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Biomedical subjects

F Takahashi

Publications and source records attributed to F Takahashi.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effects of 19-nor-1,25(OH)2D2, a new analogue of calcitriol, on secondary hyperparathyroidism in uremic rats.

The active metabolite of vitamin D, calcitriol [1,25(OH)2D3] suppresses parathyroid hormone (PTH) gene transcription and PTH secretion. Although 1,25(OH)2D3 is effective in suppressing secondary hyperparathyroidism in uremic patients, the mandatory use of large amounts of calcium salts to control serum phosphorus may preclude in some patients the use of ideal therapeutic doses of 1,25(OH)2D3 because of hypercalcemia. We have studied a new analogue of calcitriol,19-nor-1,25(OH)2D2 that possesses low calcemic and phosphatemic activity. We have clearly demonstrated that this analogue of calcitriol can suppress secondary hyperparathyroidism without inducing hypercalcemia or hyperphosphatemia in uremic rats. In addition, this analogue of vitamin D supresses pre-pro PTH messenger RNA in a similar fashion to that of 1,25(OH)2D3. Contrary to the effect of 1,25(OH)2D3 that increases the intestinal vitamin D receptor, this analogue of vitamin D suppresses the intestinal vitamin D receptor. This finding may be critical for the lack of calcemic activity of 19-nor-1,25(OH)2D2 seen in these studies. One of the explanations for the lack of an increasing intestinal VDR is the fact that 19-nor-1,25(OH)2D2 decreases endogenous levels of 1,25(OH)2D3. In summary, we have shown that 19-nor-1,25(OH)2D2, a new analogue of calcitriol is effective in suppressing PTH in uremic rats with secondary hyperparathyroidism. In addition, there is a significant decrease in the VDR in the intestine, which may explain in part the less calcemic and hyperphosphatemic effect of this analogue.

Animals↗
PubMed1998

The carboxyl-terminal fragment of osteopontin suppresses arginine-glycine-asparatic acid-dependent cell adhesion.

Osteopontin (OPN) is a secreted glycoprotein implicated in cell adhesion. It contains the arginine-glycine-asparatic acid (RGD) cell adhesive domain and the thrombin cleavage sequence. Although thrombin cleavage of OPN has been shown to be of physiological importance, the function of C-terminal OPN fragment cleaved by thrombin remains unknown. To determine its role, we performed cell adhesion assays using glutathione S-transferase-OPN fusion protein fragments and full-length OPN fusion protein. The N-terminal fragment containing RGD motif promoted enhanced adhesion of mouse and human fibroblasts by 2.9 and 2.8 folds in comparison with full-length OPN, respectively. The enhanced adhesion of both cells mediated by N-terminal fragment was significantly suppressed by addition of C-terminal fragment lacking RGD motif that has less cell adhesive property than full-length OPN. These results suggest that the C-terminal domain may play a pivotal role in regulating OPN functions by suppressing the RGD-dependent cell adhesion.

3T3 Cells↗
PubMed1998

Difference of (Ca2+)i movements in platelets stimulated by thrombin and TRAP: the involvement of alpha(IIb)beta3-mediated TXA2 synthesis.

This study investigated the difference of [Ca2+]i movement in platelets in response to thrombin and TRAP. The involvement of alpha(IIb)beta3 in this signaling was also studied. Stimulation of platelets with thrombin at 0.03 U/ml caused platelet aggregation and a two-peak increase in [Ca2+]i. The second peak of [Ca2+]i, but not the first peak was abolished by the inhibition of platelet aggregation with alpha(IIb)beta3 antagonists or by scavenging endogenous ADP with apyrase. A cyclooxygenase inhibitor, aspirin, and a TXA2 receptor antagonist, BM 13505, also abolished the second peak of [Ca2+]i but not the first peak, although these regents did not inhibit aggregation. Under the same assay conditions, measurement of TXB2 demonstrated that alpha(IIb)beta3 antagonists and aspirin almost completely inhibited the production of TXB2. In contrast to thrombin-stimulation, TRAP caused only a single peak of [Ca2+]i even in the presence of platelet aggregation, and a high level of [Ca2+]i increase was needed for the induction of platelet aggregation. The inhibition of aggregation with alpha(IIb)beta3 antagonists had no effect on [Ca2+]i change and TXB2 production induced by TRAP. Inhibition studies using anti-GPIb antibodies suggested that GPIb may be involved in the thrombin response, but not in the TRAP. Our findings suggest that low dose thrombin causes a different [Ca2+]i response and TXA2 producing signal from TRAP. Endogenous ADP release and fibrinogen binding to alpha(IIb)beta3 are responsible for the synthesis of TXA2 which results in the induction of the second peak of [Ca2+]i in low thrombin- but not TRAP-stimulated platelets.

