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Biomedical subjects

Y Sawai

Publications and source records attributed to Y Sawai.

At least 19 recordsLinked to original sources
PubMed1997

Recombinant human TSH receptor expressed in E. coli.

We expressed the extracellular domain (20-408 aa, (T) of human TSH receptor (TSHR) in E. coli to detect TSHR autoantibodies (TRAb) and, moreover, we expressed the two portions (20-218 aa (5') and 217-408 aa (3')) of the extracellular domain thought to distinguish thyroid stimulating antibodies (TSAb) from blocking antibodies (TSBAb), using pGEX.3X as the expression vector. Using Western blotting analysis of the sera from patients with autoimmune thyroid disease, sera from Graves' patients and patients with idiopathic myxedema who had TSBAb reacted with the fusion protein (T), but none of the control sera reacted with it. We further evaluated whether or not the positive sear for T recognized fusion proteins (5') or (3'). The sera from Graves' patients reacted with both fusion proteins (5') and (3'). The sera from patients with idiopathic myxedema did not react with either of fusion proteins (5') or (3'). These findings suggest that these recombinant TSHR proteins could be used as antigens to detect TRAb, and differentiate TSABb from patients with idiopathic myxedema.

Antibodies, Blocking↗
PubMed1997

Alteration of platelet aggregation in patients with thyroid disorders.

To determine whether Graves' disease or primary hypothyroidism influence platelet function, we evaluated platelet aggregation in the platelet-rich plasma (PRP) from such patients. Platelet aggregation induced by adenosine diphosphate (ADP) in blood obtained from patients with untreated Graves' disease was significantly lower than normal, whereas that in patients with untreated primary hypothyroidism was relatively increased. The magnitude of platelet aggregation induced by collagen in both groups of patients resembled that induced by ADP. However, significant differences were evident between the two diseases (P < .05). In addition, we observed a significant inverse correlation between the extent of platelet aggregation and plasma levels of thyroid hormones (triiodothyronine [T3], thyroxine [T4], and free T3). Platelet aggregation returned to normal when the euthyroid condition was obtained in the patients following administration of antithyroid drugs or thyroid hormone. The findings are consistent with the possibility that thyroid hormones influence platelet aggregation partly via inhibition of myosin light-chain kinase (MLCK).

Adenosine Diphosphate↗
PubMed1997

Moment analysis of intestinal first-pass metabolism by portal-systemic concentration difference in single conscious rat using 5'-deoxy-5-fluorouridine and 5-fluorouracil as model drug system.

Intestinal first-pass metabolism was evaluated in a single conscious rat based on a difference in concentrations of parent drug and its metabolite between the portal and systemic bloods (P-S difference method). 5'-Deoxy-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-FU) were selected as model drug (prodrug of 5-FU) and metabolite pair. The portal vein and the femoral artery of the rat were cannulated so blood samples could be obtained simultaneously from the two sites. 5'-DFUR (100 mg/kg) was administered intraarterially or orally. Concentrations of 5'-DFUR and 5-FU in the portal and arterial samples were assayed by HPLC. The concentration-time profiles of 5'-DFUR and 5-FU were analyzed by local moment analysis. The extent of systemic bioavailability (F) of 5'-DFUR was estimated to be 75.8%. After oral administration, the local absorption ratio (Fa) and the mean local absorption time (ta) of 5'-DFUR were estimated to be 65.8 +/- 7.3% of dose and 74.0 +/- 21.7 min, respectively. The Fa value was close to F, which suggests that the metabolic conversion from 5'-DFUR to 5-FU is not extensive in the liver. The mean absorption time (MAT), calculated to be 76.3 min, almost coincided with ta, which suggests that the mean hepatic transit time is negligible in this experimental scale. The local absorption ratio of metabolite (Fam) was 6.8 +/- 1.7% of orally administered 5'-DFUR, which means that approximately 7% of 5'-DFUR arrived as 5-FU at the portal system. The mean local absorption time (tam) of 5-FU was estimated to be 75.5 min, which is close to that (74.0 min) of 5'-DFUR. Local moment analysis based on P-S difference enabled simultaneous estimation of the local absorption kinetics of a parent compound and the intestinal generation of metabolites by separating the intestinal first-pass metabolism of a drug from the subsequent disposition through the liver and in the systemic circulation.

