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C Takagi

Publications and source records attributed to C Takagi.

At least 37 records · Page 2Linked to original sources
PubMed1997

Specific retinal diacylglycerol and protein kinase C beta isoform modulation mimics abnormal retinal hemodynamics in diabetic rats.

PURPOSE: Elevation of diacylglycerol (DAG) and protein kinase C (PKC) levels in diabetic vascular tissue is associated with abnormalities of retinal and renal hemodynamics. The object of this study was to determine whether direct elevation of retinal DAG levels, in the absence of diabetes or hyperglycemia, can mimic the hemodynamic abnormalities normally observed in diabetic rats. Retinal DAG levels were elevated using an inhibitor of DAG kinase that converts DAG to phosphatidic acid. The effectiveness of a specific PKC-beta isoform inhibitor introduced directly into the retinas of diabetic rats in reversing diabetes-related abnormal retinal hemodynamics was also investigated. METHODS: For retinal blood flow studies, diacylglycerol kinase (DGK) inhibitor R59949, at various concentrations, was injected into the vitreous of nondiabetic Sprague-Dawley rats (n = 33), and a PKC-beta isoform-selective inhibitor LY333531 was injected into the vitreous of rats with streptozotocin (STZ)-induced diabetes of 2 weeks' duration (n = 21). Retinal hemodynamic changes were quantitated using video-based fluorescein angiography. Total DAG levels were assayed from five nondiabetic rat retinas after DGK inhibition and retinal PKC activities were assayed from six diabetic rat retinas after PKC-beta inhibition. RESULTS: DGK inhibitor R59949 injected into the vitreous dose dependently increased the mean circulation time (MCT) and decreased retinal blood flow (EC50 = 10(-8) M). After 30 minutes, 10(-5) M R59949 induced a 1.7-fold increase in total retinal DAG levels, compared with the levels in vehicle-injected eyes, an increase in MCT from 0.87 +/- 0.05 seconds to 1.44 +/- 0.12 seconds (P < 0.01) and a decrease in retinal blood flow from 105.3 +/- 6.5 pixel2/second to 64.1 +/- 5 pixel2/second (P < 0.01). The effect of R59949 was sustained for 60 minutes after injection. These retinal hemodynamic parameters after DGK inhibition were comparable to those measured at baseline in rats with STZ-induced diabetes of 2 weeks' duration (MCT = 1.38 +/- 0.20 seconds; retinal blood flow = 68 +/- 11.2 pixel2/second). Intravitreal injection of the PKC-beta inhibitor (LY333531) at 10(-5) M in diabetic rats decreased by a factor of 1.6 the diabetes-related increased PKC activation, decreased the prolonged MCT (0.98 +/- 0.13 seconds; P < 0.01) and increased retinal blood flow (93.4 +/- 14.2 pixel2/second; P < 0.01). The measured retinal circulatory parameters after PKC inhibition in the retina were comparable to those measured at baseline in the nondiabetic rats. CONCLUSIONS: These results provide direct evidence that DAG elevation and subsequent PKC-beta isoform activation are the primary biochemical sequelae responsible for the development of the abnormal retinal hemodynamics observed in diabetic rats.

Animals↗
PubMed1996

Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor.

The vascular complications of diabetes mellitus have been correlated with enhanced activation of protein kinase C (PKC). LY333531, a specific inhibitor of the beta isoform of PKC, was synthesized and was shown to be a competitive reversible inhibitor of PKC beta 1 and beta 2, with a half-maximal inhibitory constant of approximately 5 nM; this value was one-fiftieth of that for other PKC isoenzymes and one-thousandth of that for non-PKC kinases. When administered orally, LY333531 ameliorated the glomerular filtration rate, albumin excretion rate, and retinal circulation in diabetic rats in a dose-responsive manner, in parallel with its inhibition of PKC activities.

Administration, Oral↗
PubMed1996

Enhanced expression of beta-adrenergic receptor kinase 1 in the hearts of cardiomyopathic Syrian hamsters, BIO53.58.