Adenosine Diphosphate↗
PubMed1997

Safety and kinetic properties of a humanized antibody to human interleukin-6 receptor in healthy non-human primates.

A monoclonal antibody, hPM-1, was constructed by grafting the complementarity determining regions to human interleukin-6 (IL-6) receptor, raised in mouse, onto a human antibody backbone (humanized antibody). It is expected to be useful as a therapeutic agent for IL-6-related diseases such as multiple myeloma. To investigate the toxicological and kinetic properties of hPM-1 preliminarily, normal cynomolgus monkeys, which showed cross-reactivity with hPM-1, were intravenously administered with hPM-1 at doses of 0 (vehicle), 4 or 40 mg/kg once a week for 13 weeks. Upon toxicological examination, there were no changes in clinical signs, food consumption, body weights, urinalyses, body temperatures, electrocardiograms, hematological and biochemical parameters including blood platelet counts, serum levels of immunoglobulin G and C-reactive protein, and pathological findings. In a kinetic study, serum concentrations of hPM-1 showed a linearity between doses of 4 and 40 mg/kg. The serum concentrations, even at a dose of 4 mg/kg, were maintained at a high enough level to inhibit the IL-6 functions throughout the period of the study. Concentrations of hPM-1 in bone marrow were almost equal to those in serum. The antibodies against hPM-1 were detected only in one of four monkeys receiving hPM-1. This study suggests that blockage of the IL-6 receptor by hPM-1 does not induce any influence on a healthy living body, and hPM-1 is not toxic under the conditions of this investigation.

Animals↗
PubMed1997

A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content.

We have previously reported that 19-nor-1,25-(OH)2D2, a new analog of 1,25-(OH)2D3, suppresses parathyroid hormone (PTH) secretion in uremic rats in the absence of hypercalcemia or hyperphosphatemia. In the current study, we examined the effect of 19-nor-1,25-(OH)2D2 on parathyroid gland growth and intestinal vitamin D receptor (VDR) content. After induction of uremia by 5/6 nephrectomy, rats were divided into five experimental groups and received intraperitoneal injections of vehicle, 1,25-(OH)2D3 (2 or 6 ng/rat), or 19-nor-1,25-(OH)2D2 (25 or 100 ng/rat) three times a week for 8 weeks. Twelve normal rats received vehicle and served as the normal control group. During the course of the study, rats were maintained on a 1.0% calcium and 0.8% phosphorus diet. The higher dose of 1,25-(OH)2D3, 6 ng, significantly decreased PTH from 52.7 +/- 10.2 pg/mL in the uremic control group to 25.7 +/- 6.7 pg/mL (P < 0.01). This dose of 1,25-(OH)2D3, however, increased serum levels of both ionized calcium (4.71 +/- 0.05 to 4.85 +/- 0.06 mg/dL; P < 0.05) and phosphorus (4.34 +/- 0.30 to 6.67 +/- 0.63 mg/dL; P < 0.01). Both doses of 19-nor-1,25-(OH)2D2 decreased serum PTH as effectively as 1,25-(OH)2D3 without changes in serum calcium or phosphorus. The 100-ng dose of 19-nor-1,25-(OH)2D2 decreased PTH to 20.7 +/- 3.1 pg/mL (P < 0.01) and suppressed parathyroid gland growth by more than 50%. Both doses of 19-nor-1,25-(OH)2D2 also decreased endogenous 1,25-(OH)2D3 levels compared with uremic control rats (25 ng:30.4 +/- 2.0, P < 0.05, and 100 ng:27.9 +/- 3.2, P < 0.01, v 48.4 +/- 6.6 pg/mL). The 6-ng dose of 1,25-(OH)2D3 elevated intestinal VDR content (138.5 +/- 20.0 fmol/mg protein) compared with animals receiving both doses of 19-nor-1,25-(OH)2D2 (25 ng:84.0 +/- 11.9, P < 0.05, and 100 ng:78.4 +/- 10.9, P < 0.01). This was probably attributable to the marked decrease in endogenous 1,25-(OH)2D3 levels caused by both doses of 19-nor-1,25-(OH)2D2 because intestinal VDR correlated directly with serum 1,25-(OH)2D3 (r = 0.963; P = 0.008). Thus, 19-nor-1,25-(OH)2D2 appears to exert a selective action on the parathyroid glands compared with the intestine. Its low calcemic and phosphatemic properties may result from the decreased endogenous 1,25-(OH)2D3 levels that lead to a reduction in intestinal VDR. This selectivity makes this analog ideal for the treatment of secondary hyperparathyroidism.