Animals↗
PubMed1997

Thyrotropin-receptor and thyroid peroxidase-specific T cell clones and their cytokine profile in autoimmune thyroid disease.

We studied the cytokine profile and the immune responses to thyroid antigens of specific T cell clones (TCC) isolated from patients with Hashimoto's thyroiditis (HT) and Graves' disease (GD). Antigen-specific TCC were reactive to thyroid peroxidase (TPO), thyroglobulin (Tg) or human recombinant TSH-receptor extracellular domain (TSH-R), and/or their respective peptides. Of the 43 clones derived from HT patients, 65% were reactive to TPO, and 59% of the 32 clones derived from GD patients were reactive to TSH-R. TPO epitopes 100-119 and 625-644 were recognized by 75% of HT-derived clones, whereas TSH-R epitopes 158-176, 207-222, and 343-362/357-376 were recognized by 85% of GD-derived TCC. The TCC were classified according to their cytokine profile into T helper cell (Th)0 [secreting interleukin (IL)-4, IL-5, interferon (IFN)-gamma], Th1 (secreting IFN-gamma) and Th2 (secreting IL-4 and/or IL-5). Tumor necrosis factor-beta and IL-10 were produced by all subsets. The specific TCC were predominantly Th1-like cells in HT, and were Th0- and Th1-like cells in GD. Fifty three percent of Th0 clones were derived from GD patients and were reactive to TSH-R, whereas 50% of Th1 clones were derived from HT patients and were reactive to TPO or Tg. Most Th2 clones (82%) were reactive to TPO and were established from peripheral blood. All these clones produced IL-5, and 64% produced IL-4 and IL-10. Interestingly, IFN-gamma was highly produced by TPO- or Tg-specific clones established from HT thyroid tissue. These results confirm at the clonal level our previous studies regarding T cell epitopes on TPO and TSH-R molecules and support the concept that immunodominant T cell epitopes are located on amino acid residues 100-119 and 625-644 of TPO in HT and amino acid residues 158-176, 207-222 and 343-362/357-376 of TSH-R in GD. Our studies also demonstrate that thyroid-specific T cells can be classified into Th0, Th1, and Th2 subsets. TPO- or Tg-specific clones with Th1 phenotype appear to be involved in the pathogenesis of HT, mediating thyroid tissue destruction, whereas TSH-R clones with Th0 phenotype may induce thyroid-stimulating autoantibodies in GD.

Autoantigens↗
PubMed1997

Simultaneous evaluation of intestinal absorption and hepatic extraction of 5-fluorouracil using portal-systemic concentration difference by short-period double dosing in a single conscious rat.

The intestinal local absorption and the hepatic local disposition of 5-fluorouracil (5-FU) in a single conscious rat was investigated by the simultaneous sampling of portal and systemic bloods (PS method). The portal blood flow rate, measured using a compact electromagnetic flow-meter, was estimated to be 15.3 +/- 2.2 ml/min per body weight (250g). The portal vein and the femoral artery of the rat were cannulated to simultaneously obtain blood samples from two sites. 5-FU (30 mg/kg) was administered first intraarterially, and subsequently orally 90 min after intraarterial administration to a single conscious rat (short-period double dosing; DD). Concentrations of 5-FU in the portal and arterial bloods were determined by HPLC. The local absorption ratio (Fa) and the absolute bioavailability (F) were 71.2 +/- 15.4 and 25.1 +/- 13.2%, respectively. Consequently, the hepatic extraction ratio (F[H] = F/Fa) was estimated to be 34.9 +/- 14.4%. The mean local absorption time (t[a]) and the mean absorption time (MAT) were 37.5 +/- 15.5 and 31.4 +/- 13.7 min, respectively and they were statistically the same. In conclusion, a PS method by short-period double dosing (PS-DD method) has been developed to evaluate the first-pass effect, separating the intestinal absorption and hepatic elimination of a drug in a single conscious rat. It was demonstrated by applying PS-DD method that the low bioavailability of 5-FU can be explained by the large hepatic first-pass extraction, and that the large inter-individual variation in bioavailability of 5-FU is caused mainly by a large variation in the hepatic first-pass effect. The large variation in t(a) (or MAT) was predicted to be due to a variation in the gastric emptying time.

