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Exposure to glyceryl trinitrate during gun powder production: plasma glyceryl trinitrate concentration, elimination kinetics, and discomfort among production workers.

Plasma glyceryl trinitrate (GTN) concentration was studied in 12 volunteers producing gun powder. Serial blood samples were obtained from the cubital vein before and during work at two sites of production; high concentrations of GTN were detected in the plasma. Control specimens from a femoral vein contained much less GTN, indicating that blood in the cubital vein was enriched by dermally absorbed GTN. In the roll mill area concentrations of GTN in the cubital vein were higher than in the press area, but individual factors were also important since some workers consistently had higher concentration of GTN than others. Differences in absorption were more important than differences in the metabolism of GTN since only a small variation in disappearance rate was found after a sublingual test dose of GTN. Moderate changes in pulse rate and blood pressure were noted during the day. The major discomfort experienced was a headache that increased during working hours, but this was not significantly related to GTN concentrations in the air or in the blood from the cubital vein. The observations imply that major efforts should be made to reduce dermal contact with GTN during production work.

Adult↗

Effect of oxygen supply during growth on the production of cytochromes, enzymes, and acid end products by Haemophilus parasuis.

Haemophilus parasuis, grown under conditions of high aeration, was found to lack a tricarboxylic acid cycle but to possess phosphoenolpyruvate carboxylase and a reductive pathway leading to the production of succinate. Such organisms contained approximately equal quantities of b-, c-, and d-type cytochromes and excreted acetate. When the oxygen supply for growth was either reduced or eliminated, the specific activities of phosphoenolpyruvate carboxylase, malate dehydrogenase, fumarase, fumarate reductase, and NADH: fumarate oxidoreductase were increased substantially, and the acid products were succinate, acetate, and formate. Organisms grown under the latter conditions also contained increased quantities of b- and c-type cytochromes, some of which were low-potential cytochromes. These low-potential cytochromes were reduced by NADH and oxidized by fumarate, and hence, appeared to be components of NADH: furmarate oxidoreductase. Our results indicate that in H. parasuis, growing aerobically in medium containing glucose, the sole function of the reductive pathway is to provide intermediates for biosynthetic processes, and oxygen is the preferred electron acceptor. As the supply of oxygen is reduced or eliminated, the reductive pathway becomes more involved in NAD+ recycling and fumarate becomes the acceptor. In effect, irrespective of the oxygen supply, the growth of H. parasuis is absolutely dependent upon the presence of an electron transport system.

Acetates↗

Investigations into the systemic production of aldehyde-derived peroxidation products in a murine model of acute iron poisoning: a dose response study.

Acute iron poisoning remains a leading cause of morbidity and mortality in pre-school aged children in North America. Acute iron poisoning leads to organ damage, such as respiratory difficulties, cardiac arrhythmias, and possible death. The mechanism of iron toxicity is not fully understood, though it is thought that free iron is able to catalyze the production of harmful oxygen free radicals, which can damage all biochemical classes including lipid membranes, proteins, and DNA. Accordingly, we hypothesized that acute iron loading results in dose-dependent increases in oxygen free radical production, as quantified by the cytotoxic aldehydes hexanal, 4-hydroxynonenal, and malondialdehyde, in an experimental murine model. In support of our hypothesis, significant dose-dependent increases in all aldehydes investigated were reported in comparison to controls (p < 0.001). This murine model will assist in providing a better understanding of possible mechanism(s) of injury and organ dysfunction following acute iron poisoning, and for the development and evaluation of treatment regimes.

Acute Disease↗

Effect of acupuncture on adrenocortical hormone production: I. Variation in the ability for adrenocortical hormone production in relation to the duration of acupuncture stimulation.

The effect of acupuncture on adrenocortical hormone production in adult female albino rabbits of New Zealand strain was investigated. There was significant increase compared to the control cortisol and corticosterone following application of acupuncture at the locus Tsu-San-Li. In the non-locus group, such treatment resulted in only a transient raise followed by a significant fall in cortisol and corticosterone. Acupuncture treatment with electric current for 1 hour proved to be unique in that it gave rise to no biphasic change in the 14C uptake of the steroids. These results indicate that adrenal production of corticosterone and cortisol was enhanced by acupuncture and electroacupuncture at the Tsu-San-Li locus.

Acupuncture Therapy↗

Products of enteropathogenic E. coli inhibit lymphokine production by gastrointestinal lymphocytes.