We cloned an entire encoding sequence of beta-adrenergic receptor kinase 1 (beta ARK1) cDNA from the hearts of Syrian hamsters through reverse transcription and subsequent polymerase chain reaction. The cloned cDNA contained 2067 nucleotides coding 689 amino acids. The sequence had 95% homology to rat beta ARK1 and 90% homology to human homologue. Cardiomyopathic Syrian hamster, BIO53.58, has been used as a model animal of congestive heart failure. M-mode echocardiography confirmed that left ventricular contractility of 20-week-old BIO53.58 was markedly reduced. The expression of beta ARK1 mRNA in the hearts of BIO53.58 was significantly increased compared to control hamsters, F1b, suggesting that the enhanced beta ARK1 expression is acting as a negative feedback mechanism in order to maintain intracellular homeostasis against accelerated stimulation by catecholamines via phosphorylation of beta-adrenergic receptor.

Aging↗
PubMed1996

A new approach for evaluation of left ventricular diastolic function: spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography.

OBJECTIVES: To evaluate left ventricular diastolic function and differentiate the pseudonormalized transmitral flow pattern from the normal pattern, the propagation of left ventricular early filling flow was assessed quantitatively using color M-mode Doppler echocardiography. BACKGROUND: Because the propagation of left ventricular early filling flow is disturbed in the left ventricle with impaired relaxation, quantification of such alterations should provide useful indexes for the evaluation of left ventricular diastolic function. METHODS: Study subjects were classified into three groups according to the ratio of early to late transmitral flow velocity (E/A ratio) and left ventricular ejection fraction: 29 subjects with an ejection fraction > or = 60% (control group); 34 with an ejection fraction < 60% and E/A ratio < 1 (group I); and 25 with ejection fraction < 60% and E/A ratio > or = 1 (group II). The propagation of peak early filling flow was visualized by changing the first aliasing limit of the color Doppler signals. The rate of propagation of peak early filling flow velocity was defined as the distance/time ratio between two sampling points: the point of the maximal velocity around the mitral orifice and the point in the mid-left ventricle at which the velocity decreased to 70% of its initial value. High fidelity manometer-tipped measurement was performed in 40 randomly selected subjects. RESULTS: The rate of propagation decreased in groups I and II compared with that in the control group (33.8 +/- 13.8 [mean +/- SD] and 30.0 +/- 8.6 vs. 74.3 +/- 17.4 cm/s, p < 0.001, respectively) and correlated inversely with the time constant of left ventricular isovolumetric relaxation and the minimal first derivative of left ventricular pressure (peak negative dP/dt) (r = 0.82 and r = 0.72, respectively). CONCLUSIONS: Spatial and temporal analysis of filling flow propagation by color M-mode Doppler echocardiography was free of pseudonormalization and correlated well with the invasive variables of left ventricular relaxation.

Blood Flow Velocity↗
PubMed1996

Neurofibromatosis complicated with XXX syndrome and renovascular hypertension.

A 25-year-old woman with neurofibromatosis was admitted to our hospital for evaluation of hypertension. When she was 6 years old, she was diagnosed as having neurofibromatosis and XXX syndrome because of multiple café-au-lait spots, neurofibromas of the skin and mental retardation. Chromosome analysis revealed that her karyotype was 46, XX/47, XXX. Renal arteriography disclosed aneurysmal change and stenosis of the right renal artery. After right-side nephrectomy and aneurysmectomy, the kidney was autotransplanted in the left iliac fossa. Surgical procedure resulted in marked amelioration of the hypertension without medical treatment. Thus, aortorenal bypass and renal autotransplantation have emerged as the preferred revascularization operations. This is the first report of a chromosomal linkage between neurofibromatosis which is thought to be an autosomal dominant disease and the XXX syndrome.

Adult↗
PubMed1996

Endothelin-1 action via endothelin receptors is a primary mechanism modulating retinal circulatory response to hyperoxia.

