Biomedical subjects
Publications and source records attributed to N Takasu.
A patient with hypogonadotropic hypogonadism and anosmia (Kallmann's syndrome) is described. Anosmia has been believed to be due to hypoplasia of the rhinencephalon. This anatomical defect was demonstrated in vivo in a patient with Kallmann's syndrome by magnetic resonance imaging (MRI).
Ninety-four overweight subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) were followed for 10 years. No one from the NGT group developed diabetes, however 32% of the IGT subjects did develop diabetes. Initial data of the IGT subjects who developed diabetes were significantly different from those who did not develop diabetes. Fasting, peak and/or sigma plasma glucose (PG), IRI and CPR at 180 minutes and CPR/IRI at 0 and 180 minutes were increased, and the peak time of PG was delayed; also the prevalence of a positive family history was higher, and the body weight heavier. Seventy-nine percent of IGT subjects with the initial sigma PG of greater than or equal to 40 mM or a positive family history developed diabetes whereas only 3% of those with sigma PG of less than 40 mM and a negative family history developed diabetes. Therefore, it might be considered that among the overweight adults with IGT, those with sigma PG of greater than or equal to 40 mM or a positive family history are diabetes prone and those with sigma PG of less than 40 mM and a negative family history are diabetes resistant.
We investigated the effects of running load on the development of osteoarthritis (OA) in C 57 black male mice (Silberberg), a strain which spontaneously develops OA of the knee joint, and in Std:ddy male mice, a strain which does not develop OA. Six-week-old mice of both strains were randomly assigned to a non-forced running (control) group or forced running groups, which ran on treadmill 1 or 2 hours per day of 5 day/week program. Six, 18, and 30 weeks after the running period, the mice were sacrificed and the knee joints examined histologically and bone morphometrically. In the control C 57 black mice, OA occurred at 6 months of age, while in the forced running C 57 black mice, OA occurred at 3 months of age (6 weeks after the end forced running). In 6 and 9 months old C 57 black mice the incidence of OA in the forced running group was higher than that in corresponding control group. These data suggest that forced running load accelerates the process of OA in the knee joint in young mice of a strain which spontaneously develops OA.
A 56-year-old male patient on chronic hemodialysis developed liver cirrhosis. He received a total of 20 liters of blood transfusion. Bronze pigmentation of the skin and iron deposition to the liver, spleen, pancreas and thyroid gland, which was demonstrated by computed tomography and magnetic resonance imaging studies, and histological demonstration of iron deposition to the thyroid gland, bone marrow and gastric mucosa established a diagnosis of secondary hemochromatosis. Endocrine work-up revealed the presence of diabetes mellitus with minimum insulin secretory response, primary (or thyroprivic) hypothyroidism, hypoparathyroidism and hypogonadotropic hypogonadism. A wide-spread endocrine involvement as seen in this patient is a rare clinical feature of hemochromatosis secondary to massive blood transfusion in hemodialysis patients. Particularly, primary hypothyroidism due to iron deposition to the thyroid gland was quite a rare feature of hemochromatosis.
Insulin-like growth factor I (IGF-I) increased cytoplamic pH (pHi) and cytoplasmic Ca2+ [( Ca2+]i) in cultured porcine thyroid cells. Inhibition of the Na+/H(+)-antiporter by dimethylamiloride or a reduction of external Na(+)-concentrations attenuates the increases in pHi and [Ca2+]i. The [Ca2+]i response to IGF-I is a pHi-dependent process. IGF-I activates Na+/H(+)-antiporter and alkalinizes thyroid cells. The resulting increase in pHi facilitates the [Ca2+]i response by adjusting the pHi closer to the pHi-optimum of the intracellular Ca(2+)-mobilizing system. One of the biological functions of IGF-I-induced activation of the Na+/H(+)-antiporter is to shift the pHi to an optimal value for the [Ca2+]i response.