Animals↗
PubMed1997

A new device to measure the activity size distribution of radon progeny in a low level environment.

In order to easily measure the activity size distribution of radon progeny, a new instrument was developed that can determine their activity median diameter in a low level environment within 90 min. A four stage low-pressure cascade impactor was used. The particle size cut-off points were >2,100, 700, 210 and 70 nm, based on a particle density of 1 g cm(-3). A 300 metal wire screen diffusion collector facing with a silicon semiconductor detector was placed within the first air inlet in order to measure unattached radon progeny concentrations and also to prevent unattached progeny from entering the impactor. Silicon photodiodes, from which the ceramic windows were removed, were installed in each stage of the impactor. Alpha particles could be effectively detected with 46.2% efficiency as radon progeny were directly collected on the detecting surface of the photodiode. The surface of the photodiodes was coated with silicon grease to prevent particle bounce-off. An inline-type filter holder with a silicon semiconductor detector was connected at the exit of the impactor in order to collect the remaining radon progeny and to measure their concentrations. The instrument was used to concurrently measure the size distribution of radon progeny and the aerosol in the natural environment. The results indicated that the activity median diameter fell in between the median diameter of the aerosol derived from number statistics and that derived from surface-area statistics. A negative correlation was found between the unattached fraction (f(p)) and the activity median diameter.

Aerosols↗
PubMed1997

[The present state of the visiting nurse support system of our hospital].

In our hospital, a Visiting Care Service System was started in 1985, and now we have four nurses and one public health nurse. In the first half of 1996, we visited 116 patients. Their average age was 79.5 years-old, and most of them were almost bedridden all day. In 63.8% of these cases, the underlying disease was cerebrovascular. Frequency of visits was once a week in 45.7%, but in the terminal state we visited more frequently almost all days. In 79.3% of these cases, the duration of this service was less than three years, but in a few cases more than 10 years. Some patients were given the following medical care: gastrostomy (39.7%), care of bed sores (29.3%), necessity of suction of sputa (26.7%), urinary drainage tube (13.0%), tracheostomy, home oxygen therapy, home parenteral nutrition therapy, bile drainage tube insertion and so on. Persons providing care were mostly female (87.8%), and most of them were 40 to 60-year-old women. It is important to create a suitable support system to continue treatment at home.

Adult↗
PubMed1996

Regulation of cell-cell contacts in developing Drosophila eyes by Dsrc41, a new, close relative of vertebrate c-src.

