Evidence Of Synergism Research Articles

Spinal Antinociceptive Action of Na+-K+Pump Inhibitor Ouabain and Its Interaction with Morphine and Lidocaine in Rats

The Na+,K+-adenosine triphosphatase is a ubiquitous enzyme system that maintains the ion gradient across the plasma membrane of a variety of cell types, including cells in the central nervous system. We investigated the antinociceptive effect of intrathecally administered ouabain and examined its potential interaction with spinal morphine and lidocaine. Using rats chronically implanted with lumbar intrathecal catheters, the ability of intrathecally administered ouabain, morphine, and lidocaine and of mixtures of ouabain-morphine and ouabain-lidocaine to alter tail-flick latency was examined. To characterize any interactions, isobolographic analysis was performed. The effects of pretreatment with intrathecally administered atropine or naloxone also were tested. Intrathecally administered ouabain (0.1-5.0 microg), morphine (0.2-10.0 microg), and lidocaine (25-300 microg) given alone produced significant dose- and time-dependent antinociception, but systemic administration of ouabain did not produce such an effect. The median effective dose (ED50) values for intrathecally administered ouabain, morphine, and lidocaine were 2.3, 5.0, and 227.0 microg, respectively. Isobolographic analysis exhibited a synergistic interaction after the coadministration of ouabain and morphine. With ouabain and lidocaine, there was no such evidence of synergism. Intrathecally administered atropine, but not naloxone, completely blocked the antinociceptive effect of ouabain and attenuated its interaction with spinally administered morphine. Intrathecally administered ouabain produces antinociception, at least in part, via an enhancement of cholinergic transmission in the spinal nociceptive processing system. The results of the interaction of ouabain with morphine and lidocaine suggest that modulation of Na+-,K+-electrochemical gradients and thus subsequent release of neurotransmitters in the spinal cord are likely to play important roles in the spinal antinociceptive effect of intrathecally administered ouabain.

WHY ARE SOME FRUITS TOXIC? GLYCOALKALOIDS INSOLANUMAND FRUIT CHOICE BY VERTEBRATES

We examined the influence of secondary metabolites (glycoalkaloids) of Solanum fruits on fruit consumption by seed dispersers and seed predators. Our goal was to determine the degree to which secondary metabolites might explain fruit–frugivore interactions that heretofore have not been explained by other fruit-related variables (e.g., color, nutrient content, seediness, etc.). Using feeding trails with real fruits and artificial fruit pulp media, we tested two sets of hypotheses, one relating to the specificity of secondary metabolites and the other to intra- and interspecific variation in secondary metabolite content. First, the Directed Toxicity Hypothesis was tested against its alternative, the General Toxicity Hypothesis. The Directed Toxicity Hypothesis posits that fruit pulp secondary metabolites are directed primarily toward organisms that destroy seeds following fruit consumption, remaining nontoxic to organisms that disperse seeds. The General Toxicity Hypothesis states that these secondary metabolites are general in their effects. Second, the Removal Rate Hypothesis was tested against its alternative, the Nutrient–Toxin Titration Hypothesis. The Removal Rate Hypothesis posits that profitable fruits, with high natural rates of removal, contain only low levels of secondary metabolites as defenses against seed predators and pathogens. In contrast, the Nutrient–Toxin Titration Hypothesis states that profitable fruits are better able to afford protection by high levels of secondary metabolites because high nutrient levels compensate for deterrent effects of secondary metabolites. We compared Solanum carolinense, with high levels of secondary metabolites (glycoalkaloids) in ripe fruit, and S. americanum, with negligible levels, conducting four sets of feeding trials: (1) Real Fruit trials to determine the preferences of our study animals for real fruit of each plant species; (2) Fruit Mimic trials using artificial fruit pulp media to determine the relative effects of nutrient and glycoalkaloid content on fruit preferences; (3) Interaction trials using artificial fruit pulp media to examine relative and interactive effects of the two main glycoalkaloids in our fruits (α-solasonine and α-solamargine); and (4) Nutrient–Toxin Titration trials using artificial fruit pulp media to determine how much nutrient content might compensate for deterrent effects. Both seed predators and seed dispersers preferred the low-glycoalkaloid S. americanum fruits and were deterred by glycoalkaloid levels typical of ripe S. carolinense fruits. Because of the generality of the deterrent effects, we rejected the Directed Toxicity Hypothesis. Additionally, we found no evidence for differences between the two glycoalkaloids in their deterrent effects, and no evidence of synergism between them. Nutrient effects were generally small; we found no evidence that nutrient variation could compensate for the deterrence produced by levels of glycoalkaloids found in ripe S. carolinense fruits. Ripe fruits of the presumably more profitable, preferred S. americanum contain much lower levels of glycoalkaloid. Taken together, our results support the Removal Rate Hypothesis. Secondary metabolites of ripe fleshy fruits are an important determinant of fruit use by frugivores. We suggest that a primary function of these metabolites is defense against pests and pathogens. Thus, these organisms should be considered an important influence on fruit–seed disperser interactions.

