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Prolonged treatment with high doses of Pyrethrins results in thyroid gland tumors in the rat. To elucidate the mode of action for tumor formation, the effect of Pyrethrins on rat thyroid gland, thyroid hormone levels and hepatic thyroxine UDPglucuronosyltransferase activity was investigated. Male Sprague-Dawley CD rats were fed diets containing 0 (control) and 8000 ppm Pyrethrins and female rats diets containing 0, 100, 3000 and 8000 ppm Pyrethrins for periods of 7, 14 and 42 days and for 42 days followed by 42 days of reversal. As a positive control, rats were also fed diets containing 1200-1558 ppm sodium Phenobarbital (NaPB) for 7 and 14 days. The treatment of male rats with 8000 ppm Pyrethrins, female rats with 3000 and 8000 ppm Pyrethrins and both sexes with NaPB resulted in increased thyroid gland weights, which were associated with follicular cell hypertrophy. Thyroid follicular cell replicative DNA synthesis was increased by treatment with Pyrethrins and NaPB for 7 and/or 14 days. Treatment with Pyrethrins and NaPB increased hepatic microsomal thyroxine UDPglucuronosyltransferase activity and serum thyroid stimulating hormone levels (TSH), but reduced serum levels of either thyroxine (T4) and/or triiodothyronine (T3). The effects of Pyrethrins in female rats were dose-dependent, with 100 ppm being a no-effect level, and on cessation of treatment were essentially reversible in both sexes. The concordance between the effects of Pyrethrins and NaPB suggests that the mode of action for Pyrethrins-induced rat thyroid gland tumors is similar to that of some other non-genotoxic inducers of hepatic xenobiotic metabolism.

The spectrum of trace elements was determined in 19 cases of colon carcinoma with analytical electron microscope. Besides, the quantities of trace elements in the cancerous tissue and the mucosa beyond the site of cancer were measured in 31 cases by flameless atomic absorption spectrophotometry. A reprocessing technique was applied to convert the paraffin sections directly to resin sections in order to recover the assessment of elements in these tissues. Fe, Al and macro elements Ca, S were recovered in 100% of the cases in both the cancer tissue and the mucosa taken beyond the site of cancer. The recovery rates of Ni and macro elements including K, Mg, P, Cl were 50%. The recovery rates of Si in poorly-differentiated adenocarcinoma were higher than that in the mucosa far from the cancer site. The levels of Cu, Zn and Ni in the cancerous tissue were lower than those detected in the mucosa (P < 0.01). No significant difference was noticed between the cancerous tissue and the mucosa beyond the site of cancer on Fe, Mn, Pb, Co and Cr contents.

Light (LM) and electron (EM) microscope comparisons of the cytochemistry and immunocytochemistry of neuritic plaques and neurofibrillary tangles, the main histopathological changes in the brains of Alzheimer's disease sufferers, have been almost impossible because of the disparity between the two technologies. By embedding unosmicated brain tissue in the acrylic resin LR White, direct comparisons can be made between techniques applied at the LM level with those at the EM level. After partial dehydration in 70% ethanol, the tissue is embedded by rapid infiltration and polymerization at 0 degrees C, which has been shown to maximally preserve tissue immunoreactivity. Semithin sections are then receptive to routine LM stains, silver stains e.g. Gomori's methenamine silver, and immunocytochemistry with immunoperoxidase or immunocolloidal gold. Serial thin sections are stable in the EM and can be immunolabelled and directly compared with their LM counterparts. Results from the use of a mouse monoclonal antibody against beta-amyloid and a rabbit polyclonal antibody against ubiquitin are presented. LR White resin includes no elements other than carbon, oxygen and nitrogen, of which it is composed, so that sections of it are valuable for sensitive X-ray energy dispersive microanalysis.

