Evaluation of a population with occupational exposure to airborne ammonium perchlorate for possible acute or chronic effects on thyroid function

Employees at an ammonium perchlorate production facility in Nevada and a larger control population from the same chemical complex without direct AP exposure were monitored extensively for airborne perchlorate exposure. Single-shift and working-lifetime cumulative dose estimates were made using standard breathing-rate estimates and assuming rapid absorption, based upon solubility. Calculated single-shift doses ranged from 0.2 to 436 micrograms/kg, with an average of 36 micrograms/kg. Working-lifetime cumulative doses in the higher exposure group ranged from 8,000 to 88,000 micrograms/kg, with an average of 38,000 micrograms/kg. Thyroid profiles, including free thyroxine index and thyroid-stimulating hormone level, were obtained both before shift and after shift to assess thyroid-axis perturbation due to single working-shift perchlorate exposure. Thyroid-function data were also analyzed with respect to estimates of cumulative exposure to assess any measurable chronic effects on thyroid gland function. Additionally, standard clinical blood test parameters of liver, kidney, and bone marrow function were evaluated to assess any measurable chronic effects of perchlorate exposure on those organs. Multiple regression was used to assess the effects of exposure variables and demographic variables on organ function parameters. No perchlorate-attributable effects on thyroid, bone marrow, kidney, or liver function were detected.     

Comparative electronmicroscopical investigations on the influences of altered gravity on cytochrome oxidase in the inner ear of fish: a spaceflight study

The regional metabolic activity in the otolithic sensory epithelia of the inner ear of a cichlid fish (Oreochromis mossambicus) was investigated on light- and electronmicroscopical level using the cytochemical method for detection of cytochrome oxidase activity. In adult animals a characteristic distribution of mitochondria with high enzyme activity was found in sensory and non-sensory cells of otolithic sensory epithelia, which was correlated with regions with a high energy demand. These findings were the basis for studies on the influence of long-term altered gravity conditions in developing larvae: hypogravity (10(-4) g in spaceflight), normal gravity (1 g in a centrifuge in space and 1 g on earth) and hypergravity (3 g in a laboratory centrifuge). Cytochrome oxidase activity was quantified in different parts of the sensory hair cell synapse in the vestibular sensory epithelia utricle and saccule: apical and basal cytoplasm, postsynaptic area of the afferent synapse and presynaptic region of the efferent synapse. Our results show that the energy metabolism of utricle, but not of saccule is decreased after microgravity exposure during the 2nd German Spacelab Mission D-2. However, a general effect of the spaceflight is detectable in both sensory epithelia. Long-term exposure to increased acceleration (3 g) had no effects on cytochrome oxidase activity in inner ear sensory epithelia.     

Accumulative effects of 2 weeks' exposure to a 2-G hypergravity state and estrogen treatment upon intact and fractured radii of young female birds

Female birds were subjected to closed fractured of the right radius at 2 weeks post-hatching and allowed to heal for 14 d. The animals were maintained at either earth gravity or a 2-G hypergravity state with control and 2000 and 4000 IU Estrone-(estrogen) injected groups. Intact and fractured radii were measured for length, weight, average epiphysial-diaphysial diameters, and length, width and weight of fracture callus. Animals receiving 2000 IU estrogen treatment showed decreased intact and fractured bone weight, as well as smaller diaphysial diameters. Fractured, but not intact, bone length was decreased by the two estrogen levels without affecting the callus parameters. Bone weight and average epiphysial diameters of both intact and fractured radii were decreased by the hypergravity state. Intact bone diaphysis and fractured bone length were similarly affected. Large, 4000 IU, estrogen levels potentiated the hypergravity state and reduced distal epiphysial diameter of intact radii.     