ANTIFUNGAL ACTIVITY OFSOLANUMFRUIT GLYCOALKALOIDS: IMPLICATIONS FOR FRUGIVORY AND SEED DISPERSAL

We tested two sets of hypotheses about the role of secondary metabolites (glycoalkaloids) in ripe Solanum (Solanaceae) fruit. The Directed Toxicity Hypothesis states that these compounds are most toxic to frugivores that do not disperse seeds (e.g., fungi), whereas its alternative, the General Toxicity Hypothesis, states that they are generally toxic to all frugivores. The Removal Rate Hypothesis states that highly rewarding fruits, which are removed rapidly by dispersers, require only low levels of glycoalkaloids for protection against insects and microbes. The alternative Nutrient–Toxin Titration hypothesis states that highly rewarding fruits may be able to maintain higher levels of glycoalkaloids because high nutrient content may offset the negative effects of glycoalkaloids on dispersers. Our previous work with vertebrate frugivores supported the General Toxicity and Removal Rate hypotheses. We used artificial fruit pulp media to measure how the mycelial growth rate of nine fungal species was affected by two glycoalkaloids, α-solasonine and α-solamargine, both common in ripe Solanum fruits. In one set of fungal growth trials, we mimicked two species of fruit, S. americanum with low levels of glycoalkaloid in ripe fruit and S. carolinense with high levels, to determine the relative effects of nutrient and toxin content. In another set of trials, we examined the relative and interactive effects of the two glycoalkaloids. Finally, we tested whether or not increases in nutrient content could offset the negative effects of glycoalkaloids on fungal growth. All fungi tested were inhibited by the glycoalkaloids, with lower levels of antifungal activity for agars corresponding to (low-toxin) S. americanum fruits than to (high-toxin) S. carolinense fruits. Because fungi varied in their degree of inhibition by glycoalkaloids, we found only limited support for the Directed Toxicity Hypothesis. The degree of inhibition for fungi was, on average, similar in magnitude to the negative effects upon vertebrate feeding rates, providing further support for the General Toxicity Hypothesis. Additionally, we found no evidence for differences in antifungal effects between the two glycoalkaloids and no evidence of synergism between them. Nutrient effects were generally small, with little evidence that nutrient variation could compensate for the antifungal activity produced by levels of glycoalkaloids found in ripe S. carolinense fruits. Fruits that are presumably more profitable (S. americanum) are preferred by vertebrate frugivores and contain much lower levels of glycoalkaloid. These results support the Removal Rate Hypothesis. We conclude that glycoalkaloids of Solanum fruits may act as effective antifungal defenses. However, because they are also toxic to seed-dispersing vertebrates, their effects upon fruit–disperser interactions are probably general and important.