Previously we have shown that lysates of enteropathogenic Escherichia coli (EPEC) inhibit lymphokine production by mitogen-activated peripheral blood mononuclear cells (PBMCs). The aim of the present study was to determine whether products of EPEC alter lymphokine expression by gastrointestinal mucosal lymphocytes. Lysates from EPEC clones inhibited mitogen-stimulated interleukin-2 (IL-2), IL-4, IL-5, and interferon-gamma (IFN-gamma) but not IL-8 mRNA expression by lamina propria mononuclear cells isolated from surgically resected colon specimens. Inhibitory lysates did not significantly change CD25 expression on either CD4, CD8, or CD45R0 lymphocytes by flow cytometry. Bacterial supernatants of EPEC inhibited IL-2 and IL-5 protein secretion by mitogen-stimulated PBMCs. EPEC lysates inhibited IL-2 mRNA expression induced by lysates of nonpathogenic E. coli. In conclusion, EPEC contains a novel gene(s) that encodes factors that selectively inhibit IL-2, IL-4, IL-5, and IFN-gamma expression by mucosal mononuclear cells without affecting CD25 or IL-8 expression. Thus enteric bacteria can produce factors that may regulate the function of the gastrointestinal mucosal immune system.

Antigens, CD↗

Impaired cAMP production in human airway smooth muscle cells by bradykinin: role of cyclooxygenase products.

Interleukin (IL)-1beta impairs human airway smooth muscle (ASM) cell cAMP responses to isoproterenol (Iso). We investigated if bradykinin (BK) could cause a similar effect and the role of cyclooxygenase (COX) products in this event, since we have recently reported that BK, like IL-1beta, also causes COX-2 induction and prostanoid release in human ASM cells. BK pretreatment significantly attenuated Iso-induced cAMP generation in a time- and concentration-dependent manner. cAMP generation by prostaglandin (PG) E2 but not by forskolin was also impaired. The COX inhibitor indomethacin completely prevented the impairment, whereas the selective COX-2 inhibitors NS-398 and nimesulide, protein synthesis inhibitors cycloheximide and actinomycin D, and steroid dexamethasone were all partially effective. The impairment was mimicked by the B2 agonist [Tyr(Me)8]BK, the Ca2+ ionophore A-23187, and PGE2 and prevented by the B2 antagonist HOE-140, but anti-IL-1beta serum was ineffective. The results indicate that BK impairs human ASM cell responses to Iso, and the effect is largely mediated by B2 receptor-related COX product release via both COX isoforms and is independent of IL-1beta.

Adult↗

Measurement of O2 consumption, CO2 production, and water vapor production in a closed system.

Equations for the calculation of O2 consumption, CO2 production, and water vapor production in a constant-volume, closed-system respirometer are presented. Necessary measurements include only the initial temperature, pressure, and gas volume in the respirometer chamber, and the fractional concentration of O2 in gas samples taken at the beginning and end of the period of measurement. Potential errors resulting from changes in CO2 and water vapor concentrations are identified. Ignoring CO2 effects can produce up to a 6.4% error in estimates of O2 consumption, and errors due to water vapor effects can exceed 100%. Techniques are presented for minimizing potential errors and for measuring CO2 and water vapor concentrations with an O2 analyzer so that potential errors can be eliminated.

Animals↗

Metabolic aspects and viability of heparin/CPDA-1-stored red cell concentrate as a by-product of a high-yield factor VIII production method.

As a by-product of a new high-yield method of production of freeze-dried factor VIII, red cell concentrate (RCC) containing a small amount of heparin besides CPDA-1 was studied. Compared to CPDA-1 stored RCC no difference was found in hematology parameters and 2,3-DPG levels during 28 days storage. Although still in the normal range for transfusion, ATP levels were significantly lower compared to CPDA-1-stored RCC after 30 days shelf life. A survival study with 51Cr-labelled red cells showed good recovery and normal red cell half-life. Rapid transfusion of heparin/CPDA-1 RCC in 6 volunteers did not have any effect on aPTT. Heparin could not be detected in posttransfusion plasma samples.

2,3-Diphosphoglycerate↗

Effect of L-tryptophan products on function of human eosinophils: investigation of the causal mechanisms of eosinophilia myalgia syndrome associated with L-tryptophan products.