PURPOSE: To determine the role of endothelin (ET)-ETA receptor mediation and endogenous production of endothelin-1 (ET-1) in the retinal response to hyperoxia. METHODS: Brown-Norway rats (n = 30) were injected intravitreally with an ETA receptor-selective antagonist, BQ-123, and an inhibitor of ET-converting enzyme (ECE), phosphoramidon, and were exposed to a 100% oxygen breathing mixture. Control rats underwent intravitreal injection of vehicle alone (2.5% Emulphor in phosphate-buffered saline). The retinal hemodynamic responses were analyzed using video-based fluorescein angiography (VFA) methodology. Baseline measurements were made with the animals breathing room air, and this was followed by intravitreal injections of the above agents. Subsequent VFA measurements were made after 5, 10, and 15 minutes of breathing 100% oxygen. RESULTS: The 10 rats injected with vehicle alone demonstrated the expected retinal response to hyperoxia, with significant (P < 0.001) vessel constriction (18% +/- 5%), an increase in retinal mean circulation time (0.84 +/- 0.13 seconds in room air and 1.59 +/- 0.27 seconds in 100% oxygen), and a decrease in blood flow (110.7 +/- 19.2 pixel2/second in room air and 41.9 +/- 9.0 pixel2/second in 100% oxygen), compared to values measured during room air breathing. The hyperoxic response in rats (n = 9) injected with 10(-4) M BQ-123 was significantly (P < 0.001) blunted compared to the group injected with vehicle alone. In contrast, intravitreal injection of saralasin, a specific angiotensin II receptor antagonist, had no significant effect on the retinal response to hyperoxia (n = 5). Intravitreal phosphoramidon (10(-3) M, n = 6) injection also resulted in a significantly (P < 0.001) blunted circulatory response to hyperoxia compared to rats injected with vehicle alone. This blunted response after ECE inhibition was comparable to that measured after ETA receptor antagonism with BQ-123 injection. CONCLUSIONS: These results demonstrate that the enhancement of ET-1 action, possibly caused by the activation of ECE, plays a primary role in regulating the retinal hemodynamic response to hyperoxia.

Angiotensin Receptor Antagonists↗
PubMed1996

Regulation of retinal hemodynamics in diabetic rats by increased expression and action of endothelin-1.

PURPOSE: To investigate the role of endogenous endothelin-1 (ET-1) expression and its interaction with the ETA receptor in the physiologic regulation of vascular tone as well as in the development of abnormal retinal hemodynamics in diabetes. METHODS: Retinal blood flow, using digitized video fluorescein angiography recordings, was quantitated after intravitreous injections of ET-1; BQ-123, an ETA receptor antagonist; and phosporamindon, an endothelin converting enzyme inhibitor in the eyes of diabetic and nondiabetic rats. A total of 154 rats were used for these experiments. Message levels of preproendothelin-1 (preproET-1) were measured from the retina of diabetic and nondiabetic rats using competitive polymerase chain reaction (PCR) techniques. RESULTS: Retinal blood flow was reduced (33%, P < 0.001) in diabetic rats compared to nondiabetic rats. BQ-123, an ETA receptor antagonist, but not saralasin, an angiotensin receptor antagonist, increased retinal blood flow in a dose-dependent manner in diabetic (EC50 of 8 x 10(-7) M) and in nondiabetic rats (EC50 of 8 x 10(-8) M). Besides being resistant to BQ-123, the maximal response in diabetic animals occurred 20 minutes later than in nondiabetic animals. Decreasing ET-1 levels by inhibiting endothelin-converting enzyme with phosphoramidon normalized retinal blood flow in diabetic rats. In nondiabetic rats, the intravitreous injection of exogenous ET-1 (10(-8) M) resulted in retinal blood flow decreases comparable to those measured in diabetic animals, and the subsequent injection of 10(-4) M BQ-123 produced retinal blood flow changes comparable to those measured in BQ-123 injected diabetic rats. Comparison of preproET-1 messenger RNA expression in the retina, brain and lung of control and diabetic rats using quantitative PCR and Northern blot analysis showed 2.0- and 1.7-fold increases in the retina and the brain, respectively, without changes in the lung. CONCLUSIONS: These data suggest that ET-1 is involved in the regulation of retinal blood flow in normal physiologic outcome, and an increase in the endogenous expression of ET-1 contributes to the reduction of retinal blood flow reported in the early stages of diabetes mellitus.

