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PubMed1970

The effects of some drugs which induce agranulocytosis on the metabolism of separated human polymorphonuclear leucocytes and lymphocytes.

1. Lymphocytes and polymorphonuclear leucocytes were separated from normal human blood by the method of Rabinowitz (1964).2. The oxygen uptake, lactic acid production and glucose uptake of suspensions of these cells in vitro were measured. The values obtained agree with published data using comparable techniques.3. Amidopyrine, chloramphenicol, chlorpromazine, phenylbutazone and thiouracil, in high concentrations, depressed the oxygen uptake of polymorphs, but not that of lymphocytes. With amidopyrine, chlorpromazine and thiouracil significant inhibition was produced by concentrations equal to therapeutic plasma levels. High concentrations of the drugs, except chlorpromazine, stimulated the glucose uptake of lymphocytes but not that of polymorphs. Tetracycline and sulphisoxazole were without effect on either parameter of leucocyte metabolism.4. Because of erythrocyte contamination the lactic acid production of lymphocytes could not be determined. Lactate production by polymorphs was not affected by any of the drugs studied.5. The significance of these results is discussed. It is suggested that there is a relationship between ability to induce agranulocytosis and effect on leucocyte metabolism in vitro.

Agranulocytosis↗
PubMed2005

Different approaches for assaying melanosome transfer.

Many approaches have been tried to establish assays for melanosome transfer to keratinocytes. In this report, we describe and summarize various novel attempts to label melanosomes in search of a reliable, specific, reproducible and quantitative assay system. We tried to fluorescently label melanosomes by transfection of GFP-labeled melanosomal proteins and by incubation of melanocytes with fluorescent melanin intermediates or homologues. In most cases a weak cytoplasmic fluorescence was perceived, which was probably because of incorrect sorting or deficient incorporation of the fluorescent protein and different localization. We were able to label melanosomes via incorporation of 14C-thiouracil into melanin. Consequently, we tried to develop an assay to separate keratinocytes with transferred radioactivity from melanocytes after co-culture. Differential trypsinization and different magnetic bead separation techniques were tested with unsatisfactory results. An attempt was also made to incorporate fluorescent thiouracil, since this would allow cells to be separated by FACS. In conclusion, different methods to measure pigment transfer between donor melanocytes and acceptor keratinocytes were thoroughly examined. This information could give other researchers a head start in the search for a melanosome transfer assay with said qualities to better understand pigment transfer.

Animals↗
PubMed1978

Estimation of the cell-to-cell spread of tobacco mosaic virus infection in mechanically inoculated leaves.

Procedures to estimate cell-to-cell spread of tobacco mosaic virus (TMV) infection in mechanically inoculated leaves are presented mathematically and experimentally. Based upon the mathematical estimation, it is demonstrated that resistance of TMV infection to 2-thiouracil and guanidine in mechanically inoculated leaves is correlated to the fraction of cells infected. The addition of 2-thiouracil or guanidine prevents cell-to-cell spread of TMV infection.

Antiviral Agents↗
PubMed1995

Stimulation by thyroid-stimulating hormone and Grave's immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo.

To elucidate the pathogenesis of thyroid gland hypervascularity in patients with Graves' disease, we studied the expression of mRNAs for vascular endothelial growth factor (VEGF) and its receptor, Flt family, using human thyroid follicles in vitro and thiouracil-fed rats in vivo. Human thyroid follicles, cultured in the absence of endothelial cells, secreted de novo-synthesized thyroid hormone in response to thyroid-stimulating hormone (TSH) and Graves' IgG. The thyroid follicles produced VEGF mRNA but not flt-1 mRNA. The expression of VEGF mRNA was enhanced by insulin, tumor-promoting phorbol ester, calcium ionophore, dibutyryl cAMP, TSH, and Graves' IgG. When rats were fed thiouracil for 4 wk, their serum levels of TSH were increased at day 3. VEGF mRNA was also increased on day 3, accompanied by an increase in flt family (flt-1 and KDR/ flk-1) mRNA expression. These in vitro and in vivo findings suggest that VEGF is produced by thyroid follicles in response to stimulators of TSH receptors, via the protein kinase A and C pathways. VEGF, a secretable angiogenesis factor, subsequently stimulates Flt receptors on endothelial cells in a paracrine manner, leading to their proliferation and producing hypervascularity of the thyroid gland, as seen in patients with Graves' disease.