Animals↗
PubMed1996

Short stature due to growth hormone deficiency associated with Cushing's disease and ulcerative colitis.

We report a rare case of Cushing's disease associated with ulcerative colitis in a patient primarily treated with growth hormone due to short stature. At the age of fifteen years, the patient had a short stature due to GHD and was treated with the extracted GH for a short period. At the age of twenty-one years, his body weight gradually increased and, based on the results of several tests, he was diagnosed with Cushing's disease and GHD was observed in our patient. The excess secretion attenuation of pituitary hormones with reduced secretion periods as well as the relation between ulcerative colitis and elevated plasma cortisol concentrations is briefly discussed in this paper.

Adult↗
PubMed1996

A case of myocarditis associated with IDDM.

We report a case of diabetic ketoacidosis (DKA) complicated by acute myocarditis, which was confirmed by cardiac biopsy. A 26-year-old man was hospitalized with severe DKA. On admission, nonspecific ST-T change was noted on the electrocardiogram (ECG). The patient's levels of creatine phosphokinase (CPK) and glutamic oxaloacetic transaminase were slightly elevated, but he did not complain of chest discomfort or symptoms of heart disease. On the first day after admission, ST-T elevation was noted on ECG during treatment of DKA. By cardiac angiography and cardiac biopsy, coronary heart disease was ruled out and postmyocarditic change was histologically confirmed. An episode of upper respiratory viral infection before the onset of acute diabetes suggested that the patient suffered from viral-induced myocarditis and consequent development of IDDM. This possibility was confirmed by the clinical course of ECG change, with elevated CPK and lactate dehydrogenase and a slightly elevated antibody titer for echovirus.

Adult↗
PubMed1996

[Double lumen--coaxial catheter system for combined CT during arterial portography and CT hepatic angiography].

The high sensitivity of CT during arterial portography (CTAP) for hepatic lesions is accompanied with a lack of specificity for diagnosis. Combined CTAP and CT hepatic angiograpy (CTHA) had been proved to improves lesion detection and heightens confidence in interpreting perfusion abnormalities. We describe a new double lumen - coaxial catheter system for performing combined CTAP and CTHA without the need for repeated transfer of the patient or bilateral arterial punctures. This technique was employed in eight patients with liver neoplasms. In all eight patients, CTAP and CTA images were obtained successfully. We concluded that this method was useful for the evaluation of liver tumors.

Catheterization↗
PubMed1995

[A rare case of a diabetic patient with small cell lung cancer, initially diagnosed as pyogenic vertebral osteomyelitis].

A rare case of a patient with non-insulin-dependent diabetes mellitus (NIDDM) with small cell lung cancer, initially diagnosed as pyogenic vertebral osteomyelitis, was reported. A 40-year-old male patient was diagnosed with NIDDM about 3 years earlier, but he did not receive any treatment. Then, a two-month history of high fever, persistent cough and back pain developed. Chest X-ray film showed a lung infiltrate with a small cavity in the upper portion of the left lung. Computed tomography and magnetic resonance imaging of the chest revealed a tumor mass shadow with osteoclasia along the bodies of the 6th and 7th thoracic vertebral bone. Staphylococcus aureus infection was confirmed by arterial blood culture. Administration of antibiotics resulted in the disappearance of the left lung infiltrate and a slight reduction of the tumor mass in the thoracic vertebral bone, suggesting pyogenic vertebral osteomyelitis as an unusual complication of NIDDM. However, as the tumor mass still remained, needle biopsy for the mass lesion was performed, resulting in the diagnosis of metastasis of small cell carcinoma from the left lung. Gene aberration in this lung disease has been reported recently, and its correlation with NIDDM which may also be induced by genetic abnormality is an interesting question that remains to be resolved.

Adult↗
PubMed1995

Pharmacokinetics of enoximone after various intravenous administrations to healthy volunteers.