In Drosophila, Dsrc64 is considered a unique ortholog of the vertebrate c-src; however, we show evidence to the contrary. The closest relative of vertebrate c-src so far found in Drosophila is not Dsrc64, but Dsrc41, a gene identified for the first time here. In contrast to Dsrc64, overexpression of wild-type Dsrc41 caused little or no appreciable phenotypic change in Drosophila. Both gain-of-function and dominant-negative mutations of Dsrc41 caused the formation of supernumerary R7-type neurons, suppressible by one-dose reduction of boss, sev, Ras1, or other genes involved in the Sev pathway. Dominant-negative mutant phenotypes were suppressed and enhanced, respectively, by increasing and decreasing the copy number of wild-type Dsrc41. Colocalization of Dsrc41 protein, actin fibers and DE-cadherin, and Dsrc41-dependent disorganization of actin fibers and putative adherens junctions in precluster cells suggested that Dsrc41 may be involved in the regulation of cytoskeleton organization and cell-cell contacts in developing ommatidia.

Actins↗
PubMed1995

Modulation of the plasma cholesteryl ester transfer by stachybotramide.

Plasma cholesteryl ester transfer protein (CETP), which mediates the transfer and exchange of neutral lipids (cholesteryl esters (CE) and triglycerides (TG) and phospholipids between plasma lipoproteins, plays an essential role in reverse cholesterol transport system. We have found that a fungal metabolite, stachybotramide, modulates the activity of CETP. Stachybotramide stimulated the [14C]CE transfer from high density lipoprotein (HDL) to very low density lipoprotein (VLDL) and low density lipoprotein (LDL) by 1.3- to 1.5-fold at 0.2-0.5 mM. This stimulation was abolished in the presence of anti-CETP antibody. On the other hand, the transfer of [14C]CE from LDL and VLDL to HDL was slightly reduced by stachybotramide at 0.5 mM. Unlike the transfer of [14C]CE, the transfer of [3H]TG from HDL was not significantly affected by stachybotramide. These results suggest that stachybotramide preferentially stimulate the CETP-mediated transfer of CE from HDL to both VLDL and LDL.

Antibodies, Monoclonal↗
PubMed1995

Theoretical analysis of image defocus with intraocular lens decentration.

We used a theoretical eye model to evaluate the effect on peripheral images when planoconvex, biconvex, and meniscus intraocular lenses (IOLs) decenter 1 mm or 2 mm upward or downward from the pupillary center. A light source was projected from an angle of 0, 20, 28, or 40 degrees downward to a retina with a radius of curvature of 11 mm. When the IOL was centered, the light focused at a single point on the retina. When the IOL was decentered, the light became more dispersed as the incident angle of the light increased. The most dispersion was noted with the meniscus IOL; the least with the biconvex IOL. Astigmatism and aberration, which IOL decentration increases, were thought to cause the image defocus. These results suggest that IOL decentration may affect the sharpness of peripheral images.

Accommodation, Ocular↗
PubMed1995

Adenine phosphoribosyltransferase deficiency identified by urinary sediment analysis: cellular and molecular confirmation.

Adenine phosphoribosyltransferase deficiency is an autosomal recessive purine enzyme defect that causes urolithiasis and, in severe cases, renal failure. Most homozygotes with this disorder were identified by analyses of excreted or surgically removed urinary stones, but some were identified only because they were family members of symptomatic individuals. We report here the detection of adenine phosphoribosyltransferase deficiency in two cases by routine analysis of urinary sediments. 2,8-Dihydroxyadenine-like spherical crystals were observed in the urinary sediment, and a diagnosis of homozygous adenine phosphoribosyltransferase deficiency was confirmed by cellular and molecular methods. A molecular diagnostic system using the polymerase-chain reaction and single-strand conformational polymorphism analysis proved to be a rapid and sensitive method to identify the APRT*J allele, a common mutant allele among the Japanese people. These methods will facilitate identification of symptomatic and asymptomatic individuals with homozygous adenine phosphoribosyltransferase deficiency.

Adenine↗
PubMed1995

Neural computation of motion in the fly visual system: quadratic nonlinearity of responses induced by picrotoxin in the HS and CH cells.