Animals↗
PubMed1976

Role of the thyroid gland in regulation of metabolic rate in an air-breathing siluroid fish, Heteropneustes fossilis (Bloch).

Studies on cyclic activity of the thyroid and seasonal variations in oxygen consumption (VO2) under experimental conditions in which surfacing was either allowed or prevented were made in H. fossilis to try to establish a relationship between these measures and to ascertain the possible role of the thyroid in the regulation of metabolic rate. A good correlation was found between the activity of the thyroid and VO2 in this species. This finding was further confirmed by the administration of L-thyroxine or thiouracil to this fish. The thyroxine-and thiouracil-treated animals showed significantly higher (P less than 0-05) and lower (P less than 0-01) rates of VO2 respectively, thus indicating the probable role of the thyroid in the regulation of metabolic rate.

Animals↗
PubMed1998

Hypersecretion of corticotrophin-releasing hormone and arginine vasopressin in hypothyroid male rats as estimated with push-pull perfusion.

The relationship between hypothyroidism and disturbance of the hypothalamo-hypophysial-adrenal axis was investigated using adult male rats. Hypothyroidism was produced by administration of 4-methyl-2-thiouracil (thiouracil) in the drinking water for 2 weeks. Hypothyroidism decreased adrenal weights to 57% of controls and plasma concentrations of corticosterone to 48% of controls. The changes in the weight of adrenals recovered to control levels by administration of thyroxine. The pituitary responsiveness to corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) for ACTH release markedly increased in hypothyroid rats as compared with euthyroid rats. In vivo release of CRH and AVP in median eminence significantly increased in hypothyroid rats as compared with euthyroid rats. There were no significant differences in hypothalamic concentrations of CRH and AVP. These results indicate that hypothyroidism causes adrenal dysfunction directly and results in hypersecretion of ACTH mediated by increases in synthesis of CRH and AVP in the hypothalamus.

Adrenal Glands↗
PubMed1984

The concerted effects of thyroid function and dietary protein on growth and protein metabolism in mice at different growth stages.

The effects of thyroxine (T4) and thiouracil (TU) on growth and protein metabolism were examined in male mice given diets containing different levels of protein (casein) at two different growth stages (25 and 60 days old). Changes in protein metabolism were assessed from the expiratory 14CO2 from [U-14C]leucine injected, the liver nucleic acid contents and the rates of synthesis and degradation of liver protein estimated by single injection method using [6-14C]arginine. Each mouse, excluding the control group, received daily intraperitoneal injection of 10 micrograms of L-thyroxine sodium salt per 100 g b.w. (T4 group) or were given a diet containing 0.05% 2-thiouracil (TU group). In the 25-day-old mice, growth of the T4 group was accelerated at protein levels above 15% and that of the TU group was severely retarded at protein levels below 10%. On the other hand, in the 60-day-old mice, growth of the TU group tended to be accelerated at protein levels from 10% to 25%, while it was significantly retarded at the 5%-protein level. The expiratory 14CO2 increased when the growth was retarded, and decreased when growth was accelerated by T4 or TU in both age groups, but was not significant in either case. The nucleic acid content of the liver was increased by both T4 and TU when the dietary protein level was above 15%. The rate of protein synthesis was increased, but not significantly, by T4, while it was not affected by TU. The rate of protein degradation was increased, but not significantly, by TU, while it was not affected by T4 in the 25-day-old mice. In the 60-day-old mice, the rates of both liver-protein synthesis and degradation were significantly increased by TU, while they were not affected by T4. These results definitely indicate that the growth stage and the dietary protein level change the effects of thyroid function on growth protein metabolism of mice.

Animals↗
PubMed1987

Avian thyroid isthmus.

An avian equivalent of the mammalian thyroid isthmus appeared in thiouracil-treated (.1% in feed nd hatching to 6 and 8 weeks of age) chickens. In two experiments in which chickens were fed a diet containing thiouracil, thyroid tissue was found connecting the thyroid glands. Histological examination of the connecting tissue revealed that it was of the same cellular composition as the thyroid glands.

Animals↗
PubMed1997

Anti-HIV active naphthyl analogues of HEPT and DABO.