We investigated the localization of group II phospholipase A2 (PLA2-II) in rat vascular smooth muscle cells (VSMCs) by applying immunofluorescence and immunoelectron microscopy with its polyclonal antibody. In unstimulated cells, no immunolabelling was detected in the cells. On the other hand, in the cells stimulated with tumor necrosis factor (TNF) and/or forskolin (FK), intense fluorescence was detected in the cytoplasm. The immunoperoxidase reactions were detected in the cisternae of rough endoplasmic reticulum (rER), trans-cisternae of Golgi apparatus, and small vesicles beneath the plasma membrane. Western blot analysis showed VSMCs secrete PLA2-II after stimulation. Secreted PLA2-II was associated with the plasma membrane and extracellular matrix. Colchicine inhibited PLA2-II synthesis and its secretion to the extracellular space. These observations indicate that in VSMCs PLA2-II is synthesized at rER. transported to Golgi apparatus, discharged into extracellular space via the small vesicles, and microtubules may concern with its process. Furthermore, in VSMCs treated with TNF or TNF + FK, prostaglandin E2 formation was also increased. Actinomycin D and cycloheximide inhibited the potentiation of the prostaglandin E2 formation induced by TNF or TNF + FK, indicating that both RNA and protein synthesis are required for the potentiation. These results suggest an involvement of PLA2-II in the prostaglandin formation.
Alloxan exhibits the most potent diabetogenicity and has been used for induction of experimental diabetes mellitus. Understanding the mechanisms of action of the typical diabetogenic agent is important for elucidating the causes of diabetes. Okamoto (Okamoto, H. (1985) BioEssays 2, 15-21) proposed a model in which DNA fragmentation plays an important role for the development of diabetes. This DNA fragmentation is supposed to result from the accumulation of superoxide or hydroxyl radicals. However, direct evidence for this accumulation is lacking. Using rat pancreatic islets, we demonstrated that alloxan stimulated H2O2 generation, which induced DNA strand breaks. These findings support Okamoto's proposal that alloxan induces diabetes through the following biochemical events: alloxan----H2O2 generation----DNA strand breaks----diabetes mellitus. Perhaps this report constitutes the first demonstration of alloxan-stimulated H2O2 generation which could conceivably act as an intermediate for alloxan-induced DNA strand breaks.
Explore the source record for details and available documents.
The temporal profiles of insulin secretion by isolated pancreatic islets of male Wistar rats with various ages up to 1-year-old were studied using high glucose, potassium (K+) depolarization, and arginine as secretagogues. In the islets of 6-month-old rats, the onset and peak of glucose-induced first phase of insulin release were delayed for 1 min compared to those of 7--week-old rats. The onset and peak were further delayed for 1 min in the islets of 1-year-old rats. The onset of glucose-induced second phase of insulin secretion, and the onset and peak of K+ depolarization- and arginine-induced insulin release were not delayed in the islets of 6-month and 1-year-old rats. Glucose-stimulated increase in cytosolic free calcium ([Ca2+]i) seemed not delayed in the islets of 1-year-old rats. We conclude that the first phase of glucose-induced insulin release by the islets is selectively delayed as rat ages. It was suggested that the defect lies distal to the elevation of [Ca2+]i.
A case of necrotizing fasciitis caused by beta-hemolytic streptococci is reported. A 66-year-old man was admitted because of pain and swelling in the right buttock. Rapid application of aspiration cytology made it possible to diagnose necrotizing fasciitis with bacterial infection. Unfortunately, however, the patient died of cardiac arrest due to hyperpotassemia 11 h after admission. Mortality from this disease is most often related to failure in recognizing it early. Rapid diagnosis and early treatment is mandatory in order to save the patients' life. We emphasize the usefulness of rapid aspiration cytology, despite the unfortunate outcome in the present case.