Changes in lower limb volume in humans during parabolic flight

Variations in gravity [head-to-foot acceleration (Gz)] induce hemodynamic alterations as a consequence of changes in hydrostatic pressure gradients. To estimate the contribution of the lower limbs to blood pooling or shifting during the different gravity phases of a parabolic flight, we measured instantaneous thigh and calf girths by using strain-gauge plethysmography in five healthy volunteers. From these circumferential measurements, segmental leg volumes were calculated at 1, 1.7, and 0 Gz. During hypergravity, leg segment volumes increased by 0.9% for the thigh (P < 0.001) and 0.5% for the calf (P < 0.001) relative to 1-Gz conditions. After sudden exposure to microgravity following hypergravity, leg segment volumes were reduced by 3.5% for the thigh (P < 0.001) and 2.5% for the calf (P < 0.001) relative to 1.7-Gz conditions. Changes were more pronounced at the upper part of the leg. Extrapolation to the whole lower limb yielded an estimated 60-ml increase in leg volume at the end of the hypergravity phase and a subsequent 225-ml decrease during microgravity. Although quantitatively less than previous estimations, these blood shifts may participate in the hemodynamic alterations observed during hypergravity and weightlessness.     

Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice

We have used a mouse model of allergen-induced airway hyperresponsiveness to demonstrate that immunostimulatory DNA sequences (ISS) containing a CpG DNA motif significantly inhibit airway eosinophilia and reduce responsiveness to inhaled methacholine. ISS not only inhibited eosinophilia of the airway (by 93%) and lung parenchyma (91%), but also significantly inhibited blood eosinophilia (86%), suggesting that ISS was exerting a significant effect on the bone marrow production of eosinophils. The inhibition of the bone marrow production of eosinophils by 58% was associated with a significant inhibition of T cell-derived cytokine generation (IL-5, granulocyte-macrophage CSF, and IL-3). ISS exerted this inhibitory effect on T cell cytokine production indirectly by stimulating monocytes/macrophages and NK cells to generate IL-12 and IFNs. The onset of the ISS effect on reducing the number of tissue eosinophils was both immediate (within 1 day of administration) and sustained (lasted 6 days), and was not due to ISS directly inducing eosinophil apoptosis. ISS was effective in inhibiting eosinophilic airway inflammation when administered either systemically (i.p.), or mucosally (i.e., intranasally or intratracheally). Interestingly, a single dose of ISS inhibited airway eosinophilia as effectively as daily injections of corticosteroids for 7 days. Moreover, while both ISS and corticosteroids inhibited IL-5 generation, only ISS was able to induce allergen-specific IFN-gamma production and redirect the immune system toward a Th1 response. Thus, systemic or mucosal administration of ISS before allergen exposure could provide a novel form of active immunotherapy in allergic diseases.     

Effects of continuous exposure to high gravity on gravity preference in rats.

Reports an experiment in which 8 male albino Sprague-Dawley rats were chronically centrifuged in excess of 2 g for 6 or 12 mo. They were then given 4 24-hr gravity-preference tests in a spiral centrifuge in which they could adjust the gravity level imposed by locomoting inward or outward radially along a track. Chronically centrifuged Ss (Group CC) spent as much time at 2 g as at 1 g, while 8 normally raised controls (Group NC) selected only 1 g. Group CC initially selected 2 g and a preference for 1 g developed over the 4 test sessions. Results suggest that hypergravity is not necessarily an aversive stimulus and that gravity preference may depend initially upon the "reference level" involved. The ultimate selection of 1 g by chronically centrifuged Ss suggests that a preference for a familiar gravity environment is replaced by a preference for low-gravity stimuli. (18 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NGF content and expression in the rat pituitary gland and regulation by thyroid hormone

The involvement of nerve growth factor (NGF) in neuroendocrine regulation is supported by several lines of evidence. In this paper, we investigated the NGF content and expression in the pituitary gland and other endocrine organs during dysendocrine states (thyroidectomized, adrenalectomized and gonadectomized male rats). We found an increase of NGF-IR in the pituitary gland and testis of hypothyroid rats whereas no differences were found in the adrenal gland and blood. Also, NGF mRNA expression had increased in the anterior pituitary of hypothyroid rats whereas it had not changed after adrenalectomy and gonadectomy. Moreover, other neurotrophins and neurotrophin high-affinity receptors were unchanged in the anterior pituitary of hypothyroid rats. These data indicate that pituitary NGF is selectively modulated by thyroid status of the animal, further supporting a close link between NGF and thyroid hormone.     