Animals↗
PubMed1995

[Unconsciousness due to hyponatremia in a patient with short stature with panhypopituitarism].

An unconscious woman of short stature (141 cm) was admitted to our hospital in March, 1994. She had hyponatremia (120 mEq/l) and had experienced massive bleeding during delivery. No increment of either plasma ACTH or cortisol levels was observed after insulin-induced hypoglycemia. However, urinary 17OHCS levels gradually increased after repeated intramuscular injections of ACTH. Plasma free T3 and free T4 levels were low. Neither plasma TSH nor prolactin (PRL) levels increased after an intravenous injection of TRH. Basal plasma LH, FSH and growth hormone (GH) levels were low and there were no observable responses to any of the stimulation tests. A magnetic resonance image (MRI) of her pituitary gland showed an empty sella. These results showed that she had a panhypopituitarism with primary empty sella. Replacement therapy with glucocorticoid was started and serum sodium levels normalized immediately. Levothyroxine was also administered. The possibility of pituitary dwarfism during her youth and a gradual postpartum reduction of other pituitary hormones may have caused an impairment of the hypothalamo-pituitary-adrenal axis.

Dwarfism, Pituitary↗
PubMed1995

Reversal of abnormal retinal hemodynamics in diabetic rats by acarbose, an alpha-glucosidase inhibitor.

Acarbose is an inhibitor of intestinal alpha-glucosidase and has been reported to decrease blood glucose concentrations and glycosuria in diabetic patients and animals. In this study we investigated whether this drug could prevent the abnormalities detected in retinal circulation of diabetic rats. Longitudinal paired studies were performed and the changes in retinal circulation were analyzed using video based fluorescein angiography (VFA) methodology in the same animal. Baseline VFA recordings were obtained from 41 rats. These rats were separated into 4 different groups: In group A (n = 12), diabetes was induced by streptozotocin (STZ) injection and the rats were fed with acarbose (40 mg/100 g powdered chow) mixed into regular rat chow; In group B (n = 10), diabetes was induced by STZ injection and the rats were fed with normal chow; In group C (n = 9), the non-diabetic rats were fed with acarbose; In group D (n = 10), the non-diabetic rats were fed with normal chow. At the end of 2 weeks, all rats again underwent VFA recordings. Blood glucose levels and body weights of rats were monitored during the experiment. The mean blood glucose concentration of Group B was raised from 98.5 +/- 8.7 to 342 +/- 30 mg/dl after STZ injection while in Group A, this change in glucose level was partially ameliorated by acarbose (from 102 +/- 15 to 247 +/- 48 mg/dl). In Group C and D, the blood glucose levels were not significantly changed during the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acarbose↗
PubMed1994

Effect of daily subcutaneous administration of recombinant erythropoietin on chronic anemia in rheumatoid arthritis.

Mean (+/- SD) serum erythropoietin (EPO) levels were 18.6 +/- 5.6 mU/ml in 180 normal Japanese subjects. Serum EPO levels were elevated with a negative correlation on a log scale (r = -0.864, P < 0.005) to hematocrit (Ht) values in anemic patients not associated with rheumatoid arthritis (RA) or chronic renal failure (CRF). Serum EPO levels in patients with RA (31.6 +/- 16.4 mU/ml) were relatively lower than those in normal subjects and anemic patients without RA or CRF when matched for comparative Ht values. Seven anemic patients with RA were treated by daily subcutaneous (sc) injection of recombinant EPO (rEPO, 500-1,000 U/day) for 4 weeks. The patients had initial Ht values of 25.1% or less and maintained stable clinical status. The treatment with rEPO raised serum EPO levels (53.8 +/- 15.2 mU/ml, P < 0.05), which resulted in an increase in Ht values (more than 3%) in 6 out of 7 patients with RA. The mean (+/- SD) Ht values at the end of the treatment with rEPO (500-1,000 U/day) were greater than those before the treatment in the 7 patients with RA (28.5 +/- 4.6 vs. 22.7 +/- 2.5%, P < 0.05). These findings suggest that chronic anemia associated with RA may be corrected by daily sc injection of a small dose of rEPO.