The effects of various agents on the in vitro secretion of parathyroid hormone (PTH) were studied previously, using bovine glands. Low calcium, (0.75 mM), vitamin A (vit A), and cytochalasin B stimulated secretion, and high calcium (3.0 mM) and vinblastine (VB) inhibited secretion, whereas hydrocortisone and VB inhibited the vit A-induced PTH secretion. In order to define subcellular mechanisms of PTH release at the morphologic level, a semiquantitative analysis of ultrastructural characteristics has been made on the same tissue with the same agents. Low calcium increased convolutions of the intercellular membrane, the number of large type I secretory granules, phagolysosomes, lipoid vacuoles, and lamellae of endoplasmic reticulum. Vit A and cytochalasin B widened intercellular spaces and increased intercellular membranous interdigitations, the number of type I secretory granules, and phagolysosomes. Vit A also dilated Golgi membranes, and cytochalasin B also increased the number of small type II secretory granules and the margination of granules along the cell membrane. High calcium increased the number of phagolysosomes and crinophagic and lipoid vacuoles. VB decreased the number of microtubules and caused stacking of endoplasmic reticulum lamellae. VB or hydrocortisone diminished some of the ultrastructural effects of vit A. The common ultrastructural findings in response to stimulation of PTH secretion by low calcium, vit A, and cytochalasin B raise the possibility that these agents may facilitate PTH secretion through a common messenger or may directly interact with the cell membrane or with the secretion granule for phagolysosome (or both). Our findings are consistent with the role of VB as a microtubule disrupter, but also suggest that VB inhibits PTH secretion through other mechanisms involving the cell membrane and endoplasmic reticulum. Microtubules may facilitate basal PTH secretion and vit A-induced secretion; however, since VB does not inhibit low calcium-stimulated PTH secretion and, ultrastructurally, microtubules were not increased in the presence of low calcium, low calcium-stimulated secretion is not dependent upon microtubular function.

Techniques employed for the recovery from biological tissues of noncombustible fine particles such as asbestos, talc, kaolin and diatomaceous material were assessed by electron microscope x-ray microanalysis. Recovery procedures which have been proven successful for lung tissue were found to be impracticable for more solid types of tissues. Digestion techniques employing acids, alkalis or enzymes and standard incineration procedures were found to be unsatisfactory for human adrenal, cervix, liver and ovarian tissues when the resultant residues were examined by electron microscope microanalysis. The recovered particles were often completely masked with residues which were shown to be composed of organic elements. The use of oxygen during the incineration process completely removed this contaminating material in nearly all cases studied. When such procedures were used, clearly defined particles were recovered from the tissue, thereby permitting x-ray analysis. A quantitative analysis could then be made to estimate the particle content in a variety of tissues.

Two patient receiving minocycline developed blue-black pigmentation on the legs. Biopsies from the pigmented areas demonstrated granules containing iron, a pigment with staining properties similar to melanin, and a third pigment which may be a degradation product of minocycline. Electron microscopy showed that some, but not all the granules were membrane-bound and they were situated mainly within macrophages. Analytical electron microscopy showed that the granules contained iron, sulphur, chlorine and, in one case, calcium.

Incubation of thyroparathyroid gland from 8-day-old rats with estradiol (10(-7) and 10(-9) M) and progesterone (10(-9) and 3 X 10(-10) M) resulted in stimulation of CT secretion. The effect of the gonadal steroids on CT secretion occurred at near physiological concentrations and persisted for at least 73 h. The studies demonstrate that exposure to gonadal steroids results in direct and prolonged stimulation of CT secretion. Therefore the decrease in bone resorption observed after the administration of gonadal steroids in vivo may at least in part be mediated via stimulation of CT secretion.

A case of mepacrine pigmentation occurring in a patient with systemic lupus erythematosus has been investigated by fluorescent light microscopy, gas--liquid chromatography and analytical electron microscopy. There is strong evidence for the presence of mepacrine itself within the typical granules, which have been shown by electron microscopy to be membrane bound and intracellular. Analytical electron microscopy also showed that the granules contain large quantities of iron and smaller quantities of sulphur.