The clinical significance of phasic duodenal intubation and ultrasonic monitoring of the gallbladder in healthy subjects

Hypoxic and low-temperature effects on the thermal regulation and the content of catecholamines (epinephrine--E and norepinephrine--NE) in mice have been compared. Continuous and repeated hypoxia brought about a significant drop of the rodent body temperature and heat content. Found was a significant elevation of catecholamines in the pituitary and adrenal tissues, and blood plasma with E prevalence after the continuous exposure. Repeated stimulus resulted in a more pronounced effect. Exception was the adrenal tissue where enhanced E and NE secretion into blood was noted. The uninterrupted and repeated cold conditions were also responsible for heat release. Continuous exposure to low temperature increased NE and decreased insignificantly E in blood and adrenal. Multiple stimulation increased sharply catecholamines concentration in blood plasma with the dominance of epinephrine in the pituitary gland, and norepinephrine in the adrenal.     

Separation of human bone marrow cells by sedimentation

Sedimentation at unit gravity of human bone marrow cells, for 15 h at 4 degrees C on linear density gradient of Ficoll in culture medium ranging from 1.020 to 1.065 g/ml shows that a differential migration of the bone marrow cell sub-populations exists with precise mean densities 1.021 +/- 1 x 10(-3) g/ml for lymphocytes; 1.024 +/- 2.5 x 10(-3) g/ml for non-eosinophil granulocytes; and 1.055 +/- 10 x 10(-3) g/ml for metamyelocytes; 1.030 x 3.5 x 10(-3) g/ml for other myeloid cells (myeloblasts, promyelocytes, myelocytes); 1.040 +/- 1.040 +/- 3 x 10(-3) g/ml for eosinophil granulocytes; and 1.055 +/- 10 x 10(-3) g/ml for megakaryocytes. The highest percentages of S phase cell and G2 and M phase cells determined by a cytofluorograph correspond to the peaks of immature myeloid cells (myeloblasts, promyelocytes and myelocytes). This method of bone marrow cell separation may be used to study the cell cycle in pathological bone marrows (leukaemia in particular) and to determine the effects and the efficiency of some antimitotics.     

Chronotropic effects of cilostazol, a new antithrombotic agent, in patients with bradyarrhythmias

Size and asymmetry (size difference between the left and right sides) of inner ear otoliths of larval cichlid fish were determined after a long-term stay in moderate hypergravity conditions (3g; centrifuge), in the course of which the animals completed their ontogenetic development from hatch to freely swimming. Neither the normal morphogenetic development nor the timely onset and gain of performance of swimming behaviour were impaired by the experimental conditions. However, both utricular and saccular otoliths (lapilli and sagittae, respectively) were significantly smaller after hyper-g exposure compared to 1g control specimens raised in parallel. The asymmetry of sagittae was significantly increased in the experimental animals, whereas the respective asymmetry of lapilli was pronouncedly decreased compared with the 1g controls. These findings suggest that growth and development of bilateral asymmetry of otoliths are guided by the environmental gravity vector. Some of the hyper-g animals revealed a kinetotic behaviour on transfer to normal 1g earth conditions, which was similar to the behaviour observed in previous experiments on the transfer from 1g to microgravity (parabolic aircraft flights). The lapillar asymmetry of kinetotic samples was found to be significantly higher than that of normally behaving experimental specimens. No differences in asymmetry of sagittae were obtained between the two groups. This supports an earlier theoretical concept, according to which human static space sickness might be based on asymmetric utricular otoliths.     

