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Sample records for acute tolerance development

  1. Modification of the development of acute opiate tolerance by increased dopamine receptor sensitivity.

    PubMed

    Martin, J R; Takemori, A E

    1987-04-01

    Earlier studies have suggested that the acute administration of an opiate can result in the development of supersensitive dopamine receptors. The present study was undertaken to determine whether the supersensitive dopamine receptors can modify the development of opiate tolerance and dependence. Administration of morphine (100 mg/kg s.c.) 6 or 24 hr before apomorphine (i.p.) potentiated apomorphine-induced climbing behavior in mice. Administration of levorphanol (12 mg/kg s.c.) 3 or 6 hr, but not 24 hr, before apomorphine also potentiated apomorphine-induced climbing behavior. Coadministration of 5 mEq/kg of LiCl with morphine or levorphanol attenuated the increased sensitivity developed to apomorphine after either opiate. Acute tolerance and dependence was induced by administration of 100 mg/kg of morphine or 12 mg/kg of levorphanol. Lithium enhanced the development of acute tolerance when coadministered with morphine 3, 6 or 24 hr before test doses of morphine, or with levorphanol 3 hr before test doses of levorphanol. Administration of apomorphine 5 min before naloxone significantly decreased the naloxone ED50 for inducing withdrawal jumping in mice that had been pretreated with morphine or levorphanol. Although coadministration of lithium with morphine or levorphanol had no significant effect on naloxone-induced withdrawal jumping, it attenuated the ability of apomorphine to decrease naloxone ED50. Morphine (100 mg/kg s.c.) increased the number of whole brain [3H]spiroperidol binding sites 3 and 6 hr after administration of morphine. This increase was no longer present 24 hr after morphine administration. Levorphanol (12 mg/kg s.c.) also increased the number of binding sites 3 hr after administration. Coadministration of lithium with morphine attenuated the increase in [3H]spiroperidol binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Sir2/Sirt1 Links Acute Inebriation to Presynaptic Changes and the Development of Alcohol Tolerance, Preference, and Reward

    PubMed Central

    Engel, Gregory L.; Marella, Sunanda; Kaun, Karla R.; Wu, Julia; Adhikari, Pratik; Kong, Eric C.

    2016-01-01

    Acute ethanol inebriation causes neuroadaptive changes in behavior that favor increased intake. Ethanol-induced alterations in gene expression, through epigenetic and other means, are likely to change cellular and neural circuit function. Ethanol markedly changes histone acetylation, and the sirtuin Sir2/SIRT1 that deacetylates histones and transcription factors is essential for the rewarding effects of long-term drug use. The molecular transformations leading from short-term to long-term ethanol responses mostly remain to be discovered. We find that Sir2 in the mushroom bodies of the fruit fly Drosophila promotes short-term ethanol-induced behavioral plasticity by allowing changes in the expression of presynaptic molecules. Acute inebriation strongly reduces Sir2 levels and increases histone H3 acetylation in the brain. Flies lacking Sir2 globally, in the adult nervous system, or specifically in the mushroom body α/β-lobes show reduced ethanol sensitivity and tolerance. Sir2-dependent ethanol reward is also localized to the mushroom bodies, and Sir2 mutants prefer ethanol even without a priming ethanol pre-exposure. Transcriptomic analysis reveals that specific presynaptic molecules, including the synaptic vesicle pool regulator Synapsin, depend on Sir2 to be regulated by ethanol. Synapsin is required for ethanol sensitivity and tolerance. We propose that the regulation of Sir2/SIRT1 by acute inebriation forms part of a transcriptional program in mushroom body neurons to alter presynaptic properties and neural responses to favor the development of ethanol tolerance, preference, and reward. SIGNIFICANCE STATEMENT We identify a mechanism by which acute ethanol inebriation leads to changes in nervous system function that may be an important basis for increasing ethanol intake and addiction liability. The findings are significant because they identify ethanol-driven transcriptional events that target presynaptic properties and direct behavioral plasticity. They also

  3. Correlation between the dose and development of acute tolerance to the hypothermic effect of THC.

    PubMed

    Uran, B; Tulunay, F C; Ayhan, I H; Ulkü, E; Kaymakçalan, S

    1980-01-01

    The administration of 0.3-40 mg/kg delta 9-tetrahydrocannabinol (THC) produced a dose-dependent hypothermia in rats. The maximal hypothermic effect was obtained with the dose of 2.5 mg/kg of THC. When the same doses of THC were repeated on days 2 and 3, tolerance to the hypothermic effect of THC was apparent. Doses of THC higher than 2.5 mg/kg induced a significant and dose-dependent tolerance after the first administration whereas with the lower doses, tolerance was only apparent after the second injection. The possible mechanism of these effects of THC is discussed.

  4. Acute Tolerance to Alcohol in At-risk Binge Drinkers

    PubMed Central

    Fillmore, Mark T.; Weafer, Jessica

    2012-01-01

    Studies of the impairing effects of alcohol on behavior often show greater tolerance in heavy drinkers compared to light drinkers, suggesting a causal link between heavy consumption and tolerance. Tolerance also develops during the time-course of a single drinking episode, and this “acute tolerance” might play an important role in the escalation to heavy drinking. The present study examined the development of acute tolerance to the impairing effects of alcohol on motor coordination and inhibitory control in a group of at-risk, binge drinkers (N = 20) and a group of non-risk, moderate drinkers (N = 20). Participants performed the testing battery in response to placebo and a moderate dose of alcohol (0.65 g/kg) twice at comparable blood alcohol concentrations (BACs): once on the ascending limb and once on the descending limb of the blood alcohol curve. Results showed marked acute tolerance to the impairing effects of alcohol on motor coordination in the at-risk drinkers. By contrast, no recovery of motor skill was observed in the non-risk drinkers. Regarding inhibitory control, both groups remained impaired on both the ascending and descending limbs, indicating no acute tolerance in either group. The findings suggest that at-risk, binge drinkers display a faster recovery in their ability to execute versus inhibit action under alcohol. Such an “activational bias” of behavior could account for their continued alcohol consumption and impulsive behaviors while intoxicated, especially as BAC begins to decline. PMID:22023021

  5. Development of tolerance to the inhibitory effects of ethanol in the rat isolated vas deferens: effect of acute and chronic ethanol administration in vivo.

    PubMed Central

    DeTurck, K. H.; Pohorecky, L. A.

    1986-01-01

    Contractions of the rat vas deferens elicited by the addition of noradrenaline (NA), K+-depolarizing solutions or by electrical stimulation were recorded before and after incubation with ethanol 181 mM. In tissues from untreated rats, the contractions were inhibited 40-50% by such exposure. Injection of ethanol (2 g kg-1) significantly attenuated ethanol's reduction of peak tension generated by the lowest concentration of NA (10(-4) mM). Chronic administration of ethanol, 18-14 g kg-1 daily for two weeks, resulted in significant tolerance to ethanol. Tissues of treated animals demonstrated ethanol-induced decreases of roughly one-half those of the maltose dextrin (isocaloric) and water (fluid control) groups. This tolerance persisted for at least 48 h after ethanol treatment had been terminated. Overall, the data suggest that ethanol acts both pre- and postsynaptically to produce acute inhibition of smooth muscle contractions or tolerance to these actions upon chronic exposure. PMID:3730699

  6. Physiological Determinants of Human Acute Hypoxia Tolerance

    DTIC Science & Technology

    2013-11-01

    variables. We chose variables that have been historically associated with both anaerobic and aerobic metabolism, as well as with responses to acute onset...carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique–1995 update. Am J Respir Crit Care Med 152: 2185–2198... Respiration . New Haven, CT: Yale University Press, 1922. Hart MC, Orzalesi MM, Cook CD. Relation between anatomic respiratory dead space and body size and

  7. Acute alcohol tolerance on subjective intoxication and simulated driving performance in binge drinkers.

    PubMed

    Marczinski, Cecile A; Fillmore, Mark T

    2009-06-01

    High rates of binge drinking and alcohol-related problems, including drinking and driving, occur among college students. Underlying reasons for the heightened impaired driving rates in this demographic group are not known. The authors hypothesized that acute tolerance to the interoceptive cues of intoxication may contribute to these maladaptive decisions to drive in binge drinkers. Groups of binge-drinking and non-binge-drinking college students (N = 28) attended sessions during which they received a moderate dose of alcohol (0.65 g/kg) or a placebo. The development of acute tolerance to subjective ratings of intoxication and simulated driving performance was assessed by comparing measures taken during the ascending phase and descending phases of the blood alcohol curve. Compared with placebo, alcohol increased ratings of intoxication and impaired multiple aspects of simulated driving performance in both binge and non-binge drinkers. During the descending phase of the blood alcohol curve, binge drinkers showed acute tolerance to alcohol's effect on subjective intoxication, and this effect was accompanied by an increased rating of willingness to drive. By contrast, non-binge drinkers showed no acute tolerance.

  8. Intrathecal PLC(β3) oligodeoxynucleotides antisense potentiates acute morphine efficacy and attenuates chronic morphine tolerance.

    PubMed

    Quanhong, Zhou; Ying, Xue; Moxi, Chen; Tao, Xu; Jing, Wang; Xin, Zhang; Li, Wang; Derong, Cui; Xiaoli, Zhang; Wei, Jiang

    2012-09-07

    Morphine is a mainstay for chronic pain treatment, but its efficacy has been hampered by physical tolerance. The underlying mechanism for chronic morphine induced tolerance is complicated and not well understood. PLC(β3) is regarded as an important factor in the morphine tolerance signal pathway. In this study, we determined intrathecal (i.t.) administration of an antisense oligodeoxynucleotide (ODN) of PLC(β3) could quicken the on-set antinociceptive efficacy of acute morphine treatment and prolong the maximum effect up to 4h. The antisense could also attenuate the development of morphine-induced tolerance and left shift the ED50 after 7 day of coadministration with morphine. These results probably were contributed by the PLC(β3) antisense ODN as they successfully knocked down protein expression levels and reduced activity of PLC(β3) in spinal cord in rats. The mismatch group had no such effects. The results confirmed the important involvement of PLC(β3) in both acute morphine efficacy and chronic morphine tolerance at spinal level in rats. This study may provide an idea for producing a novel adjuvant for morphine treatment.

  9. Developing Political Tolerance. ERIC Digest.

    ERIC Educational Resources Information Center

    Avery, Patricia G.

    Political tolerance is the willingness to extend basic rights and civil liberties to persons and groups whose viewpoints differ from one's own. It is a central tenet of a liberal democracy. The individual rights and freedoms that U.S. citizens value encourage a wide array of ideas and beliefs, some of which may offend segments of the population.…

  10. Markers of tolerance development to food allergens.

    PubMed

    Ponce, M; Diesner, S C; Szépfalusi, Z; Eiwegger, T

    2016-10-01

    IgE-mediated reactions to food allergens are the most common cause of anaphylaxis in childhood. Although allergies to cow's milk, egg, or soy proteins, in contrast to peanut and tree nut allergens, resolve within the first 6 years of life in up to 60% due to natural tolerance development, this process is not well understood. At present, there is no cure or treatment for food allergy that would result in an induction of tolerance to the symptom-eliciting food. Avoidance, providing an emergency plan and education, is the standard of treatment. Oral immunotherapeutic approaches have been proven reasonable efficacy; however, they are associated with high rates of side-effects and low numbers of patients achieving tolerance. Nevertheless, mechanisms that take place during oral immunotherapy may help to understand tolerance development. On the basis of these therapeutic interventions, events like loss of basophil activation and induction of regulatory lymphocyte subsets and of blocking antibodies have been described. Their functional importance at a clinical level, however, remains to be investigated in detail. Consequently, there is eminent need to understand the process of tolerance development to food allergens and define biomarkers to develop and monitor new treatment strategies for food allergy.

  11. Enhanced Accident Tolerant LWR Fuels: Metrics Development

    SciTech Connect

    Shannon Bragg-Sitton; Lori Braase; Rose Montgomery; Chris Stanek; Robert Montgomery; Lance Snead; Larry Ott; Mike Billone

    2013-09-01

    The Department of Energy (DOE) Fuel Cycle Research and Development (FCRD) Advanced Fuels Campaign (AFC) is conducting research and development on enhanced Accident Tolerant Fuels (ATF) for light water reactors (LWRs). This mission emphasizes the development of novel fuel and cladding concepts to replace the current zirconium alloy-uranium dioxide (UO2) fuel system. The overall mission of the ATF research is to develop advanced fuels/cladding with improved performance, reliability and safety characteristics during normal operations and accident conditions, while minimizing waste generation. The initial effort will focus on implementation in operating reactors or reactors with design certifications. To initiate the development of quantitative metrics for ATR, a LWR Enhanced Accident Tolerant Fuels Metrics Development Workshop was held in October 2012 in Germantown, MD. This paper summarizes the outcome of that workshop and the current status of metrics development for LWR ATF.

  12. Influence of the ambient acceleration field upon acute acceleration tolerance in chickens

    NASA Technical Reports Server (NTRS)

    Smith, A. H.; Spangler, W. L.; Rhode, E. A.; Burton, R. R.

    1979-01-01

    The paper measured the acceleration tolerance of domestic fowl (Rhode Island Red cocks), acutely exposed to a 6 Gz field, as the time over which a normal heart rate can be maintained. This period of circulatory adjustment ends abruptly with pronounced bradycardia. For chickens which previously have been physiologically adapted to 2.5 -G field, the acute acceleration tolerance is greatly increased. The influence of the ambient acceleration field on the adjustment of the circulatory system appears to be a general phenomenon.

  13. Ontogenetic studies of tolerance development: effects of chronic morphine on the hypothalamic-pituitary-adrenal axis.

    PubMed

    Little, P J; Kuhn, C M

    1995-11-01

    Endogenous opiates are important regulators of the hypothalamic-pituitary-adrenal (HPA) axis in rats. Tolerance clearly develops to morphine-induced stimulation of the HPA axis in adult rats (Ignar and Kuhn 1990). The goal of the present study was to determine whether tolerance to morphine-induced stimulation of the HPA axis developed in neonatal and weanling rats treated chronically with morphine. Rats were injected with morphine or saline between days 4-8 postnatal (pups) or days 21-25 (weanlings) and tolerance assessed by determining dose-response curves for ACTH and corticosterone secretion following an acute morphine challenge. Weanlings displayed marked tolerance to the stimulation of ACTH and corticosterone secretion by morphine. Tolerance was also observed in pups to morphine-stimulated ACTH and corticosterone release. These findings suggest that the relative adaptability of the HPA axis to chronic morphine in neonatal and weanling rats is similar.