Adult↗
PubMed1994

[Complete remission induced by combined treatment with all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF) in a patient with relapsed acute promyelocytic leukemia].

In February, 1990, a 49-year-old man was admitted with petechia and gingival bleeding. The peripheral blood showed 5,200 leukocytes/microliters including 73% abnormal promyelocytes and 24,000/microliters platelets. Bone marrow puncture revealed that nucleated cell count was 331,250/microliters including 85.4% abnormal promyelocytes with 46XY, i(17q) chromosome. Coagulation tests revealed DIC. He was diagnosed as having acute promyelocytic leukemia, and he was treated with the BHAC-DMP protocol. He achieved complete remission, and received consolidation therapy and maintenance therapy. However, he relapsed in May, 1991 with 46XY, 16q-, i (17q) chromosome. He was treated with BHAC-MV protocol and again achieved complete remission. In June, 1992, he re-relapsed and 3.6% blasts and 10% abnormal promyelocytes was found in his bone marrow. He was treated for 14 days with 15 mg Aclarubicin without any change. Then he was treated with 60 mg All-trans retinoic acid (ATRA). After administration of ATRA, his peripheral blood leukocyte count increased temporarily but bone marrow suppression continued. Then he received continuous subcutaneous infusion of 24 micrograms/day granulocyte colony-stimulating factor (rhG-CSF). After treatment with ATRA and rhG-CSF, he entered a third complete remission.

Combined Modality Therapy↗
PubMed1993

Chronic idiopathic thrombocytopenic purpura complicated by chronic disseminated intravascular coagulation associated with abdominal aortic aneurysm.

A patient with chronic idiopathic thrombocytopenic purpura (ITP), chronic disseminated intravascular coagulation (DIC) and abdominal aortic aneurysm is described. He had severe thrombocytopenia and his platelet life span was shortened (29 h). Indium 111-labeled platelet scintigraphy demonstrated an increased accumulation of radioactivity over the aneurysm and the spleen. Following preoperative heparin therapy for DIC, the platelet count remained low (10 x 10(9)/l), while the DIC improved. Because of the elevated platelet-associated IgG, we considered that the patient had complicated chronic ITP. After intravenous immunoglobulin therapy, his platelet count increased. The aneurysm was successfully replaced with an artificial Y-graft vessel and a splenectomy was performed at the same time. The platelet count was maintained at about 60 x 10(9)/l after the operation and the patient is quite well now.

Aged↗
PubMed1992

[A case of Cushing's disease associated with a non-functioning adrenal tumor].

A 52-year-old woman was admitted to our hospital for further examination of central obesity, hypertension and hirsutism suggesting Cushing's syndrome. Hirsutism had been remarkable for two years, and muscle weakness of the lower extremities gradually developed during the past year. CT scan revealed a tumor in the left adrenal gland which was 1 cm in diameter, round, well-circumscribed, homogeneous and not enhanced. Endocrine data disclosed increased urinary 17-OHCS (11.5-16.4 mg/day) and elevated plasma ACTH (125 pg/ml) and cortisol (19 micrograms/dl) with a lack of diurnal rhythm. Administration of the single-dose dexamethasone (1mg) did not suppress plasma cortisol. However, consecutive administration of either 2mg or 8mg of dexamethasone for 2 days suppressed both plasma cortisol and urinary 17-OHCS. Administration of metyrapone raised both urinary 17-OHCS and plasma ACTH levels. Rapid ACTH test resulted in a hyperresponse of plasma cortisol. CRF injection raised plasma ACTH and cortisol. Bilateral adrenal glands were well demonstrated by 19-iodocholesterol (I-131) scintigraphy during the administration of dexamethasone. MRI with Gd-contrast revealed a microadenoma in the sella turcica. With the diagnosis of Cushing's disease, the microadenoma was removed by the transsphenoidal approach and adrenal function was normalized. However, the left adrenal tumor remained on CT scan but was not demonstrated by scintigraphy. These findings indicate that this is a very rare case of Cushing's disease which was associated with an unilateral non-functioning adrenal tumor.