Effects of high calcium intake on fat digestion and bile acid excretion in feces of veal calves

To diagnose visceral leishmaniasis (kala-azar), we have developed a nested PCR method based on amplification of the mini-exon gene, which is unique and tandomly repeated in the Leishmania genome. Nested PCR was sufficiently sensitive for the detection of DNA in an amount equivalent to a single Leishmania parasite or less. We examined the usefulness of this PCR method using bone marrow aspirates and buffy coat cells collected from kala-azar patients who had or had not received chemotherapy in northwest China. We obtained PCR positivity for all of the parasitologically positive bone marrow samples from the patients. Some ambiguities with the primary PCR results were eliminated by the subsequent nested PCR. The buffy coat samples from 7 of 12 patients with splenomegaly were positive by the nested PCR, although only 2 of them were positive for parasites by culture. However, buffy coat samples from nine children, whose splenomegaly has been reduced and clinically cured by antimony treatment, were all negative. Thus, this nested PCR method represents a new tool for the diagnosis of kala-azar with patient blood samples instead of bone marrow or spleen aspirates obtained by more invasive procedures.     

Effects of coal tar on hematological parameters in experimental tuberculosis

Guinea pigs were injected with coal tar (CT) (intratracheally, 25 mg per animal once a week or a month for 2 or 8 months, respectively), then they were infected with MBT (H37Rv, 0.1 mg, subcutaneously). There were changes in hematological responses to MBT changes (in the context of the cell composition of bone marrow and peripheral blood), their pattern was associated with the mode of exposure to CT preceding MBT inoculation. The greatest differences were found in the responses of bone marrow lymphopoiesis and peripheral lymphocytes upon both exposures to CT. On greater exposure to CT (once a week) the changes in the blood system indicated that CT had an adverse effect on the course of experimental tuberculosis, while on lesser exposure (once a month), the effect of CT was more favourable.     

Cell kinetics in the small intestine of suckling rats. I. Influence of hypophysectomy

Thyroid activity, pituitary and serum thyrotrophic potency in response to the administration of clomid, sexovid, PGE1 and PGF2alpha, were studied in H. fossilis. Hightened thyroidal activity and CR (conversion ratio of PB 131I in blood serum in relation to total serum 131I uptake) were noticed a week after clomid (150 microgram/fish/day) and sexovid (150 microgram/fish/day) treatment. Clomid and sexovid also elevated the serum thyrotrophic potency although pituitary TSH level was unaffected. It is evident from the results that clomid and sexovid either act via hypothalamus or directly over pituitary to increase TSH secretion followed by increased thyroid activity. PGE1 and PGF2alpha (100 microgram/fish/day, each) administration increased thyroidal 131I uptake but failed to stimulate hormone output from thyroid gland. Increased TSH level in blood and decreased level of TSH in pituitary was observed in response to the above prostaglandins. It seems that PGE1 and PGF2alpha inhibit thyroid hormone secretion like anti-thyroid drugs triggering the release of TSH into blood.     

Mobilization of hematopoietic stem and progenitor cell subpopulations from the marrow to the blood of mice following cyclophosphamide and/or granulocyte colony-stimulating factor