Administration of aminophylline to intact rats did not cause a change in serum Ca, but did cause a significant increase in serum PTH. Administration of EDTA alone caused hypocalcemia, and a greater increase in PTH than that caused by aminophylline alone. Aminophylline plus EDTA given togeather caused no greater hypocalcemia, but a significantly greater increase in PTH than that by EDTA alone. Therefore, aminophylline increased PTH secretion when given alone, and also enhanced the PTH secretion stimulated by EDTA-induced hypocalcemia in vivo.

Particles of talc have been identified on the route surface of surgeons' rubber gloves and in sections of tissue classified as 'starch' or 'foreign body' granulomas. This analytical study indicates that under certain circumstances these granulomas could have been caused by talc contamination.

This study evaluated the effect of somatostatin on immunoreactive parathyroid hormone (iPTH) and calcitonin (iCT) secretion in vivo in rats and monkeys and on iPTH secretion in vitro by normal bovine parathyroid tissue and by a human parathyroid adenoma. Somatostatin infusion promptly (within 0.5 h) suppressed both iPTH and iCT in both species studied in vivo, the suppression being progressive during the infusion period. In in vitro studies, somatostatin caused significant dose-related decreases in basal, low Ca-stimulated, and high Ca-suppressed PTH secretion from normal bovine parathyroid tissue and from basal and low Ca-stimulated PTH secretion from a human parathyroid adenoma. Therefore, somatostatin 1) suppresses both PTH and CT secretion in vivo; 2) acts directly on the parathyroid cell and presumably directly on the C-cell also; 3) acts upon normal and adenomatous parathyroid tissue; 4) suppresses basal, low Ca-stimulated and high Ca-suppressed PTH secretion; and 5) has a dose-related effect. The possible role of somatostatin in the physiological control of PTH and CT secretion (and therefore in Ca homeostasis), and in the pathogenesis of abnormalities of Ca homeostasis, requires further evaluation.

The effect of histamine and histamine H2 receptors on secretion off parathyroid hormone (PTH) was evaluated by 1) adding histamine phosphate (with or without the histamine H2 receptor antagonist, cimetidine) to the medium in in vitro incubation studies with bovine parathyroid tissue, 2) infusing histamine into rats, and 3) infusing the histamine H1 receptor antagonist, diphenhydramine, or cimetidine into normal men and patients with primary hyperparathyroidism. In vitro, histamine (10(-5)-10(-7) M) caused a dose-related significant stimulation of immunoreactive PTH (iPTH) secretion; this was blocked by the simultaneous addition of cimetidine (10(-5) M). Intravenous infusion of histamine significantly increased serum iPTH in rats. In normal man, infusion of diphenhydramine had no effect, but cimetidine (300 or 450 mg) significantly decreased serum iPTH. However, cimetidine had no effect on serum iTh in primary hyperparathyroid patients. The in vitro observations indicate that histamine can stimulate iPTH secretion by a direct effect on the parathyroid cell and that this is probably a specific effect via histamine H2 receptors because the effect was blocked by the H2 receptor antagonist, cimetidine. The observed inhibition of basal PTH concentration by cimetidine induced histamine H2 receptor blockade (but not by H1 blockade) in normal human subjects suggests that endogenous histamine with H2 receptor activation stimulates even basal PTH secretion and may serve as a modulator of PTH secretion in normal man. Loss of this modulating effect of H2 receptors on PTH secretion is a characteristic of primary hyperparathyroidism.