1. A computational model accounting for motion detection in the fly was examined by comparing responses in motion-sensitive horizontal system (HS) and centrifugal horizontal (CH) cells in the fly's lobula plate with a computer simulation implemented on a motion detector of the correlation type, the Reichardt detector. First-order (linear) and second-order (quadratic nonlinear) Wiener kernels from intracellularly recorded responses to moving patterns were computed by cross correlating with the time-dependent position of the stimulus, and were used to characterize response to motion in those cells. 2. When the fly was stimulated with moving vertical stripes with a spatial wavelength of 5-40 degrees, the HS and CH cells showed basically a biphasic first-order kernel, having an initial depolarization that was followed by hyperpolarization. The linear model matched well with the actual response, with a mean square error of 27% at best, indicating that the linear component comprises a major part of responses in these cells. The second-order nonlinearity was insignificant. When stimulated at a spatial wavelength of 2.5 degrees, the first-order kernel showed a significant decrease in amplitude, and was initially hyperpolarized; the second-order kernel was, on the other hand, well defined, having two hyperpolarizing valleys on the diagonal with two off-diagonal peaks. 3. The blockage of inhibitory interactions in the visual system by application of 10-4 M picrotoxin, however, evoked a nonlinear response that could be decomposed into the sum of the first-order (linear) and second-order (quadratic nonlinear) terms with a mean square error of 30-50%. The first-order term, comprising 10-20% of the picrotoxin-evoked response, is characterized by a differentiating first-order kernel. It thus codes the velocity of motion. The second-order term, comprising 30-40% of the response, is defined by a second-order kernel with two depolarizing peaks on the diagonal and two off-diagonal hyperpolarizing valleys, suggesting that the nonlinear component represents the power of motion. 4. Responses in the Reichardt detector, consisting of two mirror-image subunits with spatiotemporal low-pass filters followed by a multiplication stage, were computer simulated and then analyzed by the Wiener kernel method. The simulated responses were linearly related to the pattern velocity (with a mean square error of 13% for the linear model) and matched well with the observed responses in the HS and CH cells. After the multiplication stage, the linear component comprised 15-25% and the quadratic nonlinear component comprised 60-70% of the simulated response, which was similar to the picrotoxin-induced response in the HS cells. The quadratic nonlinear components were balanced between the right and left sides, and could be eliminated completely by their contralateral counterpart via a subtraction process. On the other hand, the linear component on one side was the mirror image of that on the other side, as expected from the kernel configurations. 5. These results suggest that responses to motion in the HS and CH cells depend on the multiplication process in which both the velocity and power components of motion are computed, and that a putative subtraction process selectively eliminates the nonlinear components but amplifies the linear component. The nonlinear component is directionally insensitive because of its quadratic non-linearity. Therefore the subtraction process allows the subsequent cells integrating motion (such as the HS cells) to tune the direction of motion more sharply.

Animals↗
PubMed1995

Assessment of malocclusion of Japanese junior high school pupils aged 12-13 years in Iwate prefecture according to the Dental Aesthetic Index (DAI).

The purpose of this investigation is to grasp the actual condition of malocclusion in Japanese junior high school pupils using the Dental Aesthetic Index (DAI). A total of 218 junior high school pupils aged 12-13 years were examined according to DAI. About 40% of the subjects had incisal crowding. The percentage of subjects with incisal spacing was 24%, and 71% of them had diastema of 1 mm or more. The percentage of subjects with anterior irregularity on the upper and lower arch was 39% and 33%, respectively. The percentage of subjects with anterior maxillary overjet and mandibular protrusion of 1 mm or more was 85% and 6% respectively. Dislocation by more than a half-cusp in the proximal or distal relationship in the molars was observed in 26% of all subjects. Mean +/- SD of DAI score was 25.3 +/- 7.3.

Adolescent↗
PubMed1995

Inhibition of acyl-CoA: cholesterol acyltransferase by isohalobacillin, a complex of novel cyclic acylpeptides produced by Bacillus sp. A1238.