5-Ethyl-6-(1-naphthylmethyl)uracil and 5-ethyl-6-(1-naphthylmethyl)-2-thiouracil were alkylated to give, respectively. N-1 and S2, ethoxymethyl and methylthiomethyl uracil derivatives. 5-Ethyl-6-(1-naphthylmethyl)-2-thiouracil was also S2 alkylated with methyl bromoacetate. The products showed activity against HIV-1, and the N-1 alkylated derivatives were indeed highly active.

Anti-HIV Agents↗
PubMed1975

Paracrystalloids from mitochondria in thyroid follicular cells. Normal occurrence and experimental induction.

The ultrastructure of the follicular cells of the thyroid gland of bats caught in early June, when the euthyroid state is being restored following the phase of great thyroid activity that occurs at arousal, was studied. Several ultrastructural features were found which had not been observed in animals caught at other periods of the annual life cycle. The most striking ultrastructural feature was the presence in many cells of prominent, large membrane-enclosed paracrystalloid bodies. The paracrystalloids exceeded 6.0 mum in length and were approximately 1.0 mum. in width. Examination of transition forms showed that paracrystalloids were derived from mitochondria and were formed by the reorganization of the cristae into parallel closely apposed membranes. The membranes run longitudinally in loops from one end of the mitochondrion to the other. Similar mitochondrial alterations were observed in rats by duplicating the thyroid conditions of the June bat. Rats were given thiouracil for 10 weeks followed by L-triiodothyronine injection. These animals all showed similar mitochondrial-paracrystalline alterations which were not seen in hypophysectomized animals or animals given L-triiodothyronine alone. Mitochondria from thyroids of rats given thiouracil alone showed an increase in size and number and changes in shape and internal structure. The results of the bat and rat studies suggest that rapid shutdown of active follicular cells appears to promote thyroid paracrystalloid formation from mitochondria.

Animals↗
PubMed1979

Methylation and tautomerism of 1-substituted 5-fluorocytosines.

1. Methylation and thiation of 5-fluorouracil led to 1,3-dimethyl-5-fluoro-4-thiouracil, the amination of which was examined under various conditions. At high dilution, and in the presence of a large excess of NH3, 1,3-dimethyl-5-fluoro-4-thiouracil was converted to 1,3-dimethyl-5-fluorocytosine in 60% yield. 2. Two procedures were employed for methylation of 5-fluoro-1-methylcytosine and 5-fluorocytidine. Treatment of each of these with diazomethane in alcohol-ether gave a complex mixture of products, the major one of which was the desired 3-methyl derivative. By contrast, treatment with methyl iodide in dimethylsulphoxide led exclusively to the 3-methyl derivatives in much better yeilds. 3. Ultraviolet absorption spectra and pKa values are presented for 1-substituted N-methyl-5-fluoro- and 5-bromo-cytosines. The basicity method was applied to determine the tautomeric equilibrium constants of the 1-substituted 5-halogenocytosines. The results show that the proportion of the imino forms of these compounds is of the same order of magnitude as for 1-substituted cytosines, and hence is unlikely to account for the observed mutagenic effects of 1-substituted 5-halogenocytosines.

Amination↗
PubMed1977

Oxygen consumption in the developing chick cornea.

Embryonic chick corneas at different stages of development were evaluated for O2 consumption. Some embryos were treated with thyroxine or thiouracil. In untreated animals, corneal QO2 (oxygen consumption/hr./mg. dry weight) decreased from 3.60 at stage 38 to 1.58 after hatching. The temperature coefficient Q10 increased from 1.55 at stage 40 to 2.03 after hatching. If O2 consumption is calculated as microliters of O2 consumed per hour per corneal pair, it increases between stage 38 (3.20) and hatched chicks (6.20) with a plateau between stages 40 and 45. Thiouracil treatment reduced O2 consumption by the cornea at stages 42 and 45, and thyroxine treatment elevated it at stage 40.

Age Factors↗
PubMed1984

Sulfation facilitates hepatic deiodination of iodothyronines.