Exposure of rat ovaries to talc was accomplished by intrabursal injection. As early as 1 and up to 18 months after treatment, the ovaries and associated tissue were cystic in appearance; these changes were the result of bursal distention. Histologically the ovarian tissue was decreased in amount and spread as a remnant on the inner wall of the bursa. In four to 10 treated animals but in no controls, focal areas of papillary change were noted in the surface epithelium of the ovary. Polarized light and electron microscope microanalysis confirmed the presence of talc in the surface epithelium, ovarian cortex, and connective tissue matrix of the bursa. Although the changes in the ovarian surface may be related to direct effects of talc exposure, it is postulated that these changes might also be related to constant exposure to the high concentrations of steroid hormones which have undoubtedly accumulated in the intrabursal space.

The role of adrenergic stimuli in the secretion of parathyroid hormone (PTH) in man was evaluated. Intradermal injections of isoproterenol, 0.15 mg, or epinephrine, 0.3 mg, caused significant prompt increases in serum PTH levels. These increases were not accompanied by any changes in serum calcium (Ca) during the period of observation. Phenylephrine, 1.5 mg, intradermally, did not cause any significant changes in serum PTH or serum Ca. Propranolol infusion alone significantly inhibited the basal secretion of PTH. This inhibition by propranolol was overcome by isoproterenol administration. The results indicate that 1) beta adrenergic agents increase PTH secretion whereas alpha adrenergic agents have no effect, 2) beta adrenergic stimuli probably play an important physiological role in basal PTH secretion in man.

A dense fraction from rat spleen was shown to consist of membrane bound organelles of varying shape and size which were packed with electron dense particles with the appearance of ferritin. Electron microscope microanalysis confirmed that iron was present in the organelles and the amount correlated with the density as noted in transmission electron microscopy. The organelles also stained, positively for acid phosphatase and, therefore, confirmed the biochemical findings that dense lysosomes (L30) had been isolated. The role lysosomes play in the degradation of red blood cells, and as possible sites of iron storage, are briefly discussed.

This study evaluated the effects of adrenergic agents on immunoreactive calcitonin (iCT) secretion in normal man, and compared the time course and magnitude of these adrenergic effects with those caused by modifying calcium (Ca) ion concentration. Ca infusion (15 mg Ca++/kg iv in 4 h) significantly increased plasma iCT within 1 h, reaching 140 +/- 8% of baseline at 4 h. EDTA (50 mg/kg iv in 2 h) significantly decreased plasma iCT within 15 min, with nadir value of 53 +/- 4.9% of baseline at 2 h. The beta-adrenergic agonist, isoproterenol, significantly increased plasma iCT with 5 min, reaching 136 +/- 5.9% of baseline at 30 min. The alpha-adrenergic antagonist, phentolamine, significantly increased iCT within 15 min, reaching 132 +/- 8.6% of baseline at 45 min. The beta-adrenergic antagonist, propranolol, significantly suppressed iCT with 15 min, reaching 51.8 +/-6.3% of baseline at 2 h. Therefore, 1) the adrenergic system (without induced change in serum Ca) can modify CT secretion to as great a degree as can change in Ca ion concentration induced by standard Ca and EDTA infusion tests and 2) even basal secretion of CT can be modified by adrenergic influences. These data strongly suggest 1) that the adrenergic system is an effective modifier of CT secretion and 2) that the adrenergic system, as well as Ca ion concentration, may play an improtant physiological role in control of CT secretion in man.

Gold distribution was studied in the tissues of 7 rheumatoid patients who had died from 0 to 23 years after stopping chrysotherapy (sodium aurothiomalate) and in 23 samples of synovial tissue removed surgically at intervals during chrysotherapy in 5 patients. After the application of a highly specific staining technique, the cellular localization of gold was examined microscopically in various tissues: the amounts of gold in selected areas of the same specimens which had been examined microscopically were then measured by neutron activation analysis. During active chrysotherapy gold was abundant in synovial lining cells except where a fibrin layer was present on the surface; after stopping chrysotherapy, gold disappeared from the synovial lining cells. Gold accumulated progressively in the subsynovial connective tissues during chrysotherapy, but was not uniformly distributed, and bore no relationship to fluctuations in serum gold levels. Gold deposition was not confined to joint tissue, but was found within the macrophages of many organs, renal tubular epithelium, and, after recent chrysotherapy, in seminiferous tubules, hepatocytes, and adrenal cortical cells. Gold persisted in synovial and other tissues for up to 23 years after chrysotherapy was stopped. The overall findings indicated that gold is selectively concentrated within inflamed synovial tissues during chrysotherapy.