Among 436 patients with hypertension unrelated to any renal lesion, renovascular damage, pheochromocytoma, Cushing's syndrome or hyperthyroidism, 15 patients had low plasma renin activity (PRA) and elevated plasma aldosterone concentrations in the upright position and resultant high aldosterone/PRA ratios: 8 with aldosterone-producing adenoma (APA; group 1) and 7 with idiopathic hyperaldosteronism (IHA; group 2). Thirty-nine patients had suppressed PRA in the presence of normal plasma aldosterone levels and moderately elevated aldosterone/PRA ratios (group 3). Thirty of them had elevated plasma 11-deoxycorticosterone (DOC) and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) concentrations (group 3a) and 9 of them had normal levels of those mineralocorticoids (group 3b). The rest of them (382 patients) had low aldosterone/PRA ratios (group 4). Adrenal scintigraphy with dexamethasone pretreatment revealed [13I]-cholesterol accumulation not only in patients with APA (unilateral) or IHA (bilateral), but also in patients of group 3a (bilateral). In patients in groups 3a and 3b adrenal size (especially thickness), as measured by computed tomography (CT scan), was enlarged, as in patients with IHA (group 2), and was significantly greater than in patients of group 4 (p less than 0.001). Spironolactone reduced blood pressure in all tested patients of group 3a, and the removal of adrenal tumor or hyperplastic tissue normalized blood pressure in patients of groups 1, 2 and 3a. Excised adrenal glands exhibited cortical hyperplasia with or without nodular hyperplasia in patients of group 3a. Good agreement was found between the actual size of the excised tissue and the measurement obtained by CT scan. Since beta-endorphin and beta-lipotropin were depressed in patients of group 3a, it is suggested that an unknown pituitary substance stimulates the adrenal cortex to release too large amounts of DOC and 18-OH-DOC and inappropriate secretion of aldosterone.
1. Three indexes for evaluating the severity of paraquat poisoning based on plasma-paraquat concentration are presently in use; the curves of Proudfood et al. and Scherrmann et al. and the SIPP. Their effectiveness in determining the prognosis of patients with paraquat poisoning was evaluated. 2. To determine which index was more accurate, contigency tables of the three indexes were obtained and compared; Proudfoot's curve vs the SIPP Scherrmann's curve vs the SIPP. Proudfoot's curve and the SIPP were applied to patients admitted within 24 h after intoxication. Scherrmann's curve and the SIPP were applied to patients admitted more than 24 h after intoxication. The proportions of patients with true positive and true negative results to total patients were compared by a ratio test. 3. Proudfoot's curve was found to be more accurate than the SIPP for predicting the prognosis of patients admitted within 24 h (P less than 0.05). No significant difference, however, was noted between Scherrmann's curve and the SIPP in determining the prognosis of patients admitted after more than 24 h. 4. In conclusion, Proudfoot's curve proved a better index for predicting the outcome of patients who were admitted within 24 h. However, for the prognosis of patients admitted more than 24 h after the ingestion of paraquat, further study is required.
Streptozocin (STZ) and alloxan (ALX) exhibit the most potent diabetogenicity and are used for induction of experimental diabetes mellitus. An understanding of the mechanisms of action of the typical diabetogenic agents is important for elucidating the causes of diabetes. Okamoto proposed a model in which DNA fragmentation plays an important role in the development of diabetes. DNA fragmentation supposedly results from the accumulation of superoxide or hydroxyl radicals. However, direct evidence for this accumulation is lacking. With isolated rat pancreatic islets in vitro, we demonstrated that STZ and ALX stimulated H2O2 generation and caused DNA fragmentation. Addition of STZ or ALX resulted in an increase in H2O2 generation. On DNA analysis, when incubated without STZ or ALX, DNA sedimented as a single peak; when incubated with STZ or ALX, DNA sedimented slower as a broad peak and was fragmented. Graded doses of STZ and ALX stimulated H2O2 generation and induced DNA fragmentation; their effects on H2O2 generation and DNA fragmentation were evident at a concentration of 0.1 mM and were maximal at 1 mM. Administration of STX or ALX to rats in vivo stimulated H2O2 generation and caused DNA fragmentation in pancreatic islets. H2O2 itself also induced DNA fragmentation. These findings may support Okamoto's proposal that STZ and ALX induce diabetes through the following biochemical events: STZ and ALX----H2O2 generation----DNA fragmentation----beta-cell destruction. This study may constitute the first demonstration of STZ- and ALX-stimulated H2O2 generation, which probably acts as a mediator of STZ- and ALX-induced DNA fragmentation.