Gulf war chemicals — more evidence of synergism

Gulf war chemicals — more evidence of synergism

An approach for evaluating the respiratory irritation of mixtures: application to metalworking fluids.

Recently, the sensory and pulmonary irritating properties of ten metalworking fluids (MWF) were assessed using a mouse bioassay. Relative potency of the MWFs was estimated, but it was not possible to identify the component(s) responsible for the the respiratory irritation induced by each MWF. One of the ten fluids, MWF "ET", produced sensory and pulmonary irritation in mice, and it was of moderate potency in comparison to the other nine MWFs. MWF "E" had three major components: tall oil fatty acids (TOFA), sodium sulfonate (SA), and paraffinic oil (PO). In the present study, the sensory and pulmonary irritating properties of these individual components of MWF "E" were evaluated. Mixtures of the three components were also prepared and similarly evaluated. This analysis revealed that the sensory irritation from MWF "E" was largely due to TOFA, whereas SA produced the pulmonary irritation observed with MWF "E". Both TOFA and SA were more potent irritants than was MWF "E", and the potency of TOFA and/or SA was diminished through combination with PO. There was no evidence of synergism of the components when combined to form MWF "E". This approach for identifying the biologically "active" component(s) in a mixture should be useful for other MWFs. Furthermore, the approach should be easily adapted for other applications involving concerns with mixtures.

Ingested Arsenic and Internal Cancer: A Historical Cohort Study Followed for 33 Years

A historical cohort study was conducted to investigate the long-term effect of exposure to ingested arsenic. The 454 residents who had been identified in a list made in 1959 were followed until 1992. They lived in an arsenic-polluted area, called Namiki-cho, Nakajo-machi, in Niigata Prefecture, Japan, and used well water containing inorganic arsenic. The exposure period was estimated to be about 5 years (1955-1959). Death certificates for the people who died between 1959 and 1992 were examined, and a total of 113 of the 454 residents were estimated to have drunk well water containing a high dose of arsenic (> or = 1 ppm). The standardized mortality rate ratios of these 113 residents were 15.69 for lung cancer (observed/expected = 8/0.51; 95% confidence interval (CI) 7.38-31.02) and 31.18 for urinary tract cancer (observed/expected = 3/0.10; 95% CI 8.62-91.75). Cox's proportional hazard analyses demonstrated that the hazard ratios of the highest exposure level group (> or = 1 ppm) versus the background exposure level group (0.001 ppm) were 1.74 (95% CI 1.10-2.74) for all deaths and 4.82 (95% CI 2.09-11.14) for all cancers. The analysis according to the skin signs of chronic arsenicism in 1959 showed that they were useful risk indicators for subsequent cancer development. In the development of lung cancer, there was evidence of synergism between arsenic intake and smoking habit.

Experimental investigations on model emulsion systems stabilized with non-ionic surfactant blends

We have performed experimental research into model oil-in-water emulsion systems stabilized with non-ionic surfactant blends: thin aqueous films between oil phases and oil drops coalescing against their homophase. Xylene was chosen as the oil phase, and Tween 20 and Span 20, alone or in mixtures at different molar ratios, were used as stabilizers. The roles of the surfactant mole ratio, the electrolyte concentration and pH were studied. It was shown that there is considerable electrostatic repulsion within the aqueous films. The results obtained on thin film stability and on drop lifetime at constant electrolyte concentration indicate that Tween 20 (when present) is the emulsifier that predominantly determines the stability of the systems. This conclusion can be related to the higher surface activity and higher adsorption of Tween as deducted from interfacial tension data. Some evidence of synergism was observed only at an electrolyte concentration of 10 −3 M (NaCl). We also carried out stability tests on shaken and homogenized batch emulsion systems and the results show good correlation with the data from the model investigations.