Granulomatous lymphadenopathy, associated with the presence of needle-like refractile particles, was recognised in two dogs. The material was detected in macrophages, either free within the cytoplasm or in membrane-bound lysosomes. By mineral analysis under direct vision in an electron microscope microanalyser (EMMA 4) the particles were found to contain aluminosilicate.

Estrogen therapy has been used to inhibit bone resorption and prevent osteoporosis in postmenopausal women. Previous studies have disagreed as to whether the mechanism of estrogen action involves stimulation of calcitonin (CT) secretion. We evaluated the direct effects of 17 beta-estradiol (E2) and progesterone (Prog) on CT secretion from the thyroid C cells of 8-day-old rats in vitro. Both E2 and Prog caused a significant stimulation of CT secretion within 1 h, which was progressive for the 3-h observation period. The responses were dose related from 10(-7) to 5 X 10(-10) M. There was no CT response to 10(-7) M alpha-estradiol, estriol, 3-methoxyestriol, estrone, testosterone, or 20 alpha-hydroxyprogesterone, indicating specificity of the responses to E2 and Prog. There was a minimal CT secretory response to 10(-6) M cortisol. The E2 receptor antagonist tamoxifen did not inhibit the E2 effect on CT secretion. This observation plus the rapid CT response suggest that this hormonal effect may not be via the conventional intracellular E2 receptor. Therefore, E2 and Prog can stimulate CT secretion by rapid, direct, and specific effects on the thyroid C cell. The gonadal hormones may, therefore, be important in inhibiting bone resorption via their direct stimulatory effect on CT secretion.

Purified secretin infused in an estimated physiological dose caused an increase in serum immunoreactive PTH (iPTH) and calcitonin (iCT) in man. Ingestion of a gastric acid-stimulating test meal, a procedure known to increase endogenous secretin, caused increases in serum iPTH and plasma iCT in normal subjects. Ingestion of antacid with the test meal blunted the increase in both iPTH and iCT. Ingestion of the test meal by pernicious anemia patients with achlorhydria caused no stimulation of either serum iPTH or plasma iCT. Therefore, based on the observations that 1) exogenous secretin stimulated iPTH and iCT, 2) an acid-stimulating test meal is known to stimulate endogenous secretin release (4), 3) the test meal increased both serum iPTH and iCT in normal man, an effect nullified by simultaneous antacid ingestion, and 4) the test meal caused no increase in either iPTH or iCT in achlorhydric patients, we conclude that endogenous secretin possibly mediates this effect of test meal and, therefore, may play a physiological role in modulating the secretion of PTH and CT.

This study evaluated the effect of parasympathetic agonists and antagonists on immunoreactive (i) PTH secretion in vitro and on serum iPTH in vivo in rats. In in vitro studies pilocarpine or bethanechol significantly inhibited PTH secretion. This inhibition was blocked by the simultaneous addition of atropine to the incubation medium. In in vivo studies, the cholinergic agonists pilocarpine and bethanechol and the cholinergic antagonist atropine were administered to rats by IV infusion. Blood was obtained before and again after two hours of infusion for analysis of iPTH. Pilocarpine or bethanechol significantly decreased serum iPTH. This inhibition by either agent was blocked by the simultaneous administration of atropine. Administration of atropine alone significantly increased serum iPTH above baseline. This stimulation of basal serum iPTH by parasympathetic blockade suggests that even basal PTH secretion may be influenced by endogenous parasympathetic tone. Therefore, the following conclusions were reached: (1) parasympathetic influences inhibit PTH secretion, and (2) endogenous parasympathetic tone may be an inhibitory modulator of basal secretion of PTH.