The pharmacokinetics of enoximone and its sulfoxide metabolite were investigated in healthy male volunteers after various intravenous administrations: a bolus single dose, a continuous infusion, and bolus multiple doses of enoximone. The overall pharmacokinetic profiles of enoximone and sulfoxide metabolite indicated linearity over the range of 0.25-2.0 mg/kg after single doses of enoximone. The hypothetical plasma concentration just after bolus injection of enoximone, the maximum concentration of sulfoxide, and the area under the concentration-time curves of both compounds increased proportionally with dose. The terminal half-lives of both compounds indicated similar values (2.0-2.7 h) and were not dose related. After four consecutive doses given at 3-h intervals, no accumulation was observed for either compound, and the pharmacokinetic parameters were not altered. After a 4-h infusion of enoximone, the areas under the plasma concentration-time curves of both compounds were 30% lower than the estimated values from the single dose study. Also, some pharmacokinetic parameters were changed as compared to those from the single dose study. The pharmacokinetic parameters obtained in Japanese healthy volunteers showed no marked differences from those obtained in Caucasians; thus, no racial difference was suggested in the pharmacokinetic properties of enoximone.

Adult↗
PubMed1995

Histamine H1 receptor occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography.

1. Histamine H1 receptor occupancy in the human brain was measured in 20 healthy young men by positron emission tomography (PET) using [11C]-doxepin. 2. (+)-Chlorpheniramine, a selective and classical antihistamine, occupied 76.8 +/- 4.2% of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg. Intravenous administration of 5 mg (+)-chlorpheniramine almost completely abolished the binding of [11C]-doxepin to H1 receptors (H1 receptor occupancy: 98.2 +/- 1.2%). 3. Terfenadine, a nonsedative antihistamine, occupied 17.2 +/- 14.2% of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg. 4. There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject. 5. PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea-pig brain determined by in vivo binding techniques, although for the same H1 receptor occupancy the dose was less in human subjects than in guinea-pigs. 6. The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second-generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively.

Administration, Oral↗
PubMed1995

Dexamethasone-induced changes in glucose transporter 4 in rat heart muscle, skeletal muscle and adipocytes.

To clarify the effect of glucocorticoid on glucose transporters (GLUT) in adipocytes and muscle, we examined the changes of GLUT4 in rat heart muscle, skeletal muscle and adipocytes during long-term administration of dexamethasone and the translocation of GLUT4. The levels of GLUT4 in the plasma membrane and the low-density microsome fraction were measured by Western blotting using anti-GLUT4 peptide antibody. The levels of GLUT4 in the heart and skeletal muscles of rat were unchanged by treatment of dexamethasone. In the adipocytes the level of GLUT4 in plasma membrane was changed, but it was decreased in the low-density microsome fraction. Although adipocytes are less involved in blood sugar regulation than skeletal muscle, this finding suggests that glucose metabolism in Cushing's syndrome is affected partly by a decrease of GLUT4 in the adipocytes.

5'-Nucleotidase↗
PubMed1995

Effects of thyroid hormone on coenzyme Q and other free radical scavengers in rat heart muscle.

Active oxygen species are reported to cause organ damage. This study was therefore designed to determine the behaviour of antioxidants and free radical scavengers so as to reveal changes in animals in the hyper- and hypothyroid state. Levels of antioxidant factors (i.e. coenzyme Q (CoQ)10, CoQ9 and vitamin E) and free radical scavengers (catalase, glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD)) were measured in the heart muscles of rats rendered hyper- or hypothyroid by 4 weeks of thyroxine (T4) or methimazol treatment. Serum levels of CoQ9 and total SOD were also measured. A significant reduction in CoQ9 levels was observed in the heart muscles of both hyper- and hypothyroid rats when compared with control hearts. There was no difference in serum CoQ9 levels in thyroid dysfunction when compared with control animals. Levels of vitamin E in the heart muscles of hyperthyroid rats were significantly increased, and there was no reduction in vitamin E levels in hypothyroid rats when compared with control hearts. GSH-PX levels in the heart muscle were reduced in hyperthyroid rats and increased in hypothyroid rats when compared with control hearts. However, there were no differences in catalase levels in heart muscle between hyper- and hypothyroid rats. The concentration of SOD in heart muscle was increased in hyperthyroid rats and was not decreased in hypothyroid rats compared with control rats, suggesting the induction of SOD by excessive production of O2-. These data suggest that the changes in these scavengers have some role in cardiac dysfunction in the hyper- and hypothyroid state in the rat.