The metabolism of 3,3',5'-triiodothyronine (rT3), 3,3'-5-triiodothyronine (T3) and 3,3'-diiodothyronine (3,3'-T2) by isolated rat hepatocytes in primary culture was studied by radioimmunoassay and by Sephadex LH-20 chromatography. The first step in the metabolism of rT3 is outer ring deiodination which is inhibited by thiouracil. In incubations with outer ring-labeled 3,3'-T2 or T3 the main products observed are iodide in the absence of thiouracil and the sulfate conjugates in the presence of the inhibitor. Rates of sulfation and iodide formation were both determined by the phenol sulfotransferase activity of the cells. Inner ring deiodination of T3 sulfate and subsequent outer ring deiodination of 3,3'-T2 sulfate by rat liver microsomes are much faster than the corresponding reactions for the non-conjugated iodothyronines. The results strongly suggest that sulfation precedes and in effect accelerates hepatic deiodination of T3 and 3,3'-T2.

Animals↗
PubMed1993

Experimental hypothyroidism increases plasminogen activator inhibitor activity in rat plasma.

The aim of the present study was to investigate whether hypothyroidism would affect the components of the rat plasma fibrinolytic system. Hypothyroidism was induced by feeding rats a thiouracil-containing diet for 2 weeks. During this period, half of the animals received subcutaneous injections of L-thyroxine (20 micrograms/kg daily) to restore thyroid hormone levels. Groups of euthyroid rats were similarly treated with L-thyroxine. Plasma tissue-type PA (t-PA) activity was not affected by thyroid status. Plasma urokinase-type PA (u-PA) activity was significantly decreased by the thiouracil-containing diet; however, this effect was not abolished by L-thyroxine. Plasminogen, alpha 2-antiplasmin and fibrinogen were not affected by hypothyroidism. In the hypothyroid group, plasma PAI activity was significantly increased; no such increase was found in animals simultaneously receiving L-thyroxine. Plasma PAI activity correlated with T3 (r = -0.586; P < 0.005) and cholesterol (r = +0.737; P < 0.001); in multiple regression analysis, however, the correlation between PAI activity and T3 was not significant. The increase in plasma PAI activity during hypothyroidism may thus not be a direct effect of the thyroid hormone, but an indirect one through some other, possibly cholesterol related, component.

Animals↗
PubMed1990

Ultrastructural changes in thyroid epithelium during involution of the hyperplastic thyroid gland.

The ultrastructure of the thyroid epithelial cell was examined at various time intervals after induction of involution of the hyperplastic thyroid gland. Thyroids were made hyperplastic by the feeding of thiouracil in a Remington low-iodine diet to male Fischer rats for 3 weeks. Involution was induced by replacing the thiouracil-containing diet with Purina Laboratory Chow, a high-iodine diet. During involution, organelles that play a role in the synthesis and secretion of thyroglobulin, such as the rough endoplasmic reticulum, Golgi apparatus, and apical vesicles, were well preserved and prominent features of the epithelial cell. The apical plasma membrane of many cells was highly irregular for approximately 2 weeks with signs suggesting rapid discharge of apical-vesical contents into the lumen of the follicle. Pseudopods and colloid droplets were present but were not very prominent features of the cell. No signs of extensive autophagy or obvious increased incidence of lysosomes were present, although there was an elevation in the incidence of small dense bodies starting about day 8, and prominent by 15 days. Some of these may be phagosomes formed from luminal debris. The observations indicate that involution of the hyperplastic thyroid in which there is maintenance of the protein synthetic apparatus and little sign of autophagy or death of the epithelial cells is remarkably different from phenomena occurring during involution of prostate or mammary glands.

Animals↗
PubMed1981

Regulation of alpha 1-adrenoceptors in the cerebral cortex of the rat by thyroid hormones.

The influence of thyroid hormones on the concentration and properties of alpha 1-adrenoceptors in a crude membrane fraction obtained from the rat cerebral cortex was investigated using the [3H]-WB 4101 binding assay. Animals were made hypothyroid by feeding 6-propyl-2-thiouracil for 8 weeks. Hyperthyroidism was induced by triiodothyronine injections (50 microgram/100 g body weight) for 9 days. 1. The binding of [3H]-WB 4101 was saturable and of high affinity in controls as well as in hyper- and hypothyroid animals. The maximal number of binding sites (Bmax), which amounted to 95 fmol/mg protein in control animals, was increased by 27% in cortical membranes from hyperthyroid rats and reduced by 23% in the hypothyroid group. 2. The reduction in [3H]-WB 4101 binding due to 6-propyl-2-thiouracil feeding was reversible by triiodothyronine treatment. 3. Dissociation constants (KD) calculated from saturation experiments (0.25 nM) or kinetic data (0.21 nM) remained unchanged in altered thyroid states. 4. Inhibition of [3H]-WB 4101 binding by adrenergic agonists and antagonists revealed no differences between euthyroid and hypothyroid animals. The higher affinity of prazosin to the binding sites compared with yohimbine indicated that [3H]-WB 4101 predominantly labeled alpha 1-adrenoceptors. It is concluded that thyroid hormones regulate the number of alpha 1-adrenoceptors in membranes of the rat cerebral cortex, leaving their affinities unchanged.