Committed progenitor cells and primitive stem cells mediate early and sustained engraftment, respectively, after lethal irradiation and stem cell transplantation. Peripheral blood stem cells (PBSC) from unstimulated mice are deficient in both cell types. To study techniques to mobilize both progenitor cells and primitive stem cells from the marrow to the blood, we collected peripheral blood from C57BL/6 mice 6 to 7 days after a single dose of cyclophosphamide (CY; 200 mg/kg intraperitoneally), after recombinant human granulocyte colony-stimulating factor (rhG-CSF) (250 micrograms/kg/d twice per day subcutaneously for 4 days), or after CY followed by G-CSF. Significant increases in white blood cell counts (1.6- to 2.7-fold) and circulating day 8 colony-forming unit spleen (CFU-S) (11- to 36-fold) were seen with all three mobilization methods compared with unstimulated control mice. Transplantation of mobilized blood stem cells into lethally irradiated hosts decreased the time to erythroid engraftment. Blood stem cells were analyzed for primitive stem cell content by Rs, an assay for CFU-S self-renewal, and competitive repopulation index (CRI), an assay of long-term repopulating ability. The primitive stem cell content of unstimulated blood was clearly deficient, but was significantly increased following mobilization, approaching normal bone marrow levels. These results were confirmed by an in vitro limiting dilution long-term culture assay that measures the frequency of progenitor cells and primitive stem cells. Mobilization following CY + G-CSF was accompanied by a marked loss of both progenitor cells and primitive stem cells in the marrow. In contrast, following G-CSF alone the progenitor cell and primitive stem cell content of the marrow was unchanged. Stem cell mobilization following CY + G-CSF was not affected by previous exposure of donors to cytosine arabinoside or cyclophosphamide, but was significantly reduced by previous exposure to busulfan. These data show that stem cell content in the blood may reach near-normal marrow levels after mobilization, the mobilization from the marrow to the blood is temporary and reversible, the specific technique used may mobilize different subpopulations of stem cells, and the type of prior chemotherapy may influence the ability to mobilize stem cells into the blood.     

Adaptation of bone to physiological stimuli

The ability of bone to alter its morphology in response to local physical stimuli is predicated upon the appropriate recruitment of bone cell populations. In turn, the ability to initiate cellular recruitment is influenced by numerous local and systemic factors. In this paper, we discuss data from three ongoing projects from our laboratory that examine how physiological processes influence adaptation and growth in the skeleton. In the first study, we recorded in vivo strains to quantify the locomotion-induced distribution of two parameters closely related to bone fluid flow strain rate and strain gradients. We found that the magnitude of these parameters (and thus the implied fluid flow) varies substantially within a given cross-section, and that while strain rate magnitude increases uniformly with elevated speed, strain gradients increase focally as gait speed is increased. Secondly, we examined the influence of vascular alterations on bone adaptation by assessing bone blood flow and bone mechanical properties in an in vivo model of trauma-induced joint laxity. A strong negative correlation (r2 = 0.8) was found between increased blood flow (76%) in the primary and secondary spongiosa and decreased stiffness (-34%) following 14 weeks of joint laxity. These data suggest that blood flow and/or vascular adaptation may interact closely with bone adaptation initiated by trauma. Thirdly, we examined the effect of a systemic influence upon skeletal health. After 4 weeks old rats were fed high fat-sucrose diets for 2 yr, their bone mechanical properties were significantly reduced. These changes were primarily due to interference with normal calcium absorption. In the aggregate, these studies emphasize the complexity of bone's normal physical environment, and also illustrate the potential interactions of local and systemic factors upon the process by which bone adapts to physical stimuli.     

Stimulative effect of high-level hypergravity on differentiated functions of osteoblast-like cells

The exposure of freshly isolated osteoblasts and osteoblast-like cells to high-level hypergravity caused the inhibition of cell growth, elevation of cAMP content, and the stimulation of differentiated functions such as alkaline phosphatase activity, collagen synthesis, and osteocalcin synthesis. Blockage of elevation of cAMP by SQ22536, an inhibitor of adenylate cyclase, resulted in the inhibition of the hypergravity-stimulated alkaline phosphatase activity, indicating that cAMP is the intracellular mediator of this action of hypergravity. H89, an inhibitor of cAMP-dependent protein kinase (PKA), further inhibited the cell growth that was already inhibited by the hypergravity, and further stimulated the alkaline phosphatase activity that was already stimulated by hypergravity. If cAMP acts through the PKA system, H89 should have blocked the changes in cell function effected by the exposure to hypergravity. Therefore the elevated intracellular cAMP by the exposure of hypergravity caused the changes in cell function by a PKA-independent pathway.     