Contaminants in the L-tryptophan products, known as peak-E and peak-5, at a concentration of 1-10 micrograms/ml had the ability to elicit chemokinetic migration of eosinophils. Purified eosinophils adhered to peak-E- or peak-5-stimulated human umbilical vein endothelial cells, and this adherence was inhibited by the presence of antibody to intercellular adhesion molecule-1, but not by vascular cell adhesion molecule-1 antibody. Neither contaminant affected the expression of integrins, e.g. CD11b or CD49d, on the purified eosinophils. Human peripheral blood mononuclear cells (PBMCs) produced eosinophil survival-enhancing activity when cultivated with peak-E, but not with medium alone, peak-5 or control tryptophan. This activity of peak-E was significantly inhibited (p < 0.01) by the presence of antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, expression of GM-CSF mRNA was found in total cellular RNA isolated from peak-E-stimulated PBMCs. Eosinophils acquired the ability to migrate toward interleukin-8 (IL-8) when preincubated with the contaminants of interest. IL-8 also bound to the contaminant-stimulated eosinophils, but not to those stimulated with medium alone. These findings suggest that contaminants in the L-tryptophan products modify the several functions of eosinophils and play a role in the pathogenesis of eosinophil myalgia syndrome.

Cell Adhesion↗

A useful marker for evaluating tissue-engineered products: gap-junctional communication for assessment of the tumor-promoting action and disruption of cell differentiation in tissue-engineered products.

An in vitro system for evaluating the safety of tissue-engineered products is a convenient because of its rapidity and low cost. On the basis of recent studies, intercellular channels called gap-junctions are considered to play an important role on the tumor-promotion stage during the tumorigenesis induced by polyurethanes. Further, we also demonstrate the significance of the intercellular communication during neuronal cell differentiation. From these results, we propose a survey of the function of the gap-junctional communication as a probable useful marker for evaluating the safety of tissue-engineered products.

Animals↗

Asthmatic epithelial cell proliferation and stimulation of collagen production: human asthmatic epithelial cells stimulate collagen type III production by human lung myofibroblasts after segmental allergen challenge.

Epithelial injury and subepithelial collagen deposition are characteristic of asthma. We hypothesized that epithelial cell proliferation increases after airway injury in asthmatics, that epithelial cells stimulate lung myofibroblast collagen production, and that both processes are modulated by allergen-recruited inflammatory cells. Epithelial cells obtained at baseline, 1 d, and 1 and 2 wk after endobronchial allergen challenge from asthmatics and nonasthmatics were placed in culture, with and without bronchoalveolar lavage cells obtained from the same segment. Epithelial cell proliferation and collagen synthesis by human lung myofibroblasts stimulated with culture medium from these epithelial cells were determined. Epithelial proliferation increased (108 +/- 50% above baseline, p = 0.01 for d, and p = 0.004 for group x day interaction) 1 wk postchallenge in cells from asthmatics, but not from nonasthmatics, and required bronchoalveolar lavage cell coculture. Culture medium from epithelium harvested from asthmatics, but not from nonasthmatics, at 1 to 2 wk postchallenge stimulated collagen type III production 50% to 70% (p = 0.043 for clinical group, p = 0.012 for day, and p = 0.022 for group x day interaction), but not collagen type I. This effect was independent of an acute eosinophilic response. We conclude that epithelial cells from asthmatics, but not from nonasthmatics, are stimulated to proliferate after allergen challenge, and over 1 to 2 wk postchallenge, stimulate collagen type III synthesis by lung myofibroblasts. Epithelial cell proliferation appears dependent upon infiltrating inflammatory cells, but stimulation of collagen type III does not.

Adult↗

The regulation of inflammatory mediator production by mast cell products.

Mast cells are prominent in the airways and have been implicated in the pathophysiology of asthma. The ability of mast cells to generate or release the vasoactive/spasmogenic mediators histamine, adenosine, PGD2, sulfidopeptide leukotrienes, and platelet-activating factor is thought relevant to immediate bronchospastic responses in association with mucus secretion and airway edema. Mast cell elaboration of chemotactic factors and release of enzymes with both tryptic and chymotryptic specificity is held responsible for later reactions in which airway inflammation is prominent and nonspecific bronchial hyperreactivity is present. Recent evidence indicates that in addition to direct effect of these mast cell products some mast cell mediators themselves modulate inflammatory mediator production. Thus, adenosine, by interacting with A2 receptors on the surface of mast cells, markedly augments mast cell release of preformed granule associated mediators. Mast cell-derived chemotactic factors, exemplified by low molecular weight eosinophil directed molecules, can induce cell specific synthesis of inflammatory lipids such as platelet-activating factor. These findings only begin to suggest the richness of possibilities for mast cell regulation of the inflammatory response and underline the reality that the inflammatory response in lung as in all tissue is extremely complex and dependent upon cell-to-cell communication for its full expression.