Animals↗
PubMed1995

Changes in calmodulin concentration and cyclic 3',5'-nucleotide phosphodiesterase activity in skeletal muscle of hyper- and hypothyroid rats.

Hyper- and hypothyroid states occasionally induce skeletal muscle dysfunction i.e. periodic paralysis and thyroid myopathy. The etiology of these diseases remains unclear, but several findings suggest that the catecholamine-beta-receptor-cAMP system or other messenger systems are disturbed in these diseases. In this context, we evaluated changes in the cyclic 3',5'-nucleotide metabolic enzyme, cyclic 3',5'-nucleotide phosphodiesterase (PDE) and calmodulin concentrations in skeletal muscles of hyper- and hypothyroid rats. Activities of cyclic AMP-PDE were low in skeletal muscle both from hyper- and hypothyroid rats, and calmodulin concentration was high in hyperthyroid and low in hypothyroid rats, as compared with normal rats. DE-52 column chromatographic analysis showed that the cGMP hydrolytic activity in peak I and the cAMP hydrolytic activity in peak II were decreased in hypothyroid rats, whereas cAMP hydrolytic activity in peak III was unchanged. The cAMP hydrolytic activity in peak III was decreased in hyperthyroid rats, but the activities in peaks I and II were unchanged. These findings indicate that cAMP and calmodulin may have some role in skeletal muscle function in the hyperthyroid state, and that cAMP and calmodulin-dependent metabolism may be suppressed in the hypothyroid state.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Changes in lipid peroxidation and free radical scavengers in the brain of hyper- and hypothyroid aged rats.

To determine how lipid peroxides and free radical scavengers are changed in the brain of hyper- or hypothyroid rats, we examined the behavior of lipid peroxide and free radical scavengers in the cerebral cortex of aged (1.5 years old) rats that had been made hyper- or hypothyroid by the administration of thyroxine or methimazol for 4 weeks. Concentrations of catalase, Mn-superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were increased in hyperthyroid rats compared with euthyroid rats. Concentrations of total SOD, Cu,Zn-SOD and GSH-PX were increased but that of Mn-SOD was decreased in hypothyroid animals. There were no differences among hyperthyroid, hypothyroid and euthyroid rats in the levels of coenzymes 9 or 10. The concentration of lipid peroxides, determined indirectly by the measurement of thiobarbituric acid reactants, was decreased in hyperthyroid rats but not in hypothyroid rats when compared with euthyroid animals. These findings suggest that free radicals and lipid peroxides are scavenged to compensate for the changes induced by hyper- or hypothyroidism.

Animals↗
PubMed1994

[The prevalence of antithyroid antibodies and long term follow-up in patients with lipiodol iodine-induced goiter].

We have carried out a follow-up study on iodine-induced goiter to clarify whether or not iodine could be a factor in the progression as well as the promotion of thyroid autoimmunity. We selected 143 women of child-bearing age without any previous thyroid disorders who had received hysterosalpingography (H.S.G.). 45 Sex and age-matched healthy subjects were chosen as controls. Serum nonhormonal iodine (S.N.I.) levels, frequency of goiter and antimicrosomal antibody (MCHA) in all the Lipiodol-cases were significantly higher than those in the controls (p < 0.001, < 0.01 and < 0.01), respectively. When the subjects were divided into 9 groups according to the duration of each 5 months after H.S.G., serum TSH and S.N.I. levels, incidence of goiter and MCHA in the initial group were significantly higher than those in the other groups (p < 0.05). The S.N.I. levels became normalized in 30 months after H.S.G. and the goiters disappeared in almost the same duration, while the incidence of higher MCHA titers declined gradually but significantly around 40 months after H.S.G. compared with that in the first 5 months after H.S.G. (p < 0.05). The frequency of goiter and MCHA in 44 cases after a 6-39 month follow-up decreased significantly compared to that in the initial group (p < 0.05). Therefore, we tried an individual longitudinal follow-up study on MCHA titer in 12 cases for 35-103 months, resulting in a significant reduction or negativeness of the titer in 6 cases. Likewise, MCHA titers in all cases decreased significantly (p < 0.05) on later evaluation. The present data suggest that iodine in Lipiodol administered via the vagina will act not only as the promoting factor, but as an aggravating agent for thyroid autoimmunity.

Adult↗