Irrigated spring wheat and timing and amount of nitrogen fertilizer. I. Grain yield and protein content

To improve N-use efficiency in wheat ( Triticum aestivum L.), this study determined the latest stage of development at which supplemental N fertilizer would elicit a full grain yield response. Three experiments were carried out in 1986 with early-June-sown irrigated semidwarf spring wheats in a low fertility field at Griffith in New South Wales (34°S). N was supplied as NH 4NO 3 top dressings and crop management was otherwise optimal. The grain yield response to N given at seeding was very high (in the main experiment the initial slope was 38 kg grain/kg N, with 180 kg N/ha increasing yield from 1812 kg/ha to 7113 kg/ha). Single N dressings given in this and an adjacent second experiment indicated no significant decrease in yield response until dressings were delayed beyond the onset of stem elongation. There was no evidence of synergism between early and late split N dressings. The apparent N recovery in the crop at maturity ranged from 44–77% (mean 63%) and did not decline strongly until all N was given after stem elongation began. 15N recovery in crop from labelled fertilizer applied to microplots ranged from 40 to 56% and increased slightly with later N dressings, while losses decreased. With delay of single N dressings, grain protein content only increased with dressings after the onset of stem elongation. Excluding those treatments where all N was given after this stage, protein responses were quantitatively related inversely to grain yield responses ( r 2=0.49), with negative responses accompanying the large yield responses (>35 kg grain/kgN) generated by initial increments of N. Examination in a third experiment of possible predictors of the optimum amount of supplemental N to be given at the onset of stem elongation suggest that stem base NO 3-N concentration and culm number m −2 could serve this role.

Male-produced aggregation pheromone ofCarpophilus mutilatus (Coleoptera: Nitidulidae)

Males ofCarpophilus mutilatus Erichson produce an aggregation pheromone to which both sexes respond. The pheromone includes two hydrocarbon components, (3E,5E,7E)-5-ethyl-7-methyl-3,5,7-undecatriene (1) and (3E,5E,7E)-6-ethyl-4-methyl-3,5,7-decatriene (2). These were emitted in a 10∶1 ratio and in a total amount of ca. 5 ng per feeding male per day. All tested doses of1 and2, from 0.03 to 30 ng, were more attractive than controls in wind-tunnel tests, but there was no evidence of synergism between these trienes. Dramatic synergism between the pheromone and a food-type coattractant occurred in the field, however. In a date garden in southern California, traps with a combination of synthetic1 and fermenting whole-wheat bread dough attracted 22 times more beetles than dough by itself and 295 times more than1 by itself. Volatile collections from males also contained three oxygenated compounds that were absent from females. One of these was tetradecanal (ca. 5 ng per male per day), but the structures of the other two are presently undetermined (0.8 and 1.1 ng per male per day). No function for these was demonstrated. One compound originating in the artificial diet, 2-phenylethanol, was particularly attractive in the wind-tunnel bioassay, as was the chromatographic solvent, methanol.

The effects of noradrenaline and adenosine 5'-triphosphate on polyphosphoinositide and phosphatidylcholine hydrolysis in arterial smooth muscle.