Animals↗

The P2X7 receptor is a candidate product of murine and human lupus susceptibility loci: a hypothesis and comparison of murine allelic products.

Systemic lupus erythematosus and its murine equivalent, modelled in the New Zealand Black and New Zealand White (NZB x NZW)F1 hybrid strain, are polygenic inflammatory diseases, probably reflecting an autoimmune response to debris from cells undergoing programmed cell death. Several human and murine loci contributing to disease have been defined. The present study asks whether the proinflammatory purinergic receptor P2X7, an initiator of a form of programmed cell death known as aponecrosis, is a candidate product of murine and human lupus susceptibility loci. One such locus in (NZB x NZW)F1 mice is lbw3, which is situated at the distal end of NZW chromosome 5. We first assess whether NZB mice and NZW mice carry distinct alleles of the P2RX7 gene as expressed by common laboratory strains, which differ in sensitivity to ATP stimulation. We then compare the responses of NZB lymphocytes, NZW lymphocytes and (NZB x NZW)F1 lymphocytes to P2X7 stimulation. NZB and NZW parental strains express the distinct P2X7-L and P2X7-P alleles of P2RX7, respectively, while lymphocytes from these and (NZB x NZW)F1 mice differ markedly in their responses to P2X7 receptor stimulation. NZB mice and NZW mice express functionally distinct alleles of the proinflammatory receptor, P2X7. We show that current mapping suggests that murine and human P2RX7 receptor genes lie within lupus susceptibility loci lbw3 and SLEB4, and we argue that these encode a product with the functional characteristics consistent with a role in lupus. Furthermore, we argue that aponecrosis as induced by P2X7 is a cell death mechanism with characteristics that potentially have particular relevance to disease pathogenesis.

Alleles↗

The production of hydroxyl radicals in the fetal lamb brain resulting from occlusion of the umbilical circulation and the transplacental effect of MCI-186 to inhibit hydroxyl radical production.

The present study evaluated hydroxyl radical production in fetal lamb brain during and after umbilical cord occlusion and examined the effects of injecting MCI-186 (3-metyl-1-phenyl-2-pyrazolin-5-one; Edaravone), a hydroxyl radical scavenger, into the maternal circulation. In 11 chronically instrumented lambs, intermittent total umbilical cord occlusions 1 min out of every 3 min for 1 h and 10-min persistent total umbilical cord occlusion were performed with brain microdialysis using 5 mM of sodium salicylate. In the remaining four lambs, 60 mg of MCI-186 was administered into the maternal circulation from shortly before the end of 10-min persistent total umbilical cord occlusion. Concentrations of 2,3-dihydroxy-benzoic acid (2,3-DHBA), produced by hydroxyl radical reactions with sodium salicylate, were measured in perfusate by HPLC. Concentration of 2,3-DHBA in perfusate was 23.05 +/- 10.95 nM before umbilical cord occlusion. Levels of 2,3-DHBA tended to increase slightly during and after intermittent umbilical cord occlusion, and were significantly increased by the end of 10-min occlusion (40.06 +/- 21.36 nM) and after occlusion (93.74 +/- 29.17 nM). Infusion of MCI-186 suppressed 2,3-DHBA concentration to 29.35 +/- 14.95 nM after occlusion. Administration of MCI-186 into the maternal circulation reduces hydroxyl radical production induced by umbilical cord occlusion in the fetal lamb brain.

Animals↗

Neuroendocrine control of thymic hormonal production. I. Prolactin stimulates in vivo and in vitro the production of thymulin by human and murine thymic epithelial cells.