  14. Acute and Chronic Kudzu Improves Plasma Glucose Tolerance in Non-Diabetic CD-1 Mice.

    PubMed

    Carlson, Scott; Prasain, Jeevan K; Peng, Ning; Dai, Yanying; Wyss, J Michael

    2014-01-01

    Previous studies demonstrate that kudzu root extract and its major isoflavone (puerarin) improve glucose metabolism in animal models of insulin resistance and type 2 diabetes; however, these beneficial effects have not been investigated in normal glycemic mice. The present study investigates the effect of acute and chronic kudzu root extract supplementation on glucose tolerance in normoglycemic CD-1 mice. Male, adult CD-1 mice were fed a phytoestrogen-free diet containing 0.2% or 0.0% kudzu root extract for 6 weeks. Thereafter, they were acutely administered kudzu root extract (75 mg/kg BW; oral) or vehicle followed by a glucose challenge (2 g/kg BW; oral). In control fed mice, the acute glucose challenge increased blood glucose ~300% after 30 minutes, and acute kudzu root extract administration significantly blunted this response by ~50%. In mice chronically fed a kudzu-supplemented diet, glucose tolerance was improved, and acute treatment caused no additional improvement. Irrespective of treatment, all mice were normoglycemic at the start of each glucose challenge. Administration of insulin resulted in a larger decrease in blood glucose in chronic kudzu-supplemented compared to control mice. Co-administration of phloridzin (a specific inhibitor of SGLT-mediated glucose uptake), improved glucose tolerance in acutely kudzu-treated mice but had no significant effect on glucose tolerance in chronically treated mice. These results indicate that both acute and chronic administration of kudzu root extract improves glucose tolerance in a normal glycemic mouse strain and that the effects of chronic kudzu feeding may be mediated, in part, by enhanced insulin sensitivity (chronic) and inhibition of sodium dependent glucose transport.

  15. Acute and Chronic Kudzu Improves Plasma Glucose Tolerance in Non-Diabetic CD-1 Mice

    PubMed Central

    Carlson, Scott; Prasain, Jeevan K.; Peng, Ning; Dai, Yanying; Wyss, J. Michael

    2016-01-01

    Previous studies demonstrate that kudzu root extract and its major isoflavone (puerarin) improve glucose metabolism in animal models of insulin resistance and type 2 diabetes; however, these beneficial effects have not been investigated in normal glycemic mice. The present study investigates the effect of acute and chronic kudzu root extract supplementation on glucose tolerance in normoglycemic CD-1 mice. Male, adult CD-1 mice were fed a phytoestrogen-free diet containing 0.2% or 0.0% kudzu root extract for 6 weeks. Thereafter, they were acutely administered kudzu root extract (75 mg/kg BW; oral) or vehicle followed by a glucose challenge (2 g/kg BW; oral). In control fed mice, the acute glucose challenge increased blood glucose ~300% after 30 minutes, and acute kudzu root extract administration significantly blunted this response by ~50%. In mice chronically fed a kudzu-supplemented diet, glucose tolerance was improved, and acute treatment caused no additional improvement. Irrespective of treatment, all mice were normoglycemic at the start of each glucose challenge. Administration of insulin resulted in a larger decrease in blood glucose in chronic kudzu-supplemented compared to control mice. Co-administration of phloridzin (a specific inhibitor of SGLT-mediated glucose uptake), improved glucose tolerance in acutely kudzu-treated mice but had no significant effect on glucose tolerance in chronically treated mice. These results indicate that both acute and chronic administration of kudzu root extract improves glucose tolerance in a normal glycemic mouse strain and that the effects of chronic kudzu feeding may be mediated, in part, by enhanced insulin sensitivity (chronic) and inhibition of sodium dependent glucose transport.

  16. Abundance of Plasma Antioxidant Proteins Confers Tolerance to Acute Hypobaric Hypoxia Exposure

    PubMed Central

    Padhy, Gayatri; Sethy, Niroj Kumar; Ganju, Lilly

    2013-01-01

    Abstract Padhy, Gayatri, Niroj Kumar Sethy, Lilly Ganju, and Kalpana Bhargava. Abundance of plasma antioxidant proteins confers tolerance to acute hypobaric hypoxia exposure. High Alt Med Biol 14:289–297, 2013—Systematic identification of molecular signatures for hypobaric hypoxia can aid in better understanding of human adaptation to high altitude. In an attempt to identify proteins promoting hypoxia tolerance during acute exposure to high altitude, we screened and identified hypoxia tolerant and susceptible rats based on hyperventilation time to a simulated altitude of 32,000 ft (9754 m). The hypoxia tolerance was further validated by estimating 8-isoprotane levels and protein carbonyls, which revealed that hypoxia tolerant rats possessed significant lower plasma levels as compared to susceptible rats. We used a comparative plasma proteome profiling approach using 2-dimensional gel electrophoresis (2-DGE) combined with MALDI TOF/TOF for both groups, along with an hypoxic control group. This resulted in the identification of 19 differentially expressed proteins. Seven proteins (TTR, GPx-3, PON1, Rab-3D, CLC11, CRP, and Hp) were upregulated in hypoxia tolerant rats, while apolipoprotein A-I (APOA1) was upregulated in hypoxia susceptible rats. We further confirmed the consistent higher expression levels of three antioxidant proteins (PON1, TTR, and GPx-3) in hypoxia-tolerant animals using ELISA and immunoblotting. Collectively, these proteomics-based results highlight the role of antioxidant enzymes in conferring hypoxia tolerance during acute hypobaric hypoxia. The expression of these antioxidant enzymes could be used as putative biomarkers for screening altitude adaptation as well as aiding in better management of altered oxygen pathophysiologies. PMID:24067188

  17. Improved tolerance of acute severe hypoxic stress in chronic hypoxic diaphragm is nitric oxide-dependent.

    PubMed

    Lewis, Philip; McMorrow, Clodagh; Bradford, Aidan; O'Halloran, Ken D

    2015-09-01

    The effects of chronic hypoxia (CH) on respiratory muscle performance have hardly been investigated, despite clinical relevance. Results from recent studies are indicative of unique adaptive strategies in hypoxic diaphragm. Respiratory muscle tolerance of acute severe hypoxic stress was examined in normoxic and CH diaphragm in the presence and absence of a nitric oxide (NO) synthase inhibitor. We tested the hypothesis that improved tolerance of severe hypoxic stress in CH diaphragm is NO-dependent. Wistar rats were exposed to normoxia (sea-level, n = 6) or CH (ambient pressure = 380 mmHg, n = 6) for 6 weeks. Diaphragm muscle functional properties were determined ex vivo under severe hypoxic conditions (gassed with 95%N2/5% CO2) with and without 1 mM L-N(G)-nitroarginine (L-NNA, nNOS inhibitor). Fatigue tolerance, but not force, was significantly improved in CH diaphragm (p = 0.008). CH exposure did not affect diaphragm muscle fibre oxidative capacity determined from cluster analysis of area-density plots of muscle fibre succinate dehydrogenase activity. Acute NOS inhibition reduced diaphragm peak tetanic force (p = 0.018), irrespective of gas treatment, and completely reversed improved fatigue tolerance of the CH diaphragm. We conclude that CH exposure improves fatigue tolerance during acute severe hypoxic stress in an NO-dependent manner, independent of muscle fibre oxidative capacity.

  18. Identification of genes associated with heat tolerance in Arctic charr exposed to acute thermal stress.

    PubMed

    Quinn, Nicole L; McGowan, Colin R; Cooper, Glenn A; Koop, Ben F; Davidson, William S

    2011-06-15

    Arctic charr is an especially attractive aquaculture species given that it features the desirable tissue traits of other salmonids and is bred and grown at inland freshwater tank farms year round. It is of interest to develop upper temperature tolerant (UTT) strains of Arctic charr to increase the robustness of the species in the face of climate change and to enable production in more southern regions. We used a genomics approach that takes advantage of the well-studied Atlantic salmon genome to identify genes that are associated with UTT in Arctic charr. Specifically, we conducted an acute temperature trial to identify temperature tolerant and intolerant Arctic charr individuals, which were subject to microarray and qPCR analysis to identify candidate UTT genes. These were compared with genes annotated in a quantitative trait locus (QTL) region that was previously identified as associated with UTT in rainbow trout and Arctic charr and that we sequenced in Atlantic salmon. Our results suggest that small heat shock proteins as well as HSP-90 genes are associated with UTT. Furthermore, hemoglobin expression was significantly downregulated in tolerant compared with intolerant fish. Finally, QTL analysis and expression profiling identified COUP-TFII as a candidate UTT gene, although its specific role is unclear given the identification of two transcripts, which appear to have different expression patterns. Our results highlight the importance of using more than one approach to identify candidate genes, particularly when examining a complicated trait such as UTT in a highly complex genome for which there is no reference genome.

  19. DEVELOPMENT OF CRYSTAL-TOLERANT WASTE GLASSES

    SciTech Connect

    Matyas, Josef; Vienna, John D.; Kimura, Akihiko; Schaible, Micah J.; Tate, Rachel M.

    2010-10-26

    The loading of high-level waste in borosilicate glasses is limited by crystallinity constraints that cannot prevent crystal accumulation on the melter bottom and in the glass discharge riser of the melter. Pacific Northwest National Laboratory is studying variations in composition that are designed to constrain high-level waste glass compositions and develop the crystal-tolerant high-level waste glasses. These glasses will allow high waste loading without decreasing the lifetime of the melter by keeping the small spinel crystals suspended in the molten glass. Adding ~1 wt% of NiO to the baseline glass caused large spinel crystals to form up to 210 µm in size and resulted in the highest accumulation rate, ~ 227 mm/year, of all tested glasses. Noble metals that were added to high-Ni glass prevented large spinel crystals from forming and decreased the accumulation rate ~ 8.5 times. Adding ~5 wt% of Fe2O3 to the baseline glass resulted in a high number density of ~10-μm spinel crystals that remained suspended in the glass melt even after 17 days at 850°C. The accumulation rate of spinel crystals in high-chromia crucibles was only slightly higher compared with the accumulation rate in double crucibles. Only baseline glass exhibited about 2.6 times faster accumulation rate because of increased number of bigger crystals. These crystals were the result of glass enrichment with chromium that was leached out from the walls of high-chromia crucibles.

  20. Acute effects of nicorandil on glucose tolerance in subjects with borderline fasting blood glucose levels.

    PubMed

    Boes, U; Wallner, S; Wascher, T C

    2001-02-15

    The acute effect of the anti-ischemic potassium channel opener nicorandil on glucose tolerance and post-challenge insulin levels was investigated in 11 subjects (6 males and 5 females, age 59 +/- 2 years) with borderline fasting blood glucose in a single blinded randomised study. All participants were submitted to two oral glucose tolerance tests in randomised order, once without any premedication and once 30 minutes after oral administration of 20 mg nicorandil. This single dose of nicorandil significantly increased blood glucose levels at 120 minutes (173 +/- 16 vs. 150 +/- 11 mg/dl, p < 0.05 by ANOVA) and 180 minutes (106 +/- 11 vs. 88 +/- 7 mg/dl, p < 0.05 by ANOVA) after ingestion of 75 mg of glucose. Serum insulin levels were not significantly altered. In conclusion we suggest that controlled studies in patients with coronary artery disease should be performed to investigate whether long term treatment with nicorandil increases progression rates from impaired glucose tolerance to type-II diabetes and/or from normal to impaired glucose tolerance with a possibly negative impact on the course of cardiovascular disease in comparison to conventional anti-anginal drugs.

  1. Exogenous IL-33 overcomes T cell tolerance in murine acute myeloid leukemia

    PubMed Central

    Qin, Lei; Dominguez, Donye; Chen, Siqi; Fan, Jie; Long, Alan; Zhang, Minghui; Fang, Deyu; Zhang, Yi; Kuzel, Timothy M.; Zhang, Bin

    2016-01-01

    Emerging studies suggest that dominant peripheral tolerance is a major mechanism of immune escape in disseminated leukemia. Using an established murine acute myeloid leukemia (AML) model, we here show that systemic administration of recombinant IL-33 dramatically inhibits the leukemia growth and prolongs the survival of leukemia-bearing mice in a CD8+ T cell dependent manner. Exogenous IL-33 treatment enhanced anti-leukemia activity by increasing the expansion and IFN-γ production of leukemia-reactive CD8+ T cells. Moreover, IL-33 promoted dendritic cell (DC) maturation and activation in favor of its cross presentation ability to evoke a vigorous anti-leukemia immune response. Finally, we found that the combination of PD-1 blockade with IL-33 further prolonged the survival, with half of the mice achieving complete regression. Our data establish a role of exogenous IL-33 in reversing T cell tolerance, and suggest its potential clinical implication into leukemia immunotherapy. PMID:27517629

  2. Cannabis and tolerance: acute drug impairment as a function of cannabis use history

    PubMed Central

    Ramaekers, J. G.; van Wel, J. H.; Spronk, D. B.; Toennes, S. W.; Kuypers, K. P. C.; Theunissen, E. L.; Verkes, R. J.