1. The effects of noradrenaline and alpha,beta,methylene adenosine 5'-triphosphate (alpha,beta,methylene ATP) on polyphosphoinositide metabolism, phosphatidylcholine hydrolysis and contraction in rabbit saphenous arteries were investigated. The effect of noradrenaline upon polyphosphoinositide metabolism was also investigated in the rat tail artery. 2. Noradrenaline (10(-7)-10(-4) M) evoked a concentration-dependent increase in total inositol phosphate accumulation in the rat tail but not in the rabbit saphenous artery. Propranolol (3 x 10(-6) M) did not alter this result in the rabbit saphenous artery. In addition, alpha,beta,methylene ATP (10(-6) M) significantly increased total inositol phosphate accumulation in the rabbit saphenous artery, while potassium chloride (8 x 10(-2) M) was ineffective. 3. Phorbol 1,2-myristate 1,3-acetate (3 x 10(-8) M) enhanced noradrenaline (10(-2)-10(-4) M)-evoked contractions in rabbit saphenous artery. The contractile responses to potassium chloride (1- 16 x 10(-2) M) in tissues treated with 6-hydroxydopamine (5 x 10(-4) M), in vitro, were unaffected by these concentrations of the phorbol ester. 4. Noradrenaline (10(-6)-10(-4) M) evoked a concentration-dependent increase in the levels of choline and choline phosphate, but not in those of glycerophosphocholine, in the rabbit saphenous artery. Choline levels increased significantly over the first 15-30 s then declined to control levels within 2 min of addition of noradrenaline (10(-5) M). A smaller initial rise in choline phosphate levels (15-30 s) was followed by a larger secondary rise at 2-4 min.5. alpha, beta, methylene ATP (10-1_ 0-4 M) also evoked a concentration-dependent increase in the levels of both choline and choline phosphate, but not those of glycerophosphocholine, in the rabbit saphenous artery. alpha, beta, methylene ATP (10-4 M) significantly increased levels of both of these products within the first 15-30 s of addition of the drug; these levels reached a stable plateau 1 min after addition.6. The maximum accumulation of choline or choline phosphate evoked by either noradrenaline or alpha, beta, methylene ATP, acting alone or in combination, was not significantly different. No evidence of synergism between noradrenaline and alpha, beta, methylene ATP was observed.7. This study demonstrates that each of the co-transmitters in the rabbit saphenous artery, noradrenaline and adenosine 5'-triphosphate (ATP), promote phosphatidylcholine hydrolysis. Noradrenaline seems to rely on phosphatidylcholine hydrolysis to mediate its contractile effects, whilst ATP promotes both polyphosphoinositide and phosphatidylcholine metabolism suggesting that multiple signal-transduction mechanisms are involved in stimulus-contraction coupling in this artery.

Mechanical and biochemical effects of individual co-transmitters in rat tail arteries.

1. The effects of (1) nerve stimulation (NS, 0.5 ms, 1-16 Hz, supramaximal voltage, 20 s) upon vasoconstriction, as measured by changes in perfusion pressure and (2) exogenously added co-transmitters noradrenaline (NA) and alpha, beta,-methylene ATP (alpha, beta, MeATP) upon polyphosphoinositide (PPI) breakdown, and vasoconstriction, were studied in rat tail perfused arteries or arterial rings. The interaction between NA and ATP upon contraction of artery rings and inositol phosphate (IP) accumulation was also studied. 2. Nerve stimulation evoked vasoconstriction in rat tail arteries. These pressor responses were largely (approximately 80%) blocked by the alpha 1-adrenoceptor antagonist, prazosin (10(-6) M), but not significantly affected by desensitization of P2x-purinoceptors by prior, repeated (five times) addition of alpha, beta, MeATP (10(-6) M). 3. Noradrenaline evoked a prazosin (10(-6) M)-sensitive, concentration-dependent, increase in both perfusion pressure and total inositol phosphate (IP) accumulation over the same concentration range (10(-6)-10(-4) M). The amplitude of the pressor responses to NA were about 80% of those obtained to nerve stimulation (0.5 ms, 1-16HZ 20s supramaximal voltage). 4. alpha, beta,-methylene ATP (10(-7)-10(-5) M) evoked a concentration-dependent increase in perfusion pressure which, at maximum, was equivalent in amplitude to approximately 20% of that obtained to nerve stimulation. Concentrations of the nucleotide greater than 10(-5) M were required to stimulate total IP accumulation. 5. The effects of NA (10(-6) M) and alpha, beta, MeATP (10(-5) M) upon contraction of artery rings and IP accumulation were additive and no evidence of synergism between them, on either parameter, was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors Affecting the in Vitro Dissolution of Cobalt Oxide