Electron microscopy of femoral lymph nodes of barefooted Ethiopians show the presence of numerous particles of colloid-size and electron-density in the lysosomes of the macrophages in the gland. On diffraction analysis, the particles are found to be amorphous. Elemental microanalysis of the X-ray spectrum indicate the predominance of Si, Al and Fe. In elephantiasics some particles contain silicon alone, presumably silica. The distribution of the Al/Si ratios of the particles in subjects with elephantiasis of the lower legs show a difference from that of non-elephantiasics which is statistically "highly significant" at p less than 0.001. The importance of this as a possible aetiological factor in the disease is discussed. The hypothesis that the disease is discussed. The hypothesis that the disease is a silicosis of the peripheral lymphatics of the lower limbs is supported by the present study.

The presence of microparticles of clay is demonstrated in the dermis of the foot in a patient with endemic elephantiasis. The particles are seen to be in the phagosomes of macrophages or in the cytoplasm of other cells. The conducting lymphatic in the subdermal tissue is found to be impermeable to Patent Blue Violet dye and to be fibrosed. The failure to conduct lymph to the node produces a permanent deposit of silica in the dermal tissues; a parallel is drawn with similar deposits in the lung in pneumoconiosis.

Previous studies have shown that estrogen therapy in postmenopausal women results in an increase in serum immunoreactive parathyroid hormone (iPTH) levels. It has been assumed that this effect of estrogen on PTH secretion is indirect, being mediated via mild hypocalcemia resulting from an inhibition of bone resorption. We evaluated the direct effect of 17 beta-estradiol (E2) and of progesterone (Prog) on secretion of PTH from bovine parathyroid tissue in vitro. Both E2 and Prog caused a significant stimulation of PTH secretion within one hour, which was progressive for the three-hour observation period. The responses were dose-related from 10(-7) to 5 X 10(-10) mol/L. There was no PTH response to 10(-7) mol/L alpha-E2, 3-methoxy estriol, estrone, testosterone, or 20-alpha-hydroxy progesterone, indicating specificity of the responses to E2 and Prog. There was a minimal PTH secretory response to 10(-6) mol/L cortisol and 10(-6) mol/L estrone. The E2 receptor antagonist tamoxifen did not inhibit the E2 effect on PTH secretion. This observation plus the rapid PTH response suggests that this hormonal effect may not be via the conventional intracellular E2 receptor. Therefore, E2 and Prog can stimulate PTH secretion by rapid, direct, and specific effects on parathyroid cells. These gonadal hormones may, therefore, be important in calcium homeostasis via their direct stimulatory effect on PTH secretion.

Evidence for an association of endemic non-filarial elephantiasis of the lower legs with areas of red clay soils around volcanoes has been noted in several countries bordering the Rift Valley in East Africa. It was of interest to observe whether the association is also present in an area of endemic prevalence of the disease in West Africa. Such an area occurs in the Cameroon highlands where it has been suggested that onchocerciasis might be an etiological factor. The present study describes the results of a survey in this area. There was no statistical evidence of a relationship with onchocerciasis and the content of mineral microparticles in lymphatic tissues of the lower legs was again established. Climatic, geological and soil characteristics were similar to those in East Africa. It is considered that the disease in the two widely separated non-bancrofti areas is of similar etiology and it is proposed that it may be interpreted as silicosis of peripheral lymphatics of the lower legs.

A study has been made of facial pigmentation resulting from industrial inorganic mercury exposure. Electron microscopy has shown electron-dense 400--900 nm aggregates of 12 nm particles in dermal macrophages and free in the dermis. Use of the analytical electron microscope has enabled direct confirmation of the presence of mercury in these aggregates. The unexpected finding of coexistent selenium is discussed.