Familial ureteral abnormalities syndrome: genomic mapping, clinical findings

Macrophage inflammatory protein-1 alpha (MIP-1alpha) has been shown to have a role in the control of myeloid stem and progenitor cell proliferation. Recent evidence suggests that MIP-1alpha also has a stimulatory effect on proliferation of mature progenitors as well as an inhibitory effect on immature progenitors in vitro. We have compared the effect of MIP-1alpha on myeloid and erythroid colony formation of CD34+ cells isolated from bone marrow and cord blood. In the presence of MIP-1alpha, bone marrow granulocyte-macrophage-colony forming cells (GM-CFC) were inhibited over a dose range of 15 ng/ml to 500 ng/ml, and GM-CFC from cord blood CD34+ cells were stimulated over the same dose range. MIP-1alpha suppressed BFU-E colonies in both bone marrow and cord blood. Using thymidine suicide assays, the influence of MIP-1alpha on the cycling status of the cells was assessed. A good correlation between the effect of MIP-1alpha on colony formation and cell cycle progression was observed. These results suggest that there is a differential response to MIP-1alpha when bone marrow and cord blood CD34+ cells are compared. Using flow cytometry and a biotinylated human MIP-1alpha/avidin fluorescein conjugate, the expression of MIP-1alpha receptors on CD34+ cells was assessed. The data indicated that there was little quantitative difference in overall expression of receptors (82.9% versus 93%) from bone marrow or cord blood, respectively. However, when Northern blot analysis was used, mRNA for two different MIP-1alpha receptors CCR1 and CCR5 could be detected in bone marrow, but only CCR1 mRNA was seen in cord blood CD34+ samples. Therefore, the expression of different receptor subtypes on CD34+ cells may be responsible for the difference in MIP-1alpha responsiveness observed.     

Hypergravity effects on normal and avulsed developing avian radii

Rhode Island Red female chicks were subjected to complete closed fracture of the right radius at 2 weeks post-hatching. The animals were allowed to heal for 1 week at either earth gravity or 2 G hypergravity state with control and estrogen-injected groups. Intact and fractured radial length, weight, average epiphysial-diaphysial diameters, and length, width, and weight of healing fracture callus were measured. Daily 2000 IU estrogen administration for 7 d increased intact radial length. Estrogen augments the effects of the 2-G state by inhibiting growth and depleting the mass of both intact and fractured radii and by decreasing the average distal epiphysial diameter of fractured bones. Animals exposed to the hypergravity state without hormonal treatment showed decreased fractured radial length, weight, and smaller proximal epiphysial diameters. The measurable parameters of the fracture callus (width, length, and weight) were depressed by the hypergravity state regardless of whether the animal was untreated or supplemented with estrogen.     

Hemoglobin switching in sheep and goats. VI. Commitment of erythroid colony-forming cells to the synthesis of betaC globin

Bone marrow from mature goats and sheep was cultured in plasma clots, and three erythropoietin (ESF)-dependent responses-growth (colony formation), differentiation (globin production), and initiation of hemoglobin C (alpha2beta2C) synthesis--were quantitated. ESF concentrations below 0.01 U/ml supported colony growth and adult hemoglobin production in cultures of goat marrow, while maximal hemoglobin C synthesis (70%), as measured between 72 and 96 h in culture, required a 100-fold higher ESF concentration. Sheep marrow was cultured in a medium enriched to enhance growth and to permit complete maturation of colonies. These colonies active in hemoglobin synthesis between 24 and 96 h produced mainly adult hemoglobin, and only between 96 and 120 h did sheep colonies develop which produced mainly hemoglobin C (up to 70%). A similar heterogeneity may exist among goat colonies. Thus, when goat bone marrow was fractionated by unit gravity sedimentation, more hemoglobin C synthesis was observed in colonies derived from cells of intermediate sedimentation velocity than in colonies derived from the most rapidly sedimenting cells. Brief exposure of sheep (in vivo) and goat (in vitro) bone marrow to a high ESF concentration committed precursor cells to the generation of colonies which, even at low ESF concentration, produced hemoglobin C. Committment to hemoglobin phenotype appears to be an early and probably irreversible event in the development of an erythroid cell.