Animals↗
PubMed1996

Prebiotic synthesis of diaminopyrimidine and thiocytosine.

The reaction of guanidine hydrochloride with cyanoacetaldehyde gives high yields (40-85%) of 2,4-diaminopyrimidine under the concentrated conditions of a drying lagoon model of prebiotic synthesis, in contrast to the low yields previously obtained under more dilute conditions. The prebiotic source of cyanoacetaldehyde, cyanoacetylene, is produced from electric discharges under reducing conditions. The effect of pH and concentration of guanidine hydrochloride on the rate of synthesis and yield of diaminopyrimidine were investigated, as well as the hydrolysis of diaminopyrimidine to cytosine, isocytosine, and uracil. Thiourea also reacts with cyanoacetaldehyde to give 2-thiocytosine, but the pyrimidine yields are much lower than with guanidine hydrochloride or urea. Thiocytosine hydrolyzes to thiouracil and cytosine and then to uracil. This synthesis would have been a significant prebiotic source of 2-thiopyrimidines and 5-substituted derivatives of thiouracil, many of which occur in tRNA. The applicability of these results to the drying lagoon model of prebiotic synthesis was tested by dry-down experiments where dilute solutions of cyanoacetaldehyde, guanidine hydrochloride, and 0.5 M NaCl were evaporated over varying periods of time. The yields of diaminopyrimidine varied from 1 to 7%. These results show that drying lagoons and beaches may have been major sites of prebiotic syntheses.

Acetaldehyde↗
PubMed2006

Is it safe to treat hyperthyroid patients with I-131 without fear of thyroid storm?

OBJECTIVES: Thyroid storm is extremely rare. However, hyperthyroid patients with severe thyrotoxicosis are frequently not treated immediately with I-131 for fear of thyroid storm but are placed on thiouracil drugs for varying periods of time. We demonstrate herein that it is safe to treat these patients with 1-131, without pretreatment with thiouracil drugs, provided they do not have complicating intercurrent disease. Our definition of severe hyperthyroidism includes marked signs and symptoms of thyrotoxicosis, suppressed TSH, markedly elevated free T4 and/or free T3 and elevated radioactive iodine uptake (RAIU) (>30%) at 4 or 24 hours. Our diagnostic criteria for thyroid storm include two or more findings of fever (>38 degrees C, 100 degrees F), severe tachycardia, high pulse pressure, agitation with tremors, flushing, sweating, heart failure, nausea, vomiting, diarrhea, jaundice associated with high free T4 and/or free T3. METHODS: Patients were selected retrospectively for the period between August 2003 and December 2004. One hundred and twenty-two patient visits were identified. These patients were treated with 370-740 MBq (10-20 mCi) of I-131 and were evaluated for any evidence of thyroid storm. Most of the patients were placed on beta blocker drugs at the time of initial I-131 therapy; these were continued for at least two months, when the first follow-up visit occurred. At the time of I-131 therapy, it is our policy to educate the patients to seek immediate medical attention for exacerbation of symptoms of thyrotoxicosis. RESULTS: Not one of these patients developed thyroid storm. A subset of 25% of these cases with higher potential for thyroid storm (RAIU more than 65%, very marked signs and symptoms, and very markedly elevated free T4 and/or free T3) also tolerated the I-131 therapy well with marked clinical improvement and no exacerbation of the thyrotoxic state. CONCLUSION: It is safe to administer I-131 to patients who are severely hyperthyroid without fear of thyroid storm, provided beta blockade drugs are used to control the signs and symptoms; patient education is also important. With these steps, 4-6 weeks of prior medical treatment may not be necessary.

Adolescent↗