Hypothyroid patients with Hashimoto's thyroiditis usually receive lifelong thyroxine therapy. Some are known to recover thyroid function, but identification of these patients during continued thyroxine therapy has been impossible. 92 patients with hypothyroidism after Hashimoto's thyroiditis and 70 normal controls were studied. All controls but not patient before thyroxine was started had a normal thyroid response to thyroid stimulating hormone (TSH), circulating concentrations of which were increased by administration of 500 micrograms thyrotropin releasing hormone (TRH). During treatment with thyroxine, 22 patients recovered thyroid responsiveness to TSH, and when treatment was stopped these patients have remained euthyroid for 1-8 years, whereas all 70 who did not recover thyroid TSH responsiveness became hypothyroid within 3 months. Over 20% of patients with hypothyroidism after Hashimoto's thyroiditis may recover satisfactory thyroid function, and can be identified during thyroxine treatment by their thyroid response to TSH in a TRH test.
Little is known about the factors that cause exacerbations of autoimmune thyroid dysfunction. One possibility is an alteration in adrenocortical function, since glucocorticoids are known to alter both pituitary-thyroid and immunologic function. We encountered three patients in whom overt autoimmune thyroid disease developed after unilateral adrenalectomy for Cushing's syndrome due to an adrenocortical adenoma. We compared the postoperative changes in thyroid function in these patients with those in 21 other patients with Cushing's syndrome who underwent the same treatment. After unilateral adrenalectomy, one of the three patients had transient hyperthyroidism and a low thyroid uptake of 131I, indicative of silent thyroiditis. After the same surgical procedure, the second patient had hypothyroidism, where-as the third patient had transient hyperthyroidism at first, and hypothyroidism then gradually developed. All three patients had serum antithyroid antibodies, the titers of which increased after surgery. In the remaining 21 patients (only 2 of whom had antithyroid antibodies initially), the serum concentrations of thyroxine, triiodothyronine, and thyroxine-binding globulin and the secretion of thyroid-stimulating hormone increased after surgery from values that were low or near the lower limit of normal to values still well within the normal range. None of these patients had clinically evident thyroid disease or increased antithyroid-antibody titers. We conclude that reductions in the secretion of glucocorticoid may exacerbate subclinical autoimmune thyroid disease. Patients with Cushing's syndrome due to adrenocortical adenoma who have thyroid antibodies should be followed closely after treatment, because thyroid dysfunction may develop.
PURPOSE: The purpose of this study was to elucidate the mechanism of regulation of serum thyroglobulin concentration in patients with Graves' disease and to establish the clinical usefulness of this measurement. PATIENTS AND METHODS: Serum thyroglobulin concentration was analyzed in relation to serum thyrotropin receptor antibody (TRab) titer and thyrotropin concentration in 166 patients with Graves' disease without thyroglobulin antibody. RESULTS: A total of 113 patients were treated and had been kept euthyroid for at least 10 months with methimazole and underwent a triiodothyronine (T3) suppression test. At the time of the T3 suppression test, the serum thyroglobulin concentration (ng/mL) was 33 +/- 31 in 80 of them with T3-suppressible (radioiodine uptake less than 12%) thyroids, negative TRab titers (less than 15% displacement), and normal serum thyrotropin concentrations (0.1 to 3.0 mU/L). Patients with T3-non-suppressible thyroids were divided into three subgroups according to serum TRab titers and thyrotropin concentrations: those with a negative TRab titer and a normal serum thyrotropin concentration (n = 9), those with a positive TRab titer and a normal thyrotropin concentration (n = 18), and those with a positive TRab titer and undetectable thyrotropin (n = 6). Serum thyroglobulin concentrations (ng/mL) were 116 +/- 40 in the first group, 249 +/- 194 in the second group, and 399 +/- 205 in the third group. In the other 39 methimazole-treated patients, 72 determinations of serum thyroglobulin concentration were performed either before