    2016-01-01

    Cannabis use history as predictor of neurocognitive response to cannabis intoxication remains subject to scientific and policy debates. The present study assessed the influence of cannabis on neurocognition in cannabis users whose cannabis use history ranged from infrequent to daily use. Drug users (N = 122) received acute doses of cannabis (300 μg/kg THC), cocaine HCl (300 mg) and placebo. Cocaine served as active control for demonstrating neurocognitive test sensitivity. Executive function, impulse control, attention, psychomotor function and subjective intoxication were significantly worse after cannabis administration relative to placebo. Cocaine improved psychomotor function and attention, impaired impulse control and increased feelings of intoxication. Acute effects of cannabis and cocaine on neurocognitive performance were similar across cannabis users irrespective of their cannabis use history. Absence of tolerance implies that that frequent cannabis use and intoxication can be expected to interfere with neurocognitive performance in many daily environments such as school, work or traffic. PMID:27225696

  3. Cannabis and tolerance: acute drug impairment as a function of cannabis use history.

    PubMed

    Ramaekers, J G; van Wel, J H; Spronk, D B; Toennes, S W; Kuypers, K P C; Theunissen, E L; Verkes, R J

    2016-05-26

    Cannabis use history as predictor of neurocognitive response to cannabis intoxication remains subject to scientific and policy debates. The present study assessed the influence of cannabis on neurocognition in cannabis users whose cannabis use history ranged from infrequent to daily use. Drug users (N = 122) received acute doses of cannabis (300 μg/kg THC), cocaine HCl (300 mg) and placebo. Cocaine served as active control for demonstrating neurocognitive test sensitivity. Executive function, impulse control, attention, psychomotor function and subjective intoxication were significantly worse after cannabis administration relative to placebo. Cocaine improved psychomotor function and attention, impaired impulse control and increased feelings of intoxication. Acute effects of cannabis and cocaine on neurocognitive performance were similar across cannabis users irrespective of their cannabis use history. Absence of tolerance implies that that frequent cannabis use and intoxication can be expected to interfere with neurocognitive performance in many daily environments such as school, work or traffic.

  4. Advanced development for space robotics with emphasis on fault tolerance

    NASA Technical Reports Server (NTRS)

    Tesar, D.; Chladek, J.; Hooper, R.; Sreevijayan, D.; Kapoor, C.; Geisinger, J.; Meaney, M.; Browning, G.; Rackers, K.

    1995-01-01

    This paper describes the ongoing work in fault tolerance at the University of Texas at Austin. The paper describes the technical goals the group is striving to achieve and includes a brief description of the individual projects focusing on fault tolerance. The ultimate goal is to develop and test technology applicable to all future missions of NASA (lunar base, Mars exploration, planetary surveillance, space station, etc.).

  5. Effectiveness, tolerability and safety of azithromycin 1% in DuraSite® for acute bacterial conjunctivitis

    PubMed Central

    McLean, Susannah; Sheikh, Aziz

    2010-01-01

    Purpose: Bacterial eye infections are commonly treated with topical antibiotics, despite limited evidence of effectiveness. Azithromycin 1% in DuraSite® is a new formulation of azithromycin in a gel polymer designed for use in acute bacterial conjunctivitis. Methods: We conducted systematic searches of the Cochrane Database of Clinical Trials, PubMed and Google Scholar to find randomized controlled trials of “azithromycin DuraSite®”. These searches of published literature were supplemented with searches for unpublished trials and trials in progress. Results: We found six reports of randomized controlled trials investigating the role of azithromycin 1% in DuraSite® for the management of acute bacterial conjunctivitis. The quality of these trials was judged to be moderate to high. These trials assessed effectiveness, tolerability and safety outcomes, but we found no trials looking at cost-effectiveness. DuraSite® is a relatively stable formulation and so azithromycin 1% in DuraSite® has a simpler dosing schedule than other available topical antibiotics. It appears to be similar to other topical antibiotics in its effectiveness, but minor side effects are quite common. Conclusion: Acute bacterial conjunctivitis is a relatively mild, typically self-limiting, infection. Antibiotics should seldom be required. If, however, a decision to prescribe antibiotics is made, azithromycin 1% in DuraSite® is likely to be broadly comparable in its effectiveness to most other antibiotics used to treat acute bacterial conjunctivitis. Further research is needed to determine its cost-effectiveness. PMID:20517467

  6. Multimodal examination of distress tolerance and posttraumatic stress disorder symptoms in acute-care psychiatric inpatients.

    PubMed

    Vujanovic, Anka A; Dutcher, Christina D; Berenz, Erin C

    2016-09-01

    Distress tolerance (DT), the actual or perceived capacity to withstand negative internal states, has received increasing scholarly attention due to its theoretical and clinical relevance to posttraumatic stress disorder (PTSD). Past studies have indicated that lower self-reported - but not behaviorally observed - DT is associated with greater PTSD symptoms; however, studies in racially and socioeconomically diverse clinical samples are lacking. The current study evaluated associations between multiple measures of DT (self-report and behavioral) and PTSD symptoms in an urban, racially and socioeconomically diverse, acute-care psychiatric inpatient sample. It was hypothesized that lower self-reported DT (Distress Tolerance Scale [DTS]), but not behavioral DT (breath-holding task [BH]; mirror-tracing persistence task [MT]), would be associated with greater PTSD symptoms, above and beyond the variance contributed by trauma load, substance use, gender, race/ethnicity, and subjective social status. Participants were 103 (41.7% women, Mage=33.5) acute-care psychiatric inpatients who endorsed exposure to potentially traumatic events consistent with DSM-5 PTSD Criterion A. Results of hierarchical regression analyses indicated that DTS was negatively associated with PTSD symptom severity (PCL-5 Total) as well as with each of the four DSM-5 PTSD symptom clusters (p's<0.001), contributing between 5.0%-11.1% of unique variance in PTSD symptoms across models. BH duration was positively associated with PTSD arousal symptom severity (p<0.05). Covariates contributed between 21.3%-40.0% of significant variance to the models. Associations between DT and PTSD in this sample of acute-care psychiatric inpatients are largely consistent with those observed in community samples.

  7. [Recent findings on nitrates: their action, bioactivation and development of tolerance].

    PubMed

    Münzel, T

    2008-10-01

    Organic nitrates still are one of the most important drug classes used in the treatment of an acute coronary syndrome and stable coronary artery disease as well as acute and chronic congestive heart failure. The mechanism of vasodilatation comprises the release of nitric oxide, which in turn activates soluble guanylate cyclase and lowers the intracellular calcium content leading to relaxation of vascular smooth muscle. Recent research has demonstrated that highly reactive nitrates, such as nitroglycerin (or glyceryl trinitrate) and pentaerthrityl tetranitrate (PETN) are bioactivated by aldehyde dehydrogenase 2 (ALDH-2), an enzyme located in mitochondria. The enzyme, which bioactivates mono- and dinitrates is not yet identified. Despite being effective in the acute treatment of patients, its long-term efficacy is limited by the development of tolerance to nitrates and of endothelial dysfunction. Both of these side effects of nitrate therapy are due to increased production of reactive oxygen species. This review focuses on new aspects of the process of bioactivation of organic nitrates, the conception of oxidative stress of endothelial dysfunction and of the development of tolerance and their therapeutic consequences. Also discussed are more recent findings on nitric oxide donors such as molsidomine, PETN and the combination treatment of isosorbide dinitrate and hydralazine of patients with coronary artery disease and chronic heart failure.

  8. Acute hypoxia up-regulates HIF-1α and VEGF mRNA levels in Amazon hypoxia-tolerant Oscar (Astronotus ocellatus).

    PubMed

    Baptista, R B; Souza-Castro, N; Almeida-Val, V M F

    2016-10-01

    Amazon fish maintain oxygen uptake through a variety of strategies considered evolutionary and adaptive responses to the low water oxygen saturation, commonly found in Amazon waters. Oscar (Astronotus ocellatus) is among the most hypoxia-tolerant fish in Amazon, considering its intriguing anaerobic capacity and ability to depress oxidative metabolism. Previous studies in hypoxia-tolerant and non-tolerant fish have shown that hypoxia-inducible factor-1α (HIF-1α) gene expression is positively regulated during low oxygen exposure, affecting vascular endothelial growth factor (VEGF) transcription and fish development or tolerance in different manners. However, whether similar isoforms exists in tolerant Amazon fish and whether they are affected similarly to others physiological responses to improve hypoxia tolerance remain unknown. Here we evaluate the hepatic HIF-1α and VEGF mRNA levels after 3 h of acute hypoxia exposure (0.5 mgO2/l) and 3 h of post-hypoxia recovery. Additionally, hematological parameters and oxidative enzyme activities of citrate synthase (CS) and malate dehydrogenase (MDH) were analyzed in muscle and liver tissues. Overall, three sets of responses were detected: (1) as expected, hematocrit, hemoglobin concentration, red blood cells, and blood glucose increased, improving oxygen carrying capacity and glycolysis potential; (2) oxidative enzymes from liver decreased, corroborating the tendency to a widespread metabolic suppression; and (3) HIF-1α and VEGF increased mRNA levels in liver, revealing their role in the oxygen homeostasis through, respectively, activation of target genes and vascularization. This is the first study to investigate a hypoxia-related transcription factor in a representative Amazon hypoxia-tolerant fish and suggests that HIF-1α and VEGF mRNA regulation have an important role in enhancing hypoxia tolerance in extreme tolerant species.

  9. Development of a novel aluminum tolerance phenotyping platform used for comparisons of cereal aluminum tolerance and investigations into rice aluminum tolerance mechanisms.

    PubMed

    Famoso, Adam N; Clark, Randy T; Shaff, Jon E; Craft, Eric; McCouch, Susan R; Kochian, Leon V

    2010-08-01

    The genetic and physiological mechanisms of aluminum (Al) tolerance have been well studied in certain cereal crops, and Al tolerance genes have been identified in sorghum (Sorghum bicolor) and wheat (Triticum aestivum). Rice (Oryza sativa) has been reported to be highly Al tolerant; however, a direct comparison of rice and other cereals has not been reported, and the mechanisms of rice Al tolerance are poorly understood. To facilitate Al tolerance phenotyping in rice, a high-throughput imaging system and root quantification computer program was developed, permitting quantification of the entire root system, rather than just the longest root. Additionally, a novel hydroponic solution was developed and optimized for Al tolerance screening in rice and compared with the Yoshida's rice solution commonly used for rice Al tolerance studies. To gain a better understanding of Al tolerance in cereals, comparisons of Al tolerance across cereal species were conducted at four Al concentrations using seven to nine genetically diverse genotypes of wheat, maize (Zea mays), sorghum, and rice. Rice was significantly more tolerant than maize, wheat, and sorghum at all Al concentrations, with the mean Al tolerance level for rice found to be 2- to 6-fold greater than that in maize, wheat, and sorghum. Physiological experiments were conducted on a genetically diverse panel of more than 20 rice genotypes spanning the range of rice Al tolerance and compared with two maize genotypes to determine if rice utilizes the well-described Al tolerance mechanism of root tip Al exclusion mediated by organic acid exudation. These results clearly demonstrate that the extremely high levels of rice Al tolerance are mediated by a novel mechanism, which is independent of root tip Al exclusion.

  10. Development and application of diagnostic systems to achieve fault tolerance

    SciTech Connect

    King, R.W.; Singer, R.M.

    1989-01-01

    Much work is currently being done to develop and apply diagnostic systems that are tolerant to faulted conditions in the process being monitored and in the sensors that measure the critical parameters associated with the process. A fault-tolerant diagnostic system based on state-determination, pattern-recognition techniques is currently undergoing testing and evaluation in certain applications at the EBR-II reactor. Testing and operational experience with the system to date has shown a high degree of tolerance to sensor failures, while being sensitive to very slight changes in the plant operational state. This paper briefly mentions related work being done by others, and describes in more detail the pattern-recognition system and the results of the testing and operational experience with the system at EBR-II. 9 refs., 10 figs.

  11. Impaired glucose tolerance in pediatric burn patients at discharge from the acute hospital stay.

    PubMed

    Fram, Ricki Y; Cree, Melanie G; Wolfe, Robert R; Barr, David; Herndon, David N

    2010-01-01

    Hyperglycemia, secondary to the hypermetabolic stress response, is a common occurrence after thermal injury. This stress response has been documented to persist up to 9 months postburn. The purpose of this study was to measure insulin sensitivity in severely burned children before discharge when wounds are 95% healed. Twenty-four children, aged 4 to 17 years, with burns > or = 40% TBSA underwent a 2-hour oral glucose tolerance test before discharge from the acute pediatric burn unit. Plasma glucose and insulin levels as well as the Homeostasis Model Assessment for Insulin Resistance (HOMAIR) were compared with published oral glucose tolerance test data from healthy, nonburned children. There was a significant difference between severely burned children and nonburned, healthy children with respect to the HOMAIR. Severely burned children had a HOMAIR of 3.53 +/- 1.62 compared with the value in nonburned, healthy children of 1.28 +/- 0.16 (P < .05). Insulin resistance secondary to the hypermetabolic stress response persists in severely burned children when burn wounds are at least 95% healed. The results of this study warrant future investigations into therapeutic options for the burned child during the rehabilitative phase of their care after injury.

  12. Application of acute maximal exercise to protect orthostatic tolerance after simulated microgravity

    NASA Technical Reports Server (NTRS)

    Engelke, K. A.; Doerr, D. F.; Crandall, C. G.; Convertino, V. A.

    1996-01-01

    We tested the hypothesis that one bout of maximal exercise performed at the conclusion of prolonged simulated microgravity would improve blood pressure stability during an orthostatic challenge. Heart rate (HR), mean arterial blood pressure (MAP), norepinephrine (NE), epinephrine (E), arginine vasopressin (AVP), plasma renin activity (PRA), atrial natriuretic peptide (ANP), cardiac output (Q), forearm vascular resistance (FVR), and changes in leg volume were measured during lower body negative pressure (LBNP) to presyncope in seven subjects immediately prior to reambulation from 16 days of 6 degrees head-down tilt (HDT) under two experimental conditions: 1) after maximal supine cycle ergometry performed 24 h before returning to the upright posture (exercise) and 2) without exercise (control). After HDT, the reduction of LBNP tolerance time from pre-HDT levels was greater (P = 0.041) in the control condition (-2.0 +/- 0.2 min) compared with the exercise condition (-0.4 +/- 0.2 min). At presyncope after HDT, FVR and NE were higher (P < 0.05) after exercise compared with control, whereas MAP, HR, E, AVP, PRA, ANP, and leg volume were similar in both conditions. Plasma volume (PV) and carotid-cardiac baroreflex sensitivity were reduced after control HDT, but were restored by the exercise treatment. Maintenance of orthostatic tolerance by application of acute intense exercise after 16 days of simulated microgravity was associated with greater circulating levels of NE, vasoconstriction, Q, baroreflex sensitivity, and PV.