A complex of metabolites consisting of two isomeric cyclic acylpeptides was isolated from a culture of Bacillus sp. A1238 by successive chromatographies on Amberlite XAD-7, silica gel and silica ODS columns. By a combination of spectroscopic and chemical analyses, the two subcomponents were identified as isomers of halobacillin, and the complex was designated isohalobacillin. Each molecule of isohalobacillin subcomponents contains either a 3-hydroxy-1-oxo-13-methyltetradecyl or a 3-hydroxy-1-oxo-12 methyltetradecyl moiety in place of a 3-hydroxy-1-oxopentadecyl moiety that is found in the halobacillin molecule. In a cell-free assay, isohalobacillin inhibited acyl-CoA: cholesterol acyltransferase by 50% at a concentration of 50 microM. When added to a culture of macrophage J774, the agent inhibited oxidized low density lipoprotein-induced synthesis of cholesteryl ester from [14C]oleate without affecting surface binding, internalization and degradation of the lipoprotein in the cells.

Amino Acid Sequence↗
PubMed1995

Bone marrow neutrophilia and suppressed bone turnover in human interleukin-6 transgenic mice. A cellular relationship among hematopoietic cells, osteoblasts, and osteoclasts mediated by stromal cells in bone marrow.

To elucidate the effect of interleukin-6 (IL-6) on bone and bone marrow (BM), human IL-6 transgenic mice (hIL-6 tgm) were produced. Their bone and BM were examined histologically, radiologically, histomorphometrically, and hematologically on a temporal basis. hIL-6 tgm showed histologically evident neutrophilia in BM. Increase in precursors of granulocytes and monocytes in hIL-6 tgm was demonstrated by an assay for colony forming unit in culture (CFU-C) of BM cells. Decrease in osteoblasts and osteoid and suppression of primary spongiosa formation were predominantly observed in hIL-6 tgm at 14 weeks old, the terminal stage of life for hIL-6 tgm. An assay for colony forming unit in fibroblastic (CFU-F) of BM cells revealed a decrease in osteoblast precursor (with regard to alkaline phosphatase-positive colonies) in hIL-6 tgm at 15 weeks old. Histomorphometry demonstrated a decrease of both osteoclast number and bone resorption in hIL-6 tgm. These results suggested that enhanced granulocytic hematopoiesis, suppressed bone turnover, and alteration of cellular population in stromal cells in BM occurred in hIL-6 tgm. Thus we provide new findings that facilitate understanding of cellular interrelationships among hematopoietic cells, osteoblasts, and osteoclasts mediated by stromal cells in BM.

Animals↗
PubMed1995

Activation of ornithine decarboxylase in epithelial cells of rat intestine.

Intestinal ornithine decarboxylase (ODC) is strongly induced by dietary amino acid and protein feeding. However, the consequence of this induction is unknown. In this study, we analyzed the relationship between intestinal ODC activity and DNA synthesis in villus and crypt cells of rat intestine. Single amino acid diets and protein diets stimulated ODC activity in villus cells, but not in crypt cells. However a 20% casein diet induced ODC activity and increased the putrescine concentration in villus and crypt cells. Administration of alpha-difluoromethylornithine, a suicide inhibitor of ODC, prevented both an increase in putrescine level and DNA synthesis in the crypt cells. Observations suggested that the induction of ODC is necessary to initiate DNA synthesis in rat intestinal epithelium.

Animals↗
PubMed1994

Postoperative results of vascularized double fibula grafts for femoral pseudoarthrosis with large bony defect.

In open femoral bone fractures osteomyelitis may develop as a complication. Many difficulties are experienced in the treatment of those fractures because an extended bone defect may be formed after repeated operations, and then amputation of the femoral bone becomes necessary. Since 1981 the present authors have performed the vascularized double fibula grafts in the treatment of 18 patients with successful results. With this grafting method, both vascularized double fibula grafts are collected at the same time, one as an intramedullary graft and the other as an onlay graft. The most important point in carrying out grafting by this method is to prepare the recipient bone bed adequately. In many cases, it is necessary to carry out the primary operation to curette the focus, and resect necrotic tissues and sequestrated bone before the vascularized double fibula grafts, and then grafting is performed as a second operation after infection has been controlled following the initial operation. Although differences in time required for recovery cannot be eliminated completely, it becomes possible for 16 out of 18 patients to walk without the use of a brace and crutches within 13 months on average.

Adolescent↗