or during treatment without the T3 suppression test, and it correlated well with the TRab titer but not with the serum thyrotropin concentration. In 14 patients who became hypothyroid due to excess methimazole, the serum thyroglobulin concentration increased concurrently with elevation of the serum thyrotropin concentration and normalized during thyroxine supplementation. In treated patients with T3-suppressible thyroids, the serum thyroglobulin concentration was similar among those with positive (n = 54) and negative (n = 26) microsomal antibody, indicating that the presence of Hashimoto's thyroiditis does not profoundly affect the serum thyroglobulin level. Among 80 patients with T3-suppressible thyroids who were followed without methimazole for a mean period of 31.1 months, eight (10%) experienced a clinically overt recurrence of hyperthyroidism. Serum thyroglobulin concentration and TRab titer (%) in these eight patients were 188.1 +/- 101.7 and 27.8 +/- 12.6, respectively. Thyroglobulin and TRab did not increase in the patients who remained euthyroid (n = 71) or who experienced subclinical recurrence (n = 1). CONCLUSIONS: Abnormal thyroid stimulator(s) and thyrotropin synergistically (if both are present in the serum) or independently (if either one is present) stimulate thyroglobulin secretion in patients with Graves' disease. Therefore, serum thyroglobulin concentration can be a useful means of assessing the degree of thyroidal stimulation and, if serum thyrotropin is normal or suppressed, correlates well with thyroidal stimulation even in patients with a negative TRab titer.
Hashimoto's and Graves' diseases represent the main two types of autoimmune thyroid disease. The combination of these two is well known. However, occurrence of Graves' disease after primary hypothyroidism is rare. We report seven patients with hypothyroidism due to Hashimoto's disease, who developed Graves' disease with hyperthyroidism. We also report one patient with hypothyroidism due to Hashimoto's disease, who continued to be hypothyroid even in the presence of TSAb (thyroid stimulating antibody). These patients were divided into three groups according to the changes in thyroid function and clinical course: (1) transient hyperthyroidism due to Graves' disease following hypothyroidism; (2) persistent hyperthyroidism due to Graves' disease following hypothyroidism; and (3) persistent hypothyroidism with positive TSAb. Such changes in thyroid function and clinical course seem to be decided by three factors: (1) TSAb and (2) TSBAb (thyroid stimulation blocking antibody) activities in the blood and (3) the responsiveness of the thyroid gland to TSAb. Seven patients had hyperthyroidism, when they had TSAb, which stimulated the thyroid gland; one of these seven patients had TSBAb during the hypothyroid state and TSAb during the hyperthyroid state, indicating that the alterations in the thyroid state related to the balance between the activities of TSAB and TSBAb. Another patient continued to be hypothyroid despite the presence of TSAb; his thyroid gland was not palpable and could not respond to TSAb.
We studied the effects of epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate (TPA), and 1-oleoyl-2-acetyl-glycerol (OAG) on cytoplasmic pH (pHi) and cell growth in cultured porcine thyroid cells. pHi was measured using 2',7'-bis(2-carboxyethyl-5,6-carboxyfluorescein (BCECF), an internalized fluorescent pH indicator. EGF, TPA, and OAG alkalinized the thyroid cells and stimulated their growth. These EGF-, TPA-, and OAG-stimulated cell alkalinization and growth depended on extracellular Na concentrations and were inhibited by amiloride, an inhibitor of Na(+)-H+ exchanger, indicating that EGF-, TPA-, and OAG-stimulated cell alkalinization and growth may occur through activation of Na(+)-H+ exchange. Alkalinization seems to be involved in thyroid cell growth. TPA (a tumor-promoting phorbol ester) and OAG (synthetic diacylglycerol), both potent activators of protein kinase C, imitate the action of EGF in rapidly elevating pHi and stimulating cell growth in thyroid cells. Trifluoperazine, an inhibitor of protein kinase C, inhibited EGF-, TPA-, and OAG-stimulated cell alkalinization and growth. The data suggest that activation of protein kinase C may be involved in the mechanism of EGF-stimulated cell alkalinization and growth of the thyroid cells.