  13. Multiscale Multiphysics Developments for Accident Tolerant Fuel Concepts

    SciTech Connect

    Gamble, K. A.; Hales, J. D.; Yu, J.; Zhang, Y.; Bai, X.; Andersson, D.; Patra, A.; Wen, W.; Tome, C.; Baskes, M.; Martinez, E.; Stanek, C. R.; Miao, Y.; Ye, B.; Hofman, G. L.; Yacout, A. M.; Liu, W.

    2015-09-01

    U3Si2 and iron-chromium-aluminum (Fe-Cr-Al) alloys are two of many proposed accident-tolerant fuel concepts for the fuel and cladding, respectively. The behavior of these materials under normal operating and accident reactor conditions is not well known. As part of the Department of Energy’s Accident Tolerant Fuel High Impact Problem program significant work has been conducted to investigate the U3Si2 and FeCrAl behavior under reactor conditions. This report presents the multiscale and multiphysics effort completed in fiscal year 2015. The report is split into four major categories including Density Functional Theory Developments, Molecular Dynamics Developments, Mesoscale Developments, and Engineering Scale Developments. The work shown here is a compilation of a collaborative effort between Idaho National Laboratory, Los Alamos National Laboratory, Argonne National Laboratory and Anatech Corp.

  14. Oxycodone recycling: a novel hypothesis of opioid tolerance development in humans.

    PubMed

    Linares, Oscar A; Fudin, Jeffrey; Schiesser, William E; Linares, Annemarie Daly; Boston, Raymond C

    2014-09-01

    We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC's exposure to local μ-opioid receptors (μORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is TΩ. TΩ estimates OC's tolerance recovery in days; It is defined as the rate of recovery of OC's pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t1/2 = 4.5h)-after which time steady-state was assumed. Repetitive OC dose TΩ fell 61% compared to single OC dose TΩ (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p = 0.001). The fall in TΩ was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravascular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of μORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface μOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance

  15. Dietary immunomodulatory factors in the development of immune tolerance.

    PubMed

    West, Christina E; D'Vaz, Nina; Prescott, Susan L

    2011-08-01

    Emerging evidence suggests that exposures during pregnancy and the early postnatal period can modify gene expression and disease propensity. Diet is a major environmental exposure, and dietary factors, including polyunsaturated fatty acids, probiotics, oligosaccharides, antioxidants, folate, and other vitamins, have effects on immune function. Some also have been implicated in reduced risk of allergy in observational studies. Intervention trials with polyunsaturated fatty acids, probiotics, and oligosaccharides suggest preliminary but as-of-yet-unconfirmed benefits. Food allergen avoidance during pregnancy, lactation, or infancy has provided no consistent evidence in allergy prevention and is no longer recommended. Rather, there is now a focus on food allergens in tolerance induction. Specific nutrients can induce changes in gene expression during early development and have been implicated in potentially heritable "epigenetic" changes in disease predisposition. Collectively, these observations emphasize that early exposures may modify tolerance development and that further research on these exposures should remain a priority.

  16. The effect of a novel pentadecapeptide BPC 157 on development of tolerance and physical dependence following repeated administration of diazepam.

    PubMed

    Jelovac, N; Sikiric, P; Rucman, R; Petek, M; Perovic, D; Marovic, A; Anic, T; Seiwerth, S; Mise, S; Pigac, B; Duplancie, B; Turkovic, B; Dodig, G; Prkacin, I; Stancic-Rokotov, D; Zoricic, I; Aralica, G; Sebecic, B; Ziger, T; Slobodnjak, Z

    1999-09-30

    A novel gastric pentadecapeptide BPC 157 with different beneficial activities and anticonvulsant effect interacting with GABAergic system could improve diazepam efficacy coadministered (10 microg/kg, 10 ng/kg i.p.) with diazepam (5.0 mg/kg i.p.) twice daily for 10 days, since diazepam chronic medication would otherwise predispose for diazepam- tolerance/withdrawal development (shorter latency to convulsion after convulsant). In diazepam chronically treated mice, it attenuated diazepam tolerance (provoked by later acute administration of diazepam together with convulsant) and postponed physical dependence/withdrawal effects (provoked by later administration of isoniazid). In tolerance assay, at 42 h after the end of conditioning regimen, shorter preconvulsive latencies than in healthy (non-diazepam conditioned) mice following isoniazid (800 mg/kg i.p.) (as hallmark of tolerance) were observed if diazepam (5.0 mg/kg i.p.) was again given acutely to mice previously conditioned with diazepam alone (use of picrotoxin 3.0 mg/kg i.p., as convulsant, with acute application of diazepam in previously diazepam conditioned mice did not lead to tolerance hallmark). This was completely avoided in diazepam+BPC 157 10 microg or diazepam+BPC 157 10 ng chronically treated animals. In physical dependence assay (isoniazid challenge assessed at 6, 14, 42 and 72 h after conditioning medication), when compared to diazepam non-conditioned healthy mice, in diazepam conditioned mice residual anticonvulsive activity was not present already at the earliest post-conditioning interval (i.e., not different latency to isoniazid-convulsions), whereas shorter preconvulsive latencies (as physical dependence/withdrawal hallmark) were noted in diazepam conditioned mice following isoniazid challenge at 42 h and at 72 h after end of conditioning treatment. In diazepam+BPC 157 10 microg- conditioned mice, a residual anticonvulsive activity (i.e., longer latency to isoniazid convulsion) was noted at 6 h

  17. Development of the Damage Tolerance Criteria for an Aging Fleet

    DTIC Science & Technology

    2014-10-20

    Laboratory Air Force Materiel Command REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this collection of...information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE (DD-MM-YYYY... Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 Development of the damage tolerance criteria for an ageing fleet. Principal Researcher

  18. Reverse of Acute and Chronic Morphine Tolerance by Lithocholic Acid via Down-Regulating UGT2B7

    PubMed Central

    Yang, Zizhao; Li, Li; Hu, Haihong; Xu, Mingcheng; Gu, Jingkai; Wang, Zaijie Jim; Yu, Lushan; Zeng, Su

    2016-01-01

    Lithocholic acid (LCA) deposited in human livers always induces drastic pains which need analgesic drug, like morphine to release. Our research showed that LCA can effectively inhibit uridine 5’-diphospho-glucuronosyltransferase 2B7 (UGT2B7) in morphine tolerance-like human normal liver cells, HL-7702, then increase μ-opioid receptor (MOR) and calcium–calmodulin dependent protein kinase IIα (CaMKIIα) expression. In vivo assay, UGT2B7 was significantly repressed in the livers of acute or chronic morphine tolerance mice pretreated with LCA (10, 50, and 100 mg/kg, p.o.). To investigate the connections between LCA function performance and change of UGT2B7 enzymatic activity in mice livers, two morphine metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were quantified by solid phase extraction (SPE)–HPLC–MS/MS. The result indicated no matter in acute or chronic morphine tolerance, the concentrations of M3G and M6G were all decreased, the later one fell even more. Besides that, 50 mg/kg of LCA administration can prevent auto-phosphorylation of CaMKIIα at Thr286 in acute or chronic morphine tolerance mice prefrontal cortexes (mPFCs) due to synthesis increase of cyclic adenosine monophosphate. As a consequence, UGT2B7 depression mediated by LCA can affect its selective catalysis ability to morphine, that may be responsible to acute or chronic morphine tolerance alleviation. These findings might assist to modify antinociception of morphine in clinic. PMID:27847477

  19. Acute postexercise effects of concentric and eccentric exercise on glucose tolerance.

    PubMed

    Cook, Matthew David; Myers, Stephen David; Kelly, John Stephen Michael; Willems, Mark Elisabeth Theodorus

    2015-02-01

    Impaired glucose tolerance was shown to be present 48 hr following muscle-damaging eccentric exercise. We examined the acute effect of concentric and muscle-damaging eccentric exercise, matched for intensity, on the responses to a 2-hr 75-g oral glucose tolerance test (OGTT). Ten men (27 ± 9 years, 178 ± 7 cm, 75 ± 11 kg, VO₂max: 52.3 ± 7.3 ml · kg⁻¹ · min⁻¹) underwent three OGTTs after an overnight 12 hr fast: rest (control), 40-min (5 × 8-min with 2-min interbout rest) of concentric (level running, 0%, CON) or eccentric exercise (downhill running, -12%, ECC). Running intensity was matched at 60% of maximal metabolic equivalent. Maximal isometric force of m. quadriceps femoris of both legs was measured before and after the running protocols. Downhill running speed was higher (level: 9.7 ± 2.1, downhill: 13.8 ± 3.2 km · hr⁻¹, p < .01). Running protocols had similar VO₂max (p = .59), heart rates (p = .20) and respiratory exchange ratio values (p = .74) indicating matched intensity and metabolic demands. Downhill running resulted in higher isometric force deficits (level: 3.0 ± 6.7, downhill: 17.1 ± 7.3%, p < .01). During OGTTs, area-under-the-curve for plasma glucose (control: 724 ± 97, CON: 710 ± 77, ECC: 726 ± 72 mmol · L⁻¹ · 120 min, p = .86) and insulin (control: 24995 ± 11229, CON: 23319 ± 10417, ECC: 21842 ± 10171 pmol · L⁻¹ · 120 min, p = .48), peak glucose (control: 8.1 ± 1.3, CON: 7.7 ± 1.2, ECC: 7.7 ± 1.1 mmol · L⁻¹, p = .63) and peak insulin levels (control: 361 ± 188, CON: 322 ± 179, ECC: 299 ± 152 pmol · L⁻¹, p = .30) were similar. It was concluded that glucose tolerance and the insulin response to an OGTT were not changed immediately by muscle-damaging eccentric exercise.

  20. Impaired glucose tolerance in pediatric burn patients at discharge from the acute hospital stay

    PubMed Central

    Fram, Ricki Y.; Cree, Melanie G.; Wolfe, Robert R.; Barr, David; Herndon, David N.

    2013-01-01

    Objective Hyperglycemia, secondary to the hypermetabolic stress response, is a common occurrence after thermal injury. This stress response has been documented to persist up to 9 months post burn. The purpose of this study was to measure insulin sensitivity in severely burned children prior to discharge when wounds are 95% healed. Methods Twenty-four children, aged 4–17 years, with burns ≥ 40% total body surface area (TBSA) underwent a 2 hour oral glucose tolerance test (OGTT) prior to discharge from the acute pediatric burn unit. Plasma glucose and insulin levels, as well as the Homeostasis Model Assessment for Insulin Resistance (HOMAIR) were compared to published OGTT data from healthy, non-burned children. Results There was a significant difference between severely burned children and non-burned, healthy children with respect to the HOMAIR. Severely burned children had a HOMAIR of 3.53±1.62 compared to the value in non-burned healthy children was 1.28±0.16 (p<0.05). Conclusion Insulin resistance secondary to the hypermetabolic stress response persists in severely burned children when burn wounds are at least 95% healed. The results of this study warrant future investigations into therapeutic options for the burned child during the rehabilitative phase of their care after injury. PMID:20634704

  1. Influence of an n-6 polyunsaturated fatty acid-enriched diet on the development of tolerance during chronic ethanol administration in rats.

    PubMed

    Meehan, E; Beaugé, F; Choquart, D; Leonard, B E

    1995-12-01

    This study investigates the effects of n-6 polyunsaturated fatty acids (PUFAs), in the form of dietary Evening Primrose Oil (EPO) and safflower oil, on the development of tolerance to ethanol. The degree of fluorescence polarization of the fluoroprobes DPH, PROP-DPH, and TMA-DPH in isolated cortical synaptosomal membranes was measured. In addition, the development of tolerance, as shown by changes in synaptosomal membrane fluidity after an acute in vitro ethanol challenge, was also determined after 20 weeks of ethanol administration, either alone or together with a PUFA-enriched diet. Although the administration of EPO-enriched diet did not significantly render the inner core of the cortical synaptosomal membrane tolerant to the acute ethanol challenge, concomitant administration of ethanol and EPO was found to increase further the rigidity and tolerance to the acute ethanol challenge in the inner core. Chronic administration of safflower oil, which lacks gamma-linolenic acid (18:3, n-6) but like EPO contains linoleic acid, either alone or together with chronic ethanol had no effect on synaptosomal membrane fluidity after an acute ethanol challenge. The results suggest that gamma-linolenic acid or its metabolites may have an important role to play in the development of tolerance to chronic ethanol.

  2. Adolescent rats are resistant to the development of ethanol-induced chronic tolerance and ethanol-induced conditioned aversion.

    PubMed

    Pautassi, Ricardo Marcos; Godoy, Juan Carlos; Molina, Juan Carlos

    2015-11-01

    The analysis of chronic tolerance to ethanol in adult and adolescent rats has yielded mixed results. Tolerance to some effects of ethanol has been reported in adolescents, yet other studies found adults to exhibit greater tolerance than adolescents or comparable expression of the phenomena at both ages. Another unanswered question is how chronic ethanol exposure affects subsequent ethanol-mediated motivational learning at these ages. The present study examined the development of chronic tolerance to ethanol's hypothermic and motor stimulating effects, and subsequent acquisition of ethanol-mediated odor conditioning, in adolescent and adult male Wistar rats given every-other-day intragastric administrations of ethanol. Adolescent and adult rats exhibited lack of tolerance to the hypothermic effects of ethanol during an induction phase; whereas adults, but not adolescents, exhibited a trend towards a reduction in hypothermia at a challenge phase (Experiment 1). Adolescents, unlike adults, exhibited ethanol-induced motor activation after the first ethanol administration. Adults, but not adolescents, exhibited conditioned odor aversion by ethanol. Subsequent experiments conducted only in adolescents (Experiment 2, Experiment 3 and Experiment 4) manipulated the context, length and predictability of ethanol administration. These manipulations did not promote the expression of ethanol-induced tolerance. This study indicated that, when moderate ethanol doses are given every-other day for a relatively short period, adolescents are less likely than adults to develop chronic tolerance to ethanol-induced hypothermia. This resistance to tolerance development could limit long-term maintenance of ethanol intake. Adolescents, however, exhibited greater sensitivity than adults to the acute motor stimulating effects of ethanol and a blunted response to the aversive effects of ethanol. This pattern of response may put adolescents at risk for early initiation of ethanol intake.

  3. Application of an alcohol clamp paradigm to examine inhibitory control, subjective responses, and acute tolerance in late adolescence.