Adenoma↗
PubMed1992

[Effect of subcutaneous administration of interleukin-1 beta on blood platelet count and serum GM-CSF in patients with myelodysplastic syndrome and aplastic anemia].

Subcutaneous administration of recombinant human Interleukin-1 beta (IL-1 beta) in a dose of 1-3 x 10(4) U/day for 14 to 72 days resulted in an increase in circulating granulocytes and bone marrow monocytes in all the 4 patients examined. Circulating platelet count was also increased in two of four patients with myelodysplastic syndrome (MDS) and aplastic anemia (AA). Bone marrow examination revealed an increase in megakaryocyte count in these patients, whereas the percentage of blast was not changed. An increase in blood platelet count was accompanied by an increase in serum GM-CSF in a patient with AA, whereas serum IL-6 level was not changed throughout the treatment with IL-1 beta. These findings suggest that IL-1 beta may be useful for the treatment of a proportion of patients with MDS and AA who are associated with thrombocytopenia.

Aged↗
PubMed1992

[Acute myelogenous leukemia transformed from myelodysplastic syndrome with tetraploid chromosome constitution].

A 57-year-old female presented with general fatigue. She had neither lymphadenopathy nor hepatosplenomegaly. Laboratory data revealed anemia and leukopenia (1,500/microliters) with a differential count of 4.5% leukemic cells. The myelogram revealed 34.4% leukemic cells, of which diameter ranged from 20 to 28 microns. The diagnosis was acute myelogenous leukemia (FAB: M2) with myelodysplasia. Cytogenetic analysis revealed that the leukemic cells had chromosome abnormalities involving both diploidy and tetraploidy with structural rearrangement. Structural rearrangement included del(5) (q22q33), del(15) (q22q24), and t(3; 12) (q25;p13). Small dose aclacinomycin-A treatment was effective in reducing the number of leukemic cells in bone marrow, and both anemia and leukocytopenia were improved.

Aclarubicin↗
PubMed1992

[Clinical use of serum erythropoietin determination by the recombigen EPO RIA kit].

Serum erythropoietin (EPO) levels were determined by the recombigen EPO RIA kit (DPC) in normal subjects and patients with renal dysfunction, diabetes mellitus, hypothyroidism and a variety of hematological disorders. Mean (+/- SD) serum EPO levels were 18.6 +/- 5.6 mU/ml in 180 normal subjects and no sex difference was obtained. Serum EPO levels in older subjects were slightly greater than those in younger subjects. There was a negative correlation between serum EPO levels and Ht values in anemic patients with normal renal function, whereas serum EPO levels were within the normal range in anemic patients with renal disorders, suggesting that serum EPO levels were relatively low in patients with chronic renal failure. Serum EPO levels were rather increased in patients with diabetes mellitus and hypothyroidism. High serum EPO levels were obtained in patients with a variety of hematological disorders such as acute leukemia, multiple myeloma, myelodysplasia syndrome, aplastic anemia and pure red cell aplasia. In a patient with pure red cell aplasia treated with glucocorticoids, serum EPO levels were lowered before anemia was recovered and reticulocytes were increased. These findings indicate that measurement of serum EPO levels are useful for not only differential diagnosis of anemia but also clinical evaluation of the treatment.

Adult↗