreased to 50% in midzonal hepatocytes and remained unchanged in periportal hepatocytes after MC administration. In addition, the present results show divergence between biochemical and immumohistochemical results previously reported on MC-inducible P-450 after MC administration to be due primarily to a curvilinear relationship between content and intensity.
Animals↗
[Metastasis of renal cell carcinoma to ipsilateral adrenal residuum and contralateral adrenal gland after radical nephrectomy: a case report].
A 68-year-old woman had undergone radical nephrectomy via a transabdominal approach 4 years earlier for a 8 cm tumor located from the midportion to the upper pole of the right kidney. Pathological diagnosis was renal cell carcinoma (RCC), clear cell subtype, G2, pT2pN0M0. Four years postoperatively, followup computed tomography scan revealed masses in bilateral adrenal region (6 cm in diameter on the left side and 5 cm on the light). Bilateral adrenalectomy confirmed the diagnosis of adrenal metastases from clear cell carcinoma. It was concluded that the tumor had metastasized to the ipsilateral adrenal tissue as the residuum of the previous surgery. She has been treated by oral steroid supplementation without evidence of recurrence for 18 months.
Adrenal Gland Neoplasms↗
[Plateau iris configuration as a risk factor for malignant glaucoma].
To provide evidence for diagnosing malignant glaucoma, as well as to elucidate the pathogenetic mechanism of the disease, ultrasound biomicroscopy (UBM) is a useful tool. We examined the anterior segments of three patients with post-operative malignant glaucoma with UBM regarding the state before operation, the state of the opposite eye, and the state after the release of the cilio-lenticular block. Case 1 was a 76-year-old female who was diagnosed as having chronic angle-closure glaucoma (CACG) and was treated by trabeculectomy, phacoemulsification, aspiration (PEA), and simultaneous intraocular lens (IOL) implantation. Case 2 was a 22-year-old male diagnosed as having CACG secondary to plateau iris syndrome and was treated by trabeculectomy. Case 3 was a 73-year-old female diagnosed as having normal-tension glaucoma with narrow angle and was treated by PEA and IOL implantation. Slit-like anterior chamber angle and anteriorly positioned ciliary body were observed in all 3 cases, which were identical to those Pavlin reported in 8 cases with plateau iris syndrome. UBM seems to be an important pre-operative examination to evaluate the risk of malignant glaucoma and to consider which surgical procedure and post-operative management is proper. The pre-operative configuration of the ciliary body may be associated with the onset of malignant glaucoma in some patients with CACG or narrow angle.
Adult↗