    PubMed

    Hendershot, Christian S; Wardell, Jeffrey D; Strang, Nicole M; Markovich, Mike S D; Claus, Eric D; Ramchandani, Vijay A

    2015-06-01

    Individual differences in acute alcohol effects on cognitive control and subjective responses--and acute tolerance to these effects--are implicated in the risk for heavy drinking and alcohol-related harms. Few studies have examined these effects in drinkers under age 21. Additionally, studies of acute tolerance typically involve bolus oral alcohol administration, such that estimates of tolerance are confounded with blood alcohol concentration (BAC) limb. The current study examined cognitive control and subjective responses in young heavy drinkers (n = 88; M = 19.8 years old, SD = 0.8) during a single-session alcohol clamp protocol. Participants completed an intravenous alcohol session comprising an ascending limb (0 to 80 mg% in 20 min) and a BAC plateau (80 mg% for 80 min). Serial assessments included a cued go/no-go task and measures of stimulation, sedation, and craving. Relevant individual difference factors (attention-deficit hyperactivity disorder [ADHD] symptoms and sensation seeking) were examined as moderators. Multilevel modeling demonstrated that response inhibition worsened following initial rise in BAC and showed increasing impairment during the BAC plateau. ADHD symptoms and sensation seeking moderated this effect. Significant within-person associations between stimulation and craving were evident on the ascending limb only. Participants with higher ADHD symptoms reported steeper increases in stimulation during the ascending limb. These findings provide initial information about subjective and behavioral responses during pseudoconstant BAC, and potential moderators of these outcomes, in late adolescence. Additional studies with placebo-controlled designs are necessary to confirm these findings.

  4. Efficacy and Tolerability of Fixed-Dose Combination of Dexketoprofen and Dicyclomine Injection in Acute Renal Colic

    PubMed Central

    Porwal, A.; Mahajan, A. D.; Oswal, D. S.; Erram, S. S.; Sheth, D. N.; Balamurugan, S.; Kamat, V.; Enadle, R. P.; Badadare, A.; Bhatnagar, S. K.; Walvekar, R. S.; Dhorepatil, S.; Naik, R. C.; Basu, I.; Kshirsagar, S. N.; Keny, J. V.; Sengupta, S.

    2012-01-01

    Objective. To evaluate the efficacy and tolerability of a fixed-dose combination of dexketoprofen and dicyclomine (DXD) injection in patients with acute renal colic. Patients and Methods. Two hundred and seventeen patients were randomized to receive either DXD (n = 109) or fixed-dose combination of diclofenac and dicyclomine injection (DLD; n = 108), intramuscularly. Pain intensity (PI) was self-evaluated by patients on visual analogue scale (VAS) at baseline and at 1, 2, 4, 6, and 8 hours. Efficacy parameters were proportion of responders, difference in PI (PID) at 8 hours, and sum of analogue of pain intensity differences (SAPID). Tolerability was assessed by patients and physicians. Results. DXD showed superior efficacy in terms of proportion of responders (98.17% versus 81.48; P < 0.0001), PID at 8 hours (P = 0.002), and SAPID0–8 hours (P = 0.004). The clinical global impression for change in pain was significantly better for DXD than DLD. The incidence of adverse events was comparable in both groups. However, global assessment of tolerability was rated significantly better for DXD. Conclusion. DXD showed superior efficacy and tolerability than DLD in patients clinically diagnosed to be suffering from acute renal colic. PMID:22577544

  5. Effect of an Acute Bout of Kettlebell Exercise on Glucose Tolerance in Sedentary Men: A Preliminary Study

    PubMed Central

    GREENWALD, SAMANTHA; SEGER, EDWARD; NICHOLS, DAVID; RAY, ANDREW D.; RIDEOUT, TODD C.; GOSSELIN, LUC E.

    2016-01-01

    Impaired glucose tolerance can have significant health consequences. The purposes of this preliminary study were to examine whether a single session of kettlebell exercise improves acute post-exercise glucose tolerance in sedentary individuals, and whether it was as effective as high-intensity interval running. Six sedentary male subjects underwent a two-hour oral glucose tolerance test following three different conditions: 1) control (no exercise); 2) kettlebell exercise (2 sets of 7 exercises, 15 repetitions per exercise with 30 seconds rest between each exercise); or 3) high-intensity interval running (10 one-minute intervals at a workload corresponding to 90% VO2max interspersed with one-minute active recovery periods). Blood glucose and insulin levels were measured before (0 minutes), and 60 and 120 minutes after glucose ingestion. Both kettlebell and high-intensity interval running exercise significantly lowered blood glucose 60 minutes after glucose ingestion compared with control. However, there was no significant difference in blood glucose between the two exercise conditions at any time point. In addition, there were no significant differences in insulin concentration between high intensity interval running, kettlebell, and control conditions at all time points. Results indicate that an acute bout of kettlebell exercise is as effective as high intensity interval running at improving glucose tolerance in sedentary young men. PMID:27766136

  6. Effect of an Acute Bout of Kettlebell Exercise on Glucose Tolerance in Sedentary Men: A Preliminary Study.

    PubMed

    Greenwald, Samantha; Seger, Edward; Nichols, David; Ray, Andrew D; Rideout, Todd C; Gosselin, Luc E

    2016-01-01

    Impaired glucose tolerance can have significant health consequences. The purposes of this preliminary study were to examine whether a single session of kettlebell exercise improves acute post-exercise glucose tolerance in sedentary individuals, and whether it was as effective as high-intensity interval running. Six sedentary male subjects underwent a two-hour oral glucose tolerance test following three different conditions: 1) control (no exercise); 2) kettlebell exercise (2 sets of 7 exercises, 15 repetitions per exercise with 30 seconds rest between each exercise); or 3) high-intensity interval running (10 one-minute intervals at a workload corresponding to 90% VO2max interspersed with one-minute active recovery periods). Blood glucose and insulin levels were measured before (0 minutes), and 60 and 120 minutes after glucose ingestion. Both kettlebell and high-intensity interval running exercise significantly lowered blood glucose 60 minutes after glucose ingestion compared with control. However, there was no significant difference in blood glucose between the two exercise conditions at any time point. In addition, there were no significant differences in insulin concentration between high intensity interval running, kettlebell, and control conditions at all time points. Results indicate that an acute bout of kettlebell exercise is as effective as high intensity interval running at improving glucose tolerance in sedentary young men.

  7. Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance

    PubMed Central

    Balza, E; Piccioli, P; Carta, S; Lavieri, R; Gattorno, M; Semino, C; Castellani, P; Rubartelli, A

    2016-01-01

    Incidence of sepsis is increasing, representing a tremendous burden for health-care systems. Death in acute sepsis is attributed to hyperinflammatory responses, but the underlying mechanisms are still unclear. We report here that proton pump inhibitors (PPIs), which block gastric acid secretion, selectively inhibited tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) secretion by Toll-like receptor (TLR)-activated human monocytes in vitro, in the absence of toxic effects. Remarkably, the oversecretion of IL-1β that represents a hallmark of monocytes from patients affected by cryopyrin-associated periodic syndrome is also blocked. Based on these propaedeutic experiments, we tested the effects of high doses of PPIs in vivo in the mouse model of endotoxic shock. Our data show that a single administration of PPI protected mice from death (60% survival versus 5% of untreated mice) and decreased TNF-α and IL-1β systemic production. PPIs were efficacious even when administered after lipopolysaccharide (LPS) injection. PPI-treated mice that survived developed a long-term cross-tolerance, becoming resistant to LPS- and zymosan-induced sepsis. In vitro, their macrophages displayed impaired TNF-α and IL-1β to different TLR ligands. PPIs also prevented sodium thioglycollate-induced peritoneal inflammation, indicating their efficacy also in a non-infectious setting independent of TLR stimulation. Lack of toxicity and therapeutic effectiveness make PPIs promising new drugs against sepsis and other severe inflammatory conditions. PMID:27441656

  8. Acute diarrhoeal disease in less developed countries

    PubMed Central

    Gordon, John E.; Béhar, Moisés; Scrimshaw, Nevin S.

    1964-01-01

    The programme presented in this article for controlling the diarrhoeas and dysenteries of less developed countries is based on epidemiological principles applicable to acute undifferentiated diarrhoeal disease—its specific as well as its non-specific elements. The dominant importance of weanling diarrhoea requires a main emphasis on maternal and child health procedures, with nutrition singled out for attention, along with public health education and medical care of patients: this in addition to the established worth of means for promoting environmental sanitation. The several features of the suggested programme are within four broad divisions: preventive measures; control of patients, contacts and the immediate environment; measures specifically useful in epidemics; and international measures conducive to broad restriction of the syndrome. PMID:14230891

  9. Acute CO2 tolerance during the early developmental stages of four marine teleosts.

    PubMed

    Kikkawa, T; Ishimatsu, A; Kita, J

    2003-12-01

    Ocean sequestration of CO2 is proposed as a possible measure to mitigate climate changes caused by increasing atmospheric concentrations of the gas, but its impact on the marine ecosystem is unknown. We investigated the acute lethal effect of CO2 during the early developmental stages of four marine teleosts: red sea bream (Pagrus major), Japanese whiting (Sillago japonica), Japanese flounder (Paralichthys olivaceus), and eastern little tuna (Euthynnus affinis). The percentages of larvae that hatched and survived were not affected by exposure to water with a PCO2 of 1.0 kPa (= 7.5 mmHg) within 24 h. Median lethal PCO2 values for a 360-min exposure were 1.4 kPa (cleavage), 5.1 kPa (embryo), 7.3 kPa (preflexion), 4.2 kPa (flexion), 4.6 kPa (postflexion), and 2.5 kPa (juvenile) for red sea bream; 2.4 kPa (cleavage), 4.9 kPa (embryo), 5.9 kPa (preflexion), 6.1 kPa (flexion), 4.1 kPa (postflexion), and 2.7 kPa (juvenile) for Japanese whiting; 2.8 kPa (cleavage) and > 7.0 kPa (young) for Japanese flounder; and 11.8 kPa (cleavage) for eastern little tuna. Red sea bream and Japanese whiting of all ontogenetic stages had similar susceptibilities to CO2: the most susceptible stages were cleavage and juvenile, whereas the most tolerant stages were preflexion and flexion.

  10. Development and Evaluation of Fault-Tolerant Flight Control Systems

    NASA Technical Reports Server (NTRS)

    Song, Yong D.; Gupta, Kajal (Technical Monitor)

    2004-01-01

    The research is concerned with developing a new approach to enhancing fault tolerance of flight control systems. The original motivation for fault-tolerant control comes from the need for safe operation of control elements (e.g. actuators) in the event of hardware failures in high reliability systems. One such example is modem space vehicle subjected to actuator/sensor impairments. A major task in flight control is to revise the control policy to balance impairment detectability and to achieve sufficient robustness. This involves careful selection of types and parameters of the controllers and the impairment detecting filters used. It also involves a decision, upon the identification of some failures, on whether and how a control reconfiguration should take place in order to maintain a certain system performance level. In this project new flight dynamic model under uncertain flight conditions is considered, in which the effects of both ramp and jump faults are reflected. Stabilization algorithms based on neural network and adaptive method are derived. The control algorithms are shown to be effective in dealing with uncertain dynamics due to external disturbances and unpredictable faults. The overall strategy is easy to set up and the computation involved is much less as compared with other strategies. Computer simulation software is developed. A serious of simulation studies have been conducted with varying flight conditions.

  11. A Comprehensive Comparison of the Efficacy and Tolerability of Racecadotril with Other Treatments of Acute Diarrhea in Adults

    PubMed Central

    Fischbach, Wolfgang; Andresen, Viola; Eberlin, Marion; Mueck, Tobias; Layer, Peter

    2016-01-01

    Racecadotril is a guideline-recommended treatment to alleviate symptoms of acute diarrhea. A systematic review of randomized studies was performed comparing efficacy and safety of treatment with racecadotril to that with placebo or active treatments in adults. In five double-blind studies, racecadotril and placebo had comparable tolerability, but racecadotril was more effective. This was consistent across multiple efficacy parameters including duration of diarrhea, number of diarrheic stools, abdominal pain, and meteorism; it was also consistent across countries in Africa, Asia, and Europe. In six randomized studies in outpatients comparing racecadotril to loperamide, resolution of symptoms occurred with similar speed and efficacy; however, racecadotril treatment was associated with less rebound constipation and less abdominal discomfort. The seventh comparative study performed in geriatric nursing home residents reported a superior efficacy of racecadotril. In direct comparison with Saccharomyces boulardii treatment, racecadotril exhibited similar tolerability but was more efficacious. One study compared racecadotril to octreotide in patients with acute diarrhea requiring hospitalization, rehydration, and antibiotic treatment; in this cohort, octreotide was more efficacious than racecadotril. In conclusion, in adults with acute diarrhea, racecadotril is more efficacious than placebo or S. boulardii, similarly efficacious as loperamide and, in patients with moderate to severe disease as add-on to antibiotics, less than octreotide. The tolerability of racecadotril is similar to that of placebo or S. boulardii and better than that of loperamide, particularly with regard to risk of rebound constipation. Taken together, these data demonstrate that racecadotril is a suitable treatment to alleviate symptoms of acute diarrhea in adults. PMID:27790616

  12. Proteomics of seed development, desiccation tolerance, germination and vigor.

    PubMed

    Wang, Wei-Qing; Liu, Shu-Jun; Song, Song-Quan; Møller, Ian Max

    2015-01-01

    Proteomics, the large-scale study of the total complement of proteins in a given sample, has been applied to all aspects of seed biology mainly using model species such as Arabidopsis or important agricultural crops such as corn and rice. Proteins extracted from the sample have typically been separated and quantified by 2-dimensional polyacrylamide gel electrophoresis followed by liquid chromatography and mass spectrometry to identify the proteins in the gel spots. In this way, qualitative and quantitative changes in the proteome during seed development, desiccation tolerance, germination, dormancy release, vigor alteration and responses to environmental factors have all been studied. Many proteins or biological processes potentially important for each seed process have been highlighted by these studies, which greatly expands our knowledge of seed biology. Proteins that have been identified to be particularly important for at least two of the seed processes are involved in detoxification of reactive oxygen species, the cytoskeleton, glycolysis, protein biosynthesis, post-translational modifications, methionine metabolism, and late embryogenesis-abundant (LEA) proteins. It will be useful for molecular biologists and molecular plant breeders to identify and study genes encoding particularly interesting target proteins with the aim to improve the yield, stress tolerance or other critical properties of our crop species.