In a recent interspecies comparison of the lung clearance of cobalt oxide (57Co3O4), differences of up to 4-fold were found in the translocation rates of 57Co to blood between seven different animal species, including man. This study investigated some factors that could influence the dissolution of this material in vitro. The effect of bicarbonate and citrate concentrations (over physiological ranges) and medium pH on in vitro dissolution of 57Co from 57Co3O4 particles was measured in a simple noncellular system. pH levels of 4.5, 6.1, and 7.2 were used to correspond to those in the alveolar macrophage lysosome, its cytoplasm, and the extracellular lung fluid. Measurements of the fractional dissolution rate were made weekly for 3 months. pH had the greatest effect on dissolution rates, with particles suspended in the lowest pH medium (4.5) dissolving at a significantly faster rate than at higher pH values. Increasing citrate concentrations resulted in slightly higher dissolution rates, but there was no effect of bicarbonate concentration. There was no evidence of synergism between the factors studied.

Factors affecting the in vitro dissolution of cobalt oxide.

In a recent interspecies comparison of the lung clearance of cobalt oxide (57Co3O4), differences of up to 4-fold were found in the translocation rates of 57Co to blood between seven different animal species, including man. This study investigated some factors that could influence the dissolution of this material in vitro. The effect of bicarbonate and citrate concentrations (over physiological ranges) and medium pH on in vitro dissolution of 57Co from 57Co3O4 particles was measured in a simple noncellular system. pH levels of 4.5, 6.1, and 7.2 were used to correspond to those in the alveolar macrophage lysosome, its cytoplasm, and the extracellular lung fluid. Measurements of the fractional dissolution rate were made weekly for 3 months. pH had the greatest effect on dissolution rates, with particles suspended in the lowest pH medium (4.5) dissolving at a significantly faster rate than at higher pH values. Increasing citrate concentrations resulted in slightly higher dissolution rates, but there was no effect of bicarbonate concentration. There was no evidence of synergism between the factors studied.

Inhibition of hemin-induced hemolysis by desferrioxamine: binding of hemin to red cell membranes and the effects of alteration of membrane sulfhydryl groups

Hemin binds to red cell membranes during hemin-induced hemolysis but the precise mechanism of hemolysis has not been characterized. Desferrioxamine (DFO), an iron chelator, inhibited hemin-induced hemolysis. DFO partially prevented hemin binding to red cell membranes and partialy removed previously bound hemin. Glutathione, an intracellular sulfhydryl compound, also inhibited hemin-induced hemolysis but was only about one tenth as potent as DFO. Decrease of membrane sulfhydryl groups by treatment of cells with either N-ethylmaleimide (NEM) or diamide (azodicar☐ylic acid bis[dimethylamide]) enhanced hemin-induced hemolysis. Enhancement of hemin-induced hemolysis by NEM and diamide and inhibition of hemolysis by DFO were independent with no evidence of synergism or interference between the two processes. Red cell membranes were saturated with hemin at approximately 75 nmol per mg protein. DFO decreased the hemin saturation level to 25 nmol per mg protein. In the presence of DFO, hemin was bound as the DFO-hemin complex since membranes preferentially removed DFO-hemin complexes from mixtures of complexed and free hemin while free DFO was not bound by the membranes. Access to the inner surface of the membrane was required of binding of the DFO-hemin complex since DFO completely prevented hemin binding in intact cells but not in cells undergoing hemolysis or red cell ghosts. Approximately 50 · 106 molecules of hemin were bound to the membrane of one red cell following hemin-induced hemolysis.