The thymic epithelium is responsible for the secretion of thymic peptides, which intervene in some steps of intra- and extrathymic T cell differentiation. Recent data suggest that thymic hormone secretion is modulated by the neuroendocrine network, comprising thyroid, adrenals, and gonads. However, the role of the pituitary gland in this regulation is still poorly understood. In the present paper we studied the in vivo and in vitro influences of PRL on the secretion of thymulin, one of the chemically defined thymic hormones, by thymic epithelial cells (TEC). When injected daily (20-100 micrograms/20 g) in young or old C57BL/6 mice, PRL induced a specific increase in thymulin synthesis and secretion, respectively, measured by the number of thymulin-producing cells in the thymus and the peripheral levels of the hormone. This stimulation was dose dependent and reversible after the end of treatment. Similar findings have been made in animals with pituitary dwarfism, known to have low levels of circulating thymulin. This stimulatory effect was also observed in primary cultures of human and mouse TEC when PRL (10(-7) to 10(-8) M) was applied to culture supernatants, thus suggesting that PRL could act directly on TEC. In addition, we induced in vivo experimental hypoprolactinemia, treating mice with bromocriptine, a dopamine receptor agonist that inhibits pituitary PRL secretion. Bromocriptine treatment (100-200 micrograms/20 g) yielded a significant decrease in thymulin secretion that could be reversed by coincident treatment with PRL. In the light of previous observations that bovine GH can also increase thymulin production in aged dogs, we performed a series of experiments in vitro to evaluate whether GH has a direct effect on TEC. We observed that only human GH preparations that are known to have a PRL-like effect were efficient in stimulating thymulin biosynthesis and release into the culture supernatants. The effects of PRL on TEC were not restricted to thymic hormone production. We observed that TEC proliferation, as well as the numbers of a TEC subset defined by the expression of cytokeratins 3 and 10, could also be increased by PRL treatment. All these findings show that the pituitary gland directly affects TEC in terms of cytoskeletal and secretory protein expression as well as cell cycle.

Animals↗

Germ cell control of testin production is inverse to that of other Sertoli cell products.

Recent studies have shown that germ cells can regulate testins, two newly identified Sertoli cell proteins that are associated with junctional complexes. To investigate this possibility, several parameters of Sertoli cell function were investigated over 2-120 days post exposure of the rat testes to x-rays (3 Grays). The irradiation-induced loss of spermatogonia resulted in a maturation-depletion process progressively affecting all germ cell classes. Testis weight began to decrease when the most numerous germ cell type (spermatids) began to decline. A complete or near complete recovery of spermatogenesis and of the testis weight had occurred by day 120 post irradiation. There was no significant change in FSH, epididymal androgen-binding protein, and tubule fluid levels during the first weeks after irradiation, when the seminiferious epithelium was depleted of spermatogonia and germ cells up to early spermatids. In contrast, when the number of the more mature forms of spermatids declined (between day 21 and 54), FSH rose and androgen-binding protein as well as fluid production declined. The subsequent recovery of these parameters was also highly correlated with the number of late spermatids. By contrast, testicular testin contents reacted to the depletion of germ cells with a biphasic increase; a doubling occurred when spermatogonia, spermatocytes, and early spermatids were absent (days 4-28), and a 7-fold rise occurred by day 37 when the number of late spermatids had decreased by 50%. By day 54, when the sperm counts had reached a nadir, testin contents had returned to levels corresponding to about four times the control levels; they progressively recovered thereafter. These observations support the postulate that germ cells negatively regulate testins. This possibility was investigated with in vitro experiments showing that addition of germ cell-conditioned medium to Sertoli cell monolayers inhibited testin secretion in a dose-dependent manner. In conclusion this study; 1) highlights the complex interplay between the various germ cell classes in the control of the Sertoli cell function in the adult testis; 2) establishes that germ cell effects may be opposite on different Sertoli cell products; 3) demonstrates that several classes of germ cells negatively control testicular testin contents; and 4) emphasizes the particular role of late spermatids in Sertoli cell regulation.

Androgen-Binding Protein↗

Rate enhancement with high ratio of the monoalkylated product to the dialkylated product in the alkylation of the lithium enolate of 1-tetralone with reactive alkyl halides.

The reactions of the lithium enolate of 1-tetralone with reactive alkyl halides were examined in the absence and in the presence of 3 eq of various ligands for the lithium. It is shown that the rates of the reactions are enhanced greatly in the presence a tetradentate amine (1,1,4,7,10,10-hexamethyltriethylenetetramine), and the ratio of the monoalkylated product to the dialkylated product is increased under shorter reaction times.

Alkylation↗