  13. Cordyceps militaris Improves Tolerance to High-Intensity Exercise After Acute and Chronic Supplementation.

    PubMed

    Hirsch, Katie R; Smith-Ryan, Abbie E; Roelofs, Erica J; Trexler, Eric T; Mock, Meredith G

    2016-07-13

    To determine the effects of a mushroom blend containing Cordyceps militaris on high-intensity exercise after 1 and 3 weeks of supplementation. Twenty-eight individuals (Mean ± standard deviation [SD]; Age = 22.7 ± 4.1 yrs; Height = 175.4 ± 8.7 cm; Weight = 71.6 ± 12.0 kg) participated in this randomized, repeated measures, double-blind, placebo-controlled design. Maximal oxygen consumption (VO2max), time to exhaustion (TTE), and ventilatory threshold (VT) were measured during a maximal graded exercise test on a cycle ergometer. Relative peak power output (RPP), average power output (AvgP), and percent drop (%drop) were recorded during a 3 minute maximal cycle test with resistance at 4.5% body weight. Subjects consumed 4 g·d(-1) mushroom blend (MR) or maltodextrin (PL) for 1 week. Ten volunteers supplemented for an additional 2 weeks. Exercise tests were separated by at least 48 hours and repeated following supplementation periods. One week of supplementation elicited no significant time × treatment interaction for VO2max (p = 0.364), VT (p = 0.514), TTE (p = 0.540), RPP (p = 0.134), AvgP (p = 0.398), or %drop (p = 0.823). After 3 weeks, VO2max significantly improved (p = 0.042) in MR (+4.8 ml·kg(-1)·min(-1)), but not PL (+0.9 ml·kg(-1)·min(-1)). Analysis of 95% confidence intervals revealed significant improvements in TTE after 1- (+28.1 s) and 3 weeks (+69.8 s) in MR, but not PL, with additional improvements in VO2max (+4.8 ml·kg(-1)·min(-1)) and VT (+0.7 l·min(-1)) after 3 weeks. Acute supplementation with a Cordyceps militaris containing mushroom blend may improve tolerance to high-intensity exercise; greater benefits may be elicited with consistent chronic supplementation.

  14. Acute tolerance to alcohol impairment of behavioral and cognitive mechanisms related to driving: drinking and driving on the descending limb

    PubMed Central

    Weafer, Jessica

    2015-01-01

    Rationale Alcohol effects on behavioral and cognitive mechanisms influence impaired driving performance and decisions to drive after drinking (Barry 1973; Moskowitz and Robinson 1987). To date, research has focused on the ascending limb of the blood alcohol curve, and there is little understanding of how acute tolerance to impairment of these mechanisms might influence driving behavior on the descending limb. Objectives To provide an integrated examination of the degree to which alcohol impairment of motor coordination and inhibitory control contributes to driving impairment and decisions to drive on the ascending and descending limbs of the blood alcohol curve. Methods Social-drinking adults (N=20) performed a testing battery that measured simulated driving performance and willingness to drive, as well as mechanisms related to driving: motor coordination (grooved pegboard), inhibitory control (cued go/no-go task), and subjective intoxication. Performance was tested in response to placebo and a moderate dose of alcohol (0.65 g/kg) twice at comparable blood alcohol concentrations: once on the ascending limb and again on the descending limb. Results Impaired motor coordination and subjective intoxication showed acute tolerance, whereas driving performance and inhibitory control showed no recovery from impairment. Greater motor impairment was associated with poorer driving performance under alcohol, and poorer inhibitory control was associated with more willingness to drive. Conclusions Findings suggest that acute tolerance to impairment of motor coordination is insufficient to promote recovery of driving performance and that the persistence of alcohol-induced disinhibition might contribute to risky decisions to drive on the descending limb. PMID:21960182

  15. Increased analgesic tolerance to acute morphine in fosB knock-out mice: a gender study.

    PubMed

    Solecki, Wojciech; Krowka, Tomasz; Kubik, Jakub; Kaczmarek, Leszek; Przewlocki, Ryszard

    2008-10-01

    The proteins of Fos family are a potential candidate to link molecular mechanisms of morphine action with behavioural effects such as morphine-induced reward, dependence and tolerance. We used both male and female mice lacking fosB gene to study its contribution to morphine effects. Morphine analgesia (tail-flick test) and hypothermia were studied using morphine at cumulative doses in morphine-naive and morphine-tolerant (tolerance induced by 24 h prior 100 mg/kg morphine administration) mice. FosB -/- mice, as compared to fosB +/+ mice, developed enhanced tolerance to morphine-induced analgesia. No effects of genotype or gender on tolerance to morphine-induced hypothermia were observed. These results suggest that fosB may be involved in the development of tolerance to morphine analgesia but not hypothermia. The gender study implicates that lack of FosB proteins in female fosB -/- mice enhanced morphine analgesic potency. In conclusion, we show that fosB gene is important to analgesia but not hypothermia phenotype indicating its role in morphine effects.

  16. Acute and chronic hypoxia: implications for cerebral function and exercise tolerance

    PubMed Central

    Goodall, Stuart; Twomey, Rosie; Amann, Markus

    2015-01-01

    Purpose To outline how hypoxia profoundly affects neuronal functionality and thus compromise exercise-performance. Methods Investigations using electroencephalography (EEG) and transcranial magnetic stimulation (TMS) detecting neuronal changes at rest and those studying fatiguing effects on whole-body exercise performance in acute (AH) and chronic hypoxia (CH) were evaluated. Results At rest during very early hypoxia (<1-h), slowing of cerebral neuronal activity is evident despite no change in corticospinal excitability. As time in hypoxia progresses (3-h), increased corticospinal excitability becomes evident; however, changes in neuronal activity are unknown. Prolonged exposure (3–5 d) causes a respiratory alkalosis which modulates Na+ channels, potentially explaining reduced neuronal excitability. Locomotor exercise in AH exacerbates the development of peripheral-fatigue; as the severity of hypoxia increases, mechanisms of peripheral-fatigue become less dominant and CNS hypoxia becomes the predominant factor. The greatest central-fatigue in AH occurs when SaO2 is ≤75%, a level that coincides with increasing impairments in neuronal activity. CH does not improve the level of peripheral-fatigue observed in AH; however, it attenuates the development of central-fatigue paralleling increases in cerebral O2 availability and corticospinal excitability. Conclusions The attenuated development of central-fatigue in CH might explain, the improvements in locomotor exercise-performance commonly observed after acclimatisation to high altitude. PMID:25593787

  17. Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat

    PubMed Central

    Bobeck, Erin N.; Haseman, Rachel A.; Hong, Dana; Ingram, Susan L.; Morgan, Michael M.

    2012-01-01

    Systemic administration of morphine typically produces greater tolerance than higher efficacy mu-opioid receptor (MOPr) agonists, such as fentanyl. The objective of the present study was to test this relationship by measuring antinociceptive efficacy and tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray (vlPAG). MOPr agonist efficacy was evaluated by microinjecting the irreversible opioid receptor antagonist β-funaltrexamine hydrochloride (β-FNA) into the vlPAG prior to a dose-response analysis of morphine and fentanyl antinociception. In contrast to systemic administration of morphine and fentanyl, microinjection of these drugs into the vlPAG had similar efficacy as measured by similar reductions in maximal antinociception following β-FNA administration. Analysis of tolerance revealed a rightward shift in the dose-response curve to a single pretreatment with morphine, but not fentanyl. Moreover, the magnitude of tolerance to morphine was comparable following one, four, or eight pretreatments. Tolerance to fentanyl also was evident following four or eight microinjections. These data are surprising in that antinociceptive efficacy appears to vary depending on the site of administration. Moreover, the similar efficacy following microinjection of morphine and fentanyl into the vlPAG was associated with comparable tolerance, with the one exception of no tolerance to acute administration of fentanyl. Perspective These data reveal that antinociceptive tolerance following vlPAG administration of opioids develops rapidly, is evident with both morphine and fentanyl, and the magnitude is relatively consistent regardless of the number of pretreatments. PMID:22766006

  18. Identification of microRNAs involved in acute rejection and spontaneous tolerance in murine hepatic allografts

    PubMed Central

    Morita, Miwa; Chen, Jiajie; Fujino, Masayuki; Kitazawa, Yusuke; Sugioka, Atsushi; Zhong, Liang; Li, Xiao-Kang

    2014-01-01

    Graft acceptance without the need for immunosuppressive drugs is the ultimate goal of transplantation therapy. In murine liver transplantation, allografts are accepted across major histocompatibility antigen complex barriers without the use of immunosuppressive drugs and constitute a suitable model for research on immunological rejection and tolerance. MicroRNA (miRNA) has been known to be involved in the immunological responses. In order to identify mRNAs in spontaneous liver allograft tolerance, miRNA expression in hepatic allografts was examined using this transplantation model. According to the graft pathological score and function, miR-146a, 15b, 223, 23a, 27a, 34a and 451 were upregulated compared with the expression observed in the syngeneic grafts. In contrast, miR-101a, 101b and 148a were downregulated. Our results demonstrated the alteration of miRNAs in the allografts and may indicate the role of miRNAs in the induction of tolerance after transplantation. Furthermore, our data suggest that monitoring the graft expression of novel miRNAs may allow clinicians to differentiate between rejection and tolerance. A better understanding of the tolerance inducing mechanism observed in murine hepatic allografts may provide a therapeutic strategy for attenuating allograft rejection. PMID:25323448

  19. The role of ontogeny in physiological tolerance: decreasing hydrostatic pressure tolerance with development in the northern stone crab Lithodes maja

    PubMed Central

    Munro, Catriona; Morris, James P.; Brown, Alastair; Hauton, Chris; Thatje, Sven

    2015-01-01

    Extant deep-sea invertebrate fauna represent both ancient and recent invasions from shallow-water habitats. Hydrostatic pressure may present a significant physiological challenge to organisms seeking to colonize deeper waters or migrate ontogenetically. Pressure may be a key factor contributing to bottlenecks in the radiation of taxa and potentially drive speciation. Here, we assess shifts in the tolerance of hydrostatic pressure through early ontogeny of the northern stone crab Lithodes maja, which occupies a depth range of 4–790 m in the North Atlantic. The zoea I, megalopa and crab I stages were exposed to hydrostatic pressures up to 30.0 MPa (equivalent of 3000 m depth), and the relative fold change of genes putatively coding for the N-methyl-d-aspartate receptor-regulated protein 1 (narg gene), two heat-shock protein 70 kDa (HSP70) isoforms and mitochondrial Citrate Synthase (CS gene) were measured. This study finds a significant increase in the relative expression of the CS and hsp70a genes with increased hydrostatic pressure in the zoea I stage, and an increase in the relative expression of all genes with increased hydrostatic pressure in the megalopa and crab I stages. Transcriptional responses are corroborated by patterns in respiratory rates in response to hydrostatic pressure in all stages. These results suggest a decrease in the acute high-pressure tolerance limit as ontogeny advances, as reflected by a shift in the hydrostatic pressure at which significant differences are observed. PMID:26041343

  20. Acute Optic Neuritis: Prognosis for the Development of Multiple Sclerosis.

    DTIC Science & Technology

    1979-12-01

    The literature was reviewed in regard to acute optic neuritis: prognosis for the development of multiple sclerosis , with specific reference to our...series, was preselected and not prospective, causing a higher incidence of later multiple sclerosis . The second factor was the definition of multiple ...development of multiple sclerosis in patients affected with acute optic neuritis. This finding leads us to conclude that an incidence of 13% to 17

  1. Development of a fish assemblage tolerance index for the National Rivers and Streams Assessment

    EPA Science Inventory

    Whittier et al (Trans. Amer. Fish. Soc. 136:254-271) developed an assemblage tolerance index (ATI) for stream fishes in the western US based on quantitative tolerance values developed for individual fish and amphibian species. The ATI is conceptually similar to the Hilsenhoff Bi...

  2. Forskolin promotes the development of ethanol tolerance in 6-hydroxydopamine-treated mice

    SciTech Connect

    Szabo, G.; Hoffman, P.L.; Tabakoff, B.

    1988-01-01

    Partial depletion of brain norepinephrine by 6-hydroxydopamine prevents the development of functional tolerance to ethanol in mice. This blockade of tolerance development was overcome by daily intracerebroventricular injections of forskolin. These results suggest that interaction of norepinephrine with post-synaptic ..beta..-adrenergic receptors, and activation of adenylate cyclase, is important for the development of ethanol tolerance. Interaction of norepinephrine with ..cap alpha../sub 1/-adrenergic receptors may be less crucial, since treatment with a phorbol ester activator of protein kinase C did not restore the development of tolerance in mice treated with 6-hydroxydopamine. The importance of the ..beta..-adrenergic receptor-coupled adenylate cyclase system for development of ethanol tolerance, in addition to its previously-reported role in long-term potentiation, suggests that this system may influence neuroadaptive processes in general. 26 references, 2 figures.

  3. The competence to acquire cellular desiccation tolerance is independent of seed morphological development.

    PubMed

    Golovina, E A; Hoekstra, F A; Van Aelst, A C

    2001-05-01

    Acquisition of desiccation tolerance and the related changes at the cellular level in wheat (Triticum aestivum cv. Priokskaya) kernels during normal development and premature drying on the ear were studied using a spin probe technique and low temperature scanning electron microscopy. During normal development, the ability of embryos to germinate after rapid drying and rehydration was acquired after completion of morphological development, which is a few days before mass maturity. The acquisition of desiccation tolerance, as assessed by germination, was associated with an upsurge in cytoplasmic viscosity, the onset of accumulation of protein and oil bodies, and the retention of membrane integrity upon dehydration/rehydration. These features were also used to assess cellular desiccation tolerance in the cases when germination could not occur. Slow premature drying was used to decouple the acquisition of cellular desiccation tolerance from morphogenesis. Upon premature drying of kernels on the ears of plants cut at 5 d after anthesis, desiccation-tolerant dwarf embryos were formed that were able to germinate. When plants were cut at earlier stages poorly developed embryos were formed that were unable to germinate, but cellular desiccation tolerance was nevertheless acquired. In such prematurely dried kernels, peripheral meristematic endosperm cells had already passed through similar physiological and ultrastructural changes associated with the acquisition of cellular desiccation tolerance. It is concluded that despite the apparent strong integration in seed development, desiccation tolerance can be acquired by the meristematic cells in the developing embryo and cambial layer of endosperm, independently of morphological development.