Recombinant Human Interferon-γ Modulates Rift Valley Fever Virus Infection in the Rhesus Monkey

Prophylactic treatment of rhesus macaques with 10(4)-10(6) U/kg of recombinant human interferon-gamma (rHuIFN-gamma) modulated Rift Valley fever (RVF) virus infection. IFN was given intramuscularly at 24 h prior to infection and daily thereafter for a total of five doses. After infection, treated monkeys showed no evidence of clinical disease; some had no detectable viremia; when viremia was observed, peak virus titers were decreased compared to control infected monkeys; and only minor and transient perturbations in hematologic and clinical chemistry values were seen. Untreated infected control monkeys developed high-titered viremia, mild to severe clinical disease, and moderate to severe changes in hemostatic parameters and clinical laboratory measurements. No evidence of synergism was noted when RVF virus-infected monkeys were treated prophylactically with combined low doses of rHuIFN-gamma and rHuIFN-alpha A.

Effects of transforming growth factor-α on parathyroid hormone- and parathyroid hormone-related protein- mediated bone resorption and adenylate cyclase stimulation in vitro

The effects of transforming growth factor-α (TGFα) were determined on the ability of parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP) to stimulate bone resorption and adenylate cyclase in vitro. Bovine PTH-(1–34) and human PTHrP-(1–34) were equipotent in their ability to stimulate bone resorption in neonatal mouse calvaria with maximal stimulation (2.9 and 2.8-fold increases in 45Ca release, respectively) at a concentration of 10 nM. Combinations of TGFα with bPTH-(1–34) or hPTHrP-(1–34) had additive effects on their ability to stimulate bone resorption when submaximal concentrations of the agonists were used. There was no evidence of synergism between TGFα and bPTH-(1–34) or hPTHrP-(1–34) in their ability to stimulate bone resorption in vitro, nor was TGFα able to increase bone resorption induced by maximal concentrations of bPTH-(1–34) or hPTHrP-(1–34). TGFα potentiated the effects of either bPTH-(1–34) or hPTHrP-(1–34) on the stimulation of adenylate cyclase in osteoblast-like ROS 17 2.8 cells. These data indicate that TGFα has additive effects with submaximal concentrations of PTH or PTHrP on their ability to stimulate bone resorption which may be important in the pathogenesis of humoral hypercalcemia of malignancy.

Trolox and ascorbate: are they synergistic in protecting liver cells in vitro and in vivo?

From in vitro studies involving multilamellar liposomes or other artificial systems, several groups of workers have deduced that Trolox (a water-soluble analogue of vitamin E) and ascorbate are synergistic antioxidants. Here, we demonstrate that while Trolox and ascorbate individually protect cultured hepatocytes against oxyradicals generated either with xanthine oxidase plus hypoxanthine or with hydrogen peroxide, the two antioxidants do not appear to be synergistic when used in equimolar combinations. Also, in a rat model of hepatic ischemia-reperfusion, we observed that infusion of Trolox or ascorbate (7.5-10 mumol/kg body weight) into the postischemic liver reduced the reperfusion injury by 76 or 67%, respectively. However, when both compounds were used together (each at the same dose as used separately), the organ salvage amounted to only 79%. Therefore, there is no evidence of synergism between Trolox and ascorbate in our in vitro and especially in vivo systems.

Nitrous Oxide Effects on Isolated Myocardium

This study examined in vitro myocardial depression by 50% N2O. Maximal isometric contractions of guinea pig right ventricular papillary muscles were studied in Tyrode's superfusate at 37 degrees C within a gas-tight chamber. Superfusate (pH at 7.45) and chamber were equilibrated with 95% O2/5% CO2. After control measurements in 95% O2, muscles were studied with 50% N2 and 50% N2O (45% O2/5% CO2) in random order with an intervening and final recovery in oxygen. Muscles were field stimulated after rest and at 0.1-3 Hz. At 37 degrees C, muscle performance deteriorated over time with exposure to reduced oxygen; therefore, identical experiments were performed at 30 degrees C in which no systematic deterioration occurred. Peak tension and maximum rate of tension development (dT/dtmax) were compared for each stimulation rate. At both temperatures, N2O caused a 10-15% depression of contractility as compared to that observed with nitrogen. In a second protocol, muscles were studied at 37 degrees C in 26 mM K+ Tyrode's solution with 0.10 microM isoproterenol to study enhanced contractions mediated by slow (Ca2(+)-channel-dependent) action potentials. Rested-state double stimulations were used (stimulus interval, 250-600 ms) resulting in a first rested-state contraction followed by a second contraction (C2) with rapid initial tension development. The muscles were exposed to nitrogen and N2O as in the force-frequency experiments and did not deteriorate over time. In this setting, N2O also caused a 10-15% depression of C2 contractility as compared with nitrogen. Another set of muscles was studied in 95% O2 to which 0.5% halothane or 1% isoflurane was added before exposure to nitrogen and N2O. The combined depressant action of N2O with either halothane or isoflurane did not differ from that predicted by the simple addition of independent effects; there was no evidence of synergism. Furthermore, N2O (50%) alone depressed dT/dtmax in a manner similar to that of 0.5% halothane and different from that of 1.0% isoflurane. Experiments conducted in iso-osmolar 40 mM Na+ Tyrode's solution, in which activator Ca2+ arose from the sarcoplasmic reticulum Ca2+, also showed greater depression by N2O than nitrogen. N2O (50%) is a myocardial depressant independent of concurrent hypoxic effects with a pattern and magnitude of contractile depression similar to that of 0.5% halothane.

Relation of arsenic exposure to lung cancer among tin miners in Yunnan Province, China.

The relation of mining and smelting exposure to arsenic and lung cancer was studied among tin miners in Yunnan Province in the People's Republic of China. Interviews were conducted in 1985 with 107 living tin miners who had lung cancer and an equal number of age matched controls from among tin miners without lung cancer to obtain information on risk factors for lung cancer including detailed history of employment and tobacco use. Occupational history was combined with industrial hygiene data to estimate cumulative arsenic exposure. Similar methods were also used to estimate radon exposure for simultaneous evaluation in this analysis. The results indicate that subjects in the highest quarter of cumulative arsenic exposure have a relative risk of 22.6 compared with subjects without exposure after adjusting for tobacco and radon exposure, and a positive dose response relation was observed. Simultaneous evaluation of arsenic and tobacco exposure indicates a greater risk for arsenic, whereas simultaneous assessment of arsenic and radon exposure suggests radon to be the greater risk. There is no evidence of synergism between arsenic and tobacco exposure. Among arsenic exposed individuals, cases of lung cancer have longer duration but lower average intensity of arsenic exposure than controls, indicating that duration of exposure to arsenic may be more important than intensity in the aetiology of lung cancer. Finally, risk of lung cancer among workers exposed to arsenic only in mining is only slightly less than for miners whose exposure to arsenic was limited to smelting, although risks are highest when workers were exposed to both mining and smelting.

Combined effect of exercise and ambient temperature on insulin absorption and postprandial glycemia in type I patients.

We studied the combined effect of cool (10 degrees C) and warm (30 degrees C) ambient temperatures and physical exercise on insulin absorption and postprandial glycemia. Nine type I (insulin-dependent) diabetic patients were injected subcutaneously with their usual morning dose of short- and intermediate-acting human insulin and were given breakfast. Warm temperature was associated with 3- to 5-fold higher insulin absorption (P less than .01) and significantly lower blood glucose concentration (P less than .001) than cool temperature regardless of exercise. Exercise was associated with 28% (P less than .01) and 22% (P less than .05) increases in plasma insulin and maximally 5.7 mM (P less than .025) and 7.1 mM (P less than .01) lower blood glucose at cool and warm temperatures, respectively. Warm temperature and exercise had an additive effect in stimulating insulin absorption and in lowering blood glucose concentrations. However, there was no evidence of synergism between higher temperature and exercise in increasing free-insulin concentrations or decreasing blood glucose concentrations. To avoid postprandial hyperglycemia at cool temperature or hypoglycemia after exercise at warm temperature, appropriate adjustments in diet and insulin dose, or both, should be made.