  4. Developing practice recommendations for endovascular revascularization for acute ischemic stroke

    PubMed Central

    Lazzaro, Marc A.; Alexandrov, Andrei V.; Darkhabani, Ziad; Edgell, Randall C.; English, Joey; Frei, Donald; Jamieson, Dara G.; Janardhan, Vallabh; Janjua, Nazli; Janjua, Rashid M.; Katzan, Irene; Khatri, Pooja; Kirmani, Jawad F.; Liebeskind, David S.; Linfante, Italo; Nguyen, Thanh N.; Saver, Jeffrey L.; Shutter, Lori; Xavier, Andrew; Yavagal, Dileep; Zaidat, Osama O.

    2012-01-01

    Guidelines have been established for the management of acute ischemic stroke; however, specific recommendations for endovascular revascularization therapy are lacking. Burgeoning investigation of endovascular revascularization therapies for acute ischemic stroke, rapid device development, and a diverse training background of the providers performing the procedures underscore the need for practice recommendations. This review provides a concise summary of the Society of Vascular and Interventional Neurology endovascular acute ischemic stroke roundtable meeting. This document was developed to review current clinical efficacy of pharmacologic and mechanical revascularization therapy, selection criteria, periprocedure management, and endovascular time metrics and to highlight current practice patterns. It therefore provides an outline for the future development of multisociety guidelines and recommendations to improve patient selection, procedural management, and organizational strategies for revascularization therapies in acute ischemic stroke. PMID:23008406

  5. Development of Peanut Germplasm with Improved Drought Tolerance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have observed significant reductions in preharvest aflatoxin contamination (PAC) in peanut genotypes with drought tolerance. These sources of resistance to drought and PAC have been entered into a hybridization program. They have been crossed with cultivars and breeding lines that have high yie...

  6. Development of custom radiation-tolerant DCDC converter ASICs

    NASA Astrophysics Data System (ADS)

    Faccio, F.; Michelis, S.; Orlandi, S.; Blanchot, G.; Fuentes, C.; Saggini, S.; Ongaro, F.

    2010-11-01

    Based on a detailed study of the radiation tolerance of high-voltage transistors, 2 commercial CMOS technologies have been selected for the design of synchronous buck DCDC converter ASICs. Three prototype converters have been produced, embedding increasingly sophisticated functions. The electrical and radiation performance of these prototypes is presented.

  7. Safety and tolerability of intrathecal liposomal cytarabine as central nervous system prophylaxis in patients with acute lymphoblastic leukemia.

    PubMed

    Valentin, Angelika; Troppan, Katharina; Pfeilstöcker, Michael; Nösslinger, Thomas; Linkesch, Werner; Neumeister, Peter

    2014-08-01

    Central nervous system recurrence in acute lymphoblastic leukemia (ALL) occurs in up to 15% of patients and is frequently associated with poor outcome. The purpose of our study was to evaluate the efficacy and safety of a slow-release liposomal formulation of cytarabine for intrathecal (IT) meningeal prophylaxis in patients suffering from ALL. Forty patients aged 20-77 years (median 36) were preventively treated with a total of 96 (range 1-6) single doses containing 50 mg of liposomal cytarabine on a compassionate use basis. After a median observation period of 23 months (range 2-118) only two patients experienced a combined medullary-leptomeningeal disease recurrence after primary diagnosis. Except for headache grade 2 in two patients, no specific toxicity attributable to IT liposomal cytarabine application was noted. Long-term neurological side effects were not observed. IT liposomal cytarabine therapy with concomitant dexamethasone appears to be feasible and well tolerated.

  8. Senescence marker protein-30/gluconolactonase deletion worsens glucose tolerance through impairment of acute insulin secretion.

    PubMed

    Hasegawa, Goji; Yamasaki, Masahiro; Kadono, Mayuko; Tanaka, Muhei; Asano, Mai; Senmaru, Takafumi; Kondo, Yoshitaka; Fukui, Michiaki; Obayashi, Hiroshi; Maruyama, Naoki; Nakamura, Naoto; Ishigami, Akihito

    2010-02-01

    Senescence marker protein-30 (SMP30) is an androgen-independent factor that decreases with age. We recently identified SMP30 as the lactone-hydrolyzing enzyme gluconolactonase (GNL), which is involved in vitamin C biosynthesis in animal species. To examine whether the age-related decrease in SMP30/GNL has effects on glucose homeostasis, we used SMP30/GNL knockout (KO) mice treated with L-ascorbic acid. In an ip glucose tolerance test at 15 wk of age, blood glucose levels in SMP30/GNL KO mice were significantly increased by 25% at 30 min after glucose administration compared with wild-type (WT) mice. Insulin levels in SMP30/GNL KO mice were significantly decreased by 37% at 30 min after glucose compared with WT mice. Interestingly, an insulin tolerance test showed a greater glucose-lowering effect in SMP30/GNL KO mice. High-fat diet feeding severely worsened glucose tolerance in both WT and SMP30/GNL KO mice. Morphometric analysis revealed no differences in the degree of high-fat diet-induced compensatory increase in beta-cell mass and proliferation. In the static incubation study of islets, insulin secretion in response to 20 mm glucose or KCl was significantly decreased in SMP30/GNL KO mice. On the other hand, islet ATP content at 20 mm in SMP30/GNL KO mice was similar to that in WT mice. Collectively, these data indicate that impairment of the early phase of insulin secretion due to dysfunction of the distal portion of the secretion pathway underlies glucose intolerance in SMP30/GNL KO mice. Decreased SMP30/GNL may contribute to the worsening of glucose tolerance that occurs in normal aging.

  9. Cyanine dyes as contrast agents for near-infrared imaging in vivo: acute tolerance, pharmacokinetics, and fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Ebert, Bernd; Riefke, Björn; Sukowski, Uwe; Licha, Kai

    2011-06-01

    We compare pharmacokinetic, tolerance, and imaging properties of two near-IR contrast agents, indocyanine green (ICG) and 1,1'-bis-(4-sulfobutyl) indotricarbocyanine-5,5'-dicarboxylic acid diglucamide monosodium salt (SIDAG). ICG is a clinically approved imaging agent, and its derivative SIDAG is a more hydrophilic counterpart that has recently shown promising imaging properties in preclinical studies. The rather lipophilic ICG has a very short plasma half-life, thus limiting the time available to image body regions during its vascular circulation (e.g., the breast in optical mammography where scanning over several minutes is required). In order to change the physicochemical properties of the indotricarbocyanine dye backbone, several derivatives were synthesized with increasing hydrophilicity. The most hydrophilic dye SIDAG is selected for further biological characterization. The acute tolerance of SIDAG in mice is increased up to 60-fold compared to ICG. Contrary to ICG, the pharmacokinetic properties of SIDAG are shifted toward renal elimination, caused by the high hydrophilicity of the molecule. N-Nitrosomethylurea (NMU)-induced rat breast carcinomas are clearly demarcated, both immediately and 24 h after intravenous administration of SIDAG, whereas ICG shows a weak tumor contrast under the same conditions. Our findings demonstrate that SIDAG is a high potential contrast agent for optical imaging, which could increase the sensitivity for detection of inflamed regions and tumors.

  10. Practical Guide to the Management of Acute and Chronic Pain in the Presence of Drug Tolerance for the Healthcare Practitioner

    PubMed Central

    Vadivelu, Nalini; Singh-Gill, Harman; Kodumudi, Gopal; Kaye, Aaron Joshua; Urman, Richard D.; Kaye, Alan David

    2014-01-01

    Background Drug tolerance has been on the rise in recent years worldwide, and consequently, pain management in our population has become challenging. Methods Discussed in this review are commonly abused drugs and considerations for treating acute and chronic pain states in patients with substance disorders. Results After marijuana, alcohol, and tobacco, the most widely abused substances are oxycodone (Oxycontin), diazepam (Valium), and methylphenidate (Ritalin). Urine testing can detect metabolites of drugs used by patients and is useful for assessing drug abuse, medication diversion, and drug interactions. The comprehensive treatment of pain in a patient with addictive disorder or tolerance must address 3 issues: the patient's addiction, any associated psychiatric conditions, and the patient's pain. Eliciting a detailed history of drug abuse—illicit drugs as well as prescription drugs—and ascertaining if the patient is currently enrolled in a methadone maintenance program for the treatment of drug addiction is vital. Conclusion Medical observation, supportive care, multidisciplinary pain management, and timely interventions as necessary are the keys to safe outcomes in these patients. PMID:25249810

  11. Acute toxicity of lead on tolerance, oxygen consumption, ammonia-N excretion, and metal accumulation in Penaeus indicus postlarvae.

    PubMed

    Chinni, Satyavathi; Khan, Ritindra N; Yallapragada, Prabhakara Rao

    2002-02-01

    The estuaries and backwaters that are the potential breeding grounds of penaeid shrimps are subject to heavy metal pollution through industrial effluents and domestic sewage. In the present investigation, laboratory experiments were conducted to study the acute toxicity of lead on tolerance, oxygen consumption, ammonia-N excretion, and metal accumulation in Penaeus indicus postlarvae. Static bioassay tests were employed to determine tolerance limits. Oxygen consumption, ammonia-N excretion, and metal accumulation were determined in postlarvae by exposing them to different concentrations of lead for a period of 48 h. Oxygen consumption measurements were made by using a respiratory chamber equipped with an oxygen electrode and ammonia-N was determined with trione (dichloro-S-triamine 2,4,6(1H,3H,5H-trione)). Accumulation of metal was estimated by wet-ash method. The LC50 value for 96 h was 7.223 ppm and the regression equation Y=4.1638+0.9738X with correlation coefficient of 0.9613 was obtained by probit method. A decrease in oxygen consumption and ammonia-N excretion was observed in postlarvae with increasing concentration of lead. A concentration-dependent accumulation of metal was noticed in these postlarvae. Modifications in O:N ratios of postlarvae suggest that lead accumulation might have altered utilization patterns.

  12. Clinical Comparative Study: Efficacy and Tolerability of Tolperisone and Thiocolchicoside in Acute Low Back Pain and Spinal Muscle Spasticity

    PubMed Central

    Rao, Rajeev; Panghate, Atul; Chandanwale, Ajay; Sardar, Indrajeet; Ghosh, Mriganka; Roy, Modan; Banerjee, Bireswar; Goswami, Ankur

    2012-01-01

    Study Design We performed a multicentric, randomized, comparative clinical trial. Eligible patients were randomly assigned to receive 150 mg of Tolperisone thrice daily or 8 mg of Thiocolchicoside twice daily for 7 days. Purpose To assess the efficacy and tolerability of Tolperisone in comparison with Thiocolchicoside in the treatment of acute low back pain with spasm of spinal muscles. Overview of Literature No head on clinical trial of Tolperisone with Thiocolchicoside is available and so this study is done. Methods The assessment of muscle spasm was made by measuring the finger-to-floor distance (FFD), articular excursion in degrees on performing Lasegue's maneuver and modified Schober's test. Assessment of pain on movement and spontaneous pain (pain at rest) of the lumbar spine was made with the help of visual analogue scale score. Results The improvement in articular excursion on Lasegue's maneuver was significantly greater on day 3 (p = 0.017) and day 7 (p = 0.0001) with Tolperisone as compared to Thiocolchicoside. The reduction in FFD score was greater on day 7 (p = 0.0001) with Tolperisone. However there was no significant difference in improvement in Schober's test score on day 3 (p = 0.664) and day 7 (p = 0.192). The improvement in pain score at rest and on movement was significantly greater with Tolperisone (p = 0.0001). Conclusions Tolperisone is an effective and well tolerated option for treatment of patients with skeletal muscle spasm associated with pain. PMID:22708015

  13. The Acute and Residual Effect of a Single Exercise Session on Meal Glucose Tolerance in Sedentary Young Adults

    PubMed Central

    Short, Kevin R.; Pratt, Lauren V.; Teague, April M.

    2012-01-01

    The study goals were to (1) establish the variability in postprandial glucose control in healthy young people consuming a mixed meal and, then (2) determine the acute and residual impact of a single exercise bout on postprandial glucose control. In study 1, 18 people completed two similar mixed meal trials and an intravenous glucose tolerance test (IVGTT). There were strong test-retest correlations for the post-meal area under the curve (AUC) for glucose, insulin, and Cpeptide (r = 0.73–0.83) and the Matsuda insulin sensitivity index (ISI, r = 0.76), and between meal and IVGTT-derived ISI (r = 0.83). In study 2, 11 untrained young adults completed 3 trials. One trial (No Ex) was completed after refraining from vigorous activity for ≥3 days. On the other 2 trials, a 45-min aerobic exercise bout was performed either 17-hours (Prior Day Ex) or 1-hour (Same Day Ex) before consuming the test meal. Compared to No Ex and Prior Day Ex, which did not differ from one another, there were lower AUCs on the Same Day Ex trial for glucose (6%), insulin (20%) and C-peptide (14%). Thus, a single moderate intensity exercise session can acutely improve glycemic control but the effect is modest and short-lived. PMID:22666560

  14. TGF-β in tolerance, development and regulation of immunity

    PubMed Central

    Johnston, Chris J.C.; Smyth, Danielle J.; Dresser, David W.; Maizels, Rick M.

    2016-01-01

    The TGF-β superfamily is an ancient metazoan protein class which cuts across cell and tissue differentiation, developmental biology and immunology. Its many members are regulated at multiple levels from intricate control of gene transcription, post-translational processing and activation, and signaling through overlapping receptor structures and downstream intracellular messengers. We have been interested in TGF-β homologues firstly as key players in the induction of immunological tolerance, the topic so closely associated with Ray Owen. Secondly, our interests in how parasites may manipulate the immune system of their host has also brought us to study the TGF-β pathway in infections with longlived, essentially tolerogenic, helminth parasites. Finally, within the spectrum of mammalian TGF-β proteins is an exquisitely tightly-regulated gene, anti-Müllerian hormone (AMH), whose role in sex determination underpins the phenotype of freemartin calves that formed the focus of Ray’s seminal work on immunological tolerance. PMID:26617281

  15. Development of LWR Fuels with Enhanced Accident Tolerance

    SciTech Connect

    Lahoda, Edward J.; Boylan, Frank A.

    2015-10-30

    Significant progress was made on the technical, licensing, and business aspects of the Westinghouse Electric Company’s Enhanced Accident Tolerant Fuel (ATF) by the Westinghouse ATF team. The fuel pellet options included waterproofed U15N and U3Si2 and the cladding options SiC composites and zirconium alloys with surface treatments. Technology was developed that resulted in U3Si2 pellets with densities of >94% being achieved at the Idaho National Laboratory (INL). The use of U3Si2 will represent a 15% increase in U235 loadings over those in UO₂ fuel pellets. This technology was then applied to manufacture pellets for 6 test rodlets which were inserted in the Advanced Test Reactor (ATR) in early 2015 in zirconium alloy cladding. The first of these rodlets are expected to be removed in about 2017. Key characteristics to be determined include verification of the centerline temperature calculations, thermal conductivity, fission gas release, swelling and degree of amorphization. Waterproofed UN pellets have achieved >94% density for a 32% U3Si2/68% UN composite pellet at Texas A&M University. This represents a U235 increase of about 31% over current UO2 pellets. Pellets and powders of UO2, UN, and U3Si2the were tested by Westinghouse and Los Alamos National Laboratory (LANL) using differential scanning calorimetry to determine what their steam and 20% oxygen corrosion temperatures were as compared to UO2. Cold spray application of either the amorphous steel or the Ti2AlC was successful in forming an adherent ~20 micron coating that remained after testing at 420°C in a steam autoclave. Tests at 1200°C in 100% steam on coatings for Zr alloy have not been successful, possibly due to the low density of the coatings which allowed steam transport to the base zirconium metal. Significant modeling and testing

  16. Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction

    PubMed Central

    Korjian, Serge; Tricoci, Pierluigi; Daaboul, Yazan; Yee, Megan; Jain, Purva; Alexander, John H.; Steg, P. Gabriel; Lincoff, A. Michael; Kastelein, John J.P.; Mehran, Roxana; D’Andrea, Denise M.; Deckelbaum, Lawrence I.; Merkely, Bela; Zarebinski, Maciej; Ophuis, Ton Oude; Harrington, Robert A.

    2016-01-01

    Background: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein–mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. Methods: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). Results: A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events

  17. Differential regional development of tolerance to increase in dopamine turnover upon repeated neuroleptic administration.

    PubMed

    Scatton, B

    1977-12-15

    Repeated treatment with haloperidol and sulpiride induced tolerance to the increases in homovanillic and dihydroxyphenyl acetic acids in the striatum, nucleus accumbens, tuberculum olfactorium and frontal cortex of the rat. The threshold dose inducing this effect appeared to be lower in the striatum than in the limbic regions. Similar results were found in the frontal cortex by measuring dopamine utilization. Moreover, tolerance developed earlier in the striatum than in the limbic areas. The possible reasons are discussed for the differential development of tolerance in the various DA areas investigated.

  18. Development of Crystal-Tolerant High-Level Waste Glasses

    SciTech Connect

    Matyas, Josef; Vienna, John D.; Schaible, Micah J.; Rodriguez, Carmen P.; Crum, Jarrod V.; Arrigoni, Alyssa L.; Tate, Rachel M.

    2010-12-17

    Twenty five glasses were formulated. They were batched from HLW AZ-101 simulant or raw chemicals and melted and tested with a series of tests to elucidate the effect of spinel-forming components (Ni, Fe, Cr, Mn, and Zn), Al, and noble metals (Rh2O3 and RuO2) on the accumulation rate of spinel crystals in the glass discharge riser of the high-level waste (HLW) melter. In addition, the processing properties of glasses, such as the viscosity and TL, were measured as a function of temperature and composition. Furthermore, the settling of spinel crystals in transparent low-viscosity fluids was studied at room temperature to access the shape factor and hindered settling coefficient of spinel crystals in the Stokes equation. The experimental results suggest that Ni is the most troublesome component of all the studied spinel-forming components producing settling layers of up to 10.5 mm in just 20 days in Ni-rich glasses if noble metals or a higher concentration of Fe was not introduced in the glass. The layer of this thickness can potentially plug the bottom of the riser, preventing glass from being discharged from the melter. The noble metals, Fe, and Al were the components that significantly slowed down or stopped the accumulation of spinel at the bottom. Particles of Rh2O3 and RuO2, hematite and nepheline, acted as nucleation sites significantly increasing the number of crystals and therefore decreasing the average crystal size. The settling rate of ≤10-μm crystal size around the settling velocity of crystals was too low to produce thick layers. The experimental data for the thickness of settled layers in the glasses prepared from AZ-101 simulant were used to build a linear empirical model that can predict crystal accumulation in the riser of the melter as a function of concentration of spinel-forming components in glass. The developed model predicts the thicknesses of accumulated layers quite well, R2 = 0.985, and can be become an efficient tool for the formulation

  19. [Advanced Development for Space Robotics With Emphasis on Fault Tolerance Technology

    NASA Technical Reports Server (NTRS)

    Tesar, Delbert

    1997-01-01

    This report describes work developing fault tolerant redundant robotic architectures and adaptive control strategies for robotic manipulator systems which can dynamically accommodate drastic robot manipulator mechanism, sensor or control failures and maintain stable end-point trajectory control with minimum disturbance. Kinematic designs of redundant, modular, reconfigurable arms for fault tolerance were pursued at a fundamental level. The approach developed robotic testbeds to evaluate disturbance responses of fault tolerant concepts in robotic mechanisms and controllers. The development was implemented in various fault tolerant mechanism testbeds including duality in the joint servo motor modules, parallel and serial structural architectures, and dual arms. All have real-time adaptive controller technologies to react to mechanism or controller disturbances (failures) to perform real-time reconfiguration to continue the task operations. The developments fall into three main areas: hardware, software, and theoretical.

  20. Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice

    PubMed Central

    Muscoli, Carolina; Cuzzocrea, Salvatore; Ndengele, Michael M.; Mollace, Vincenzo; Porreca, Frank; Fabrizi, Francesca; Esposito, Emanuela; Masini, Emanuela; Matuschak, George M.; Salvemini, Daniela

    2007-01-01

    Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, often because chronic opiate therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing side effects. The mechanisms leading to tolerance are poorly understood. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice was consistently associated with the appearance of several tyrosine-nitrated proteins in the dorsal horn of the spinal cord, including the mitochondrial isoform of superoxide (O2–) dismutase, the glutamate transporter GLT-1, and the enzyme glutamine synthase. Furthermore, antinociceptive tolerance was associated with increased formation of several proinflammatory cytokines, oxidative DNA damage, and activation of the nuclear factor poly(ADP-ribose) polymerase. Inhibition of NO synthesis or removal of O2– blocked these biochemical changes and inhibited the development of tolerance, pointing to peroxynitrite (ONOO–), the product of the interaction between O2– and NO, as a signaling mediator in this setting. Indeed, coadministration of morphine with the ONOO– decomposition catalyst, Fe(III) 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin, blocked protein nitration, attenuated the observed biochemical changes, and prevented the development of tolerance in a dose-dependent manner. Collectively, these data suggest a causal role for ONOO– in pathways culminating in antinociceptive tolerance to opiates. Peroxynitrite (ONOO–) decomposition catalysts may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain. PMID:17975673

  1. The acute temperature tolerance of green sturgeon (Acipenser medirostris) and the effect of environmental salinity.

    PubMed

    Sardella, Brian A; Sanmarti, Enio; Kültz, Dietmar

    2008-10-01

    We investigated the effect of environmental salinity on the upper thermal tolerance of green sturgeon (Acipenser medirostris), a threatened species whose natural habitat is vulnerable to temperature and salinity variation as a result of global climate change. Freshwater (FW)-reared sturgeon were gradually acclimated to salinities representing FW, estuary water (EST), or San Francisco Bay water (BAY) at 18 degrees C, and their critical thermal maximum (CTMax) was measured by increasing temperature 0.3 degrees C/min until branchial ventilation ceased. CTMax was 34.2+/-0.09 degrees C in EST-acclimated fish, with FW- and BAY-acclimated fish CTMax at 33.7+/-0.08 and 33.7+/-0.1 degrees C, respectively. Despite the higher CTMax in EST-acclimated fish, FW-acclimated sturgeon ventilation rate reached a peak that was 2 degrees C higher than EST- and BAY-acclimated groups and had a greater range of temperatures within which they exhibited normal ventilatory function as assessed by Q10 calculation. The osmoregulatory consequences of exposure to near-lethal temperatures were assessed by measuring plasma osmolality and hematocrit, as well as white muscle, brain, and heart tissue water contents. Hematocrit was increased following CTMax exposure, most likely owing to the elevated metabolic demands of temperature increase, and plasma osmolality was significantly increased in EST- and BAY-acclimated fish, which was likely the result of a greater osmotic gradient across the gill as metabolism increased. To our knowledge, this represents the first evidence for an effect of salinity on the upper thermal tolerance of sturgeon, as well as the first investigation of the osmoregulatory consequences of exposure to near-lethal temperatures.

  2. Amino acid mixture acutely improves the glucose tolerance of healthy overweight adults.

    PubMed

    Wang, Bei; Kammer, Lynne M; Ding, Zhenping; Lassiter, David G; Hwang, Jungyun; Nelson, Jeffrey L; Ivy, John L

    2012-01-01

    Certain amino acids have been reported to influence carbohydrate metabolism and blood glucose clearance, as well as improve the glucose tolerance in animal models. We hypothesized that an amino acid mixture consisting of isoleucine and 4 additional amino acids would improve the glucose response of healthy overweight men and women to an oral glucose tolerance test (OGTT). Twenty-two overweight healthy subjects completed 2 OGTTs after consuming 2 different test beverages. The amino acid mixture beverage (CHO/AA) consisted of 0.088 g cystine 2HCl, 0.043 g methionine, 0.086 g valine, 12.094 g isoleucine, 0.084 g leucine, and 100 g dextrose. The control beverage (CHO) consisted of 100 g dextrose only. Venous blood samples were drawn 10 minutes before the start of ingesting the drinks and 15, 30, 60, 120, and 180 minutes after the completion of the drinks. During the OGTT, the plasma glucose response for the CHO/AA treatment was significantly lower than that of the CHO treatment (P < .01), as was the plasma glucose area under the curve (CHO/AA 806 ± 31 mmol/L·3 hours vs CHO 942 ± 40 mmol/L·3 hours). Differences in plasma glucose between treatments occurred at 30, 60, 120, and 180 minutes after supplement ingestion. Plasma glucagon during the CHO/AA treatment was significantly higher than during the CHO treatment. However, there were no significant differences in plasma insulin or C-peptide responses between treatments. These results suggest that the amino acid mixture lowers the glucose response to an OGTT in healthy overweight subjects in an insulin-independent manner.

  3. A Study on the Development of the Tendency to Tolerance Scale and an Analysis of the Tendencies of Primary School Students to Tolerance through Certain Variables

    ERIC Educational Resources Information Center

    Caliskan, Huseyin; Saglam, Halil Ibrahim

    2012-01-01

    The purpose of this study is to develop the Tendency to Tolerance Scale and to analyze the tendencies of primary school students to tolerance through certain variables. The population of the study was comprised of 899 students who studied at five different primary schools located in Sakarya. The exploratory factor analysis yielded an 18-item…

  4. Integrating metabolic performance, thermal tolerance, and plasticity enables for more accurate predictions on species vulnerability to acute and chronic effects of global warming.

    PubMed

    Magozzi, Sarah; Calosi, Piero

    2015-01-01

    Predicting species vulnerability to global warming requires a comprehensive, mechanistic understanding of sublethal and lethal thermal tolerances. To date, however, most studies investigating species physiological responses to increasing temperature have focused on the underlying physiological traits of either acute or chronic tolerance in isolation. Here we propose an integrative, synthetic approach including the investigation of multiple physiological traits (metabolic performance and thermal tolerance), and their plasticity, to provide more accurate and balanced predictions on species and assemblage vulnerability to both acute and chronic effects of global warming. We applied this approach to more accurately elucidate relative species vulnerability to warming within an assemblage of six caridean prawns occurring in the same geographic, hence macroclimatic, region, but living in different thermal habitats. Prawns were exposed to four incubation temperatures (10, 15, 20 and 25 °C) for 7 days, their metabolic rates and upper thermal limits were measured, and plasticity was calculated according to the concept of Reaction Norms, as well as Q10 for metabolism. Compared to species occupying narrower/more stable thermal niches, species inhabiting broader/more variable thermal environments (including the invasive Palaemon macrodactylus) are likely to be less vulnerable to extreme acute thermal events as a result of their higher upper thermal limits. Nevertheless, they may be at greater risk from chronic exposure to warming due to the greater metabolic costs they incur. Indeed, a trade-off between acute and chronic tolerance was apparent in the assemblage investigated. However, the invasive species P. macrodactylus represents an exception to this pattern, showing elevated thermal limits and plasticity of these limits, as well as a high metabolic control. In general, integrating multiple proxies for species physiological acute and chronic responses to increasing

  5. Development of Novel Glyphosate-Tolerant Japonica Rice Lines: A Step Toward Commercial Release

    PubMed Central

    Cui, Ying; Huang, Shuqing; Liu, Ziduo; Yi, Shuyuan; Zhou, Fei; Chen, Hao; Lin, Yongjun

    2016-01-01

    Glyphosate is the most widely used herbicide for its low cost and high efficiency. However, it is rarely applied directly in rice field due to its toxicity to rice. Therefore, glyphosate-tolerant rice can greatly decrease the cost of rice production and provide a more effective weed management strategy. Although, several approaches to develop transgenic rice with glyphosate tolerance have been reported, the agronomic performances of these plants have not been well evaluated, and the feasibility of commercial production has not been confirmed yet. Here, a novel glyphosate-tolerant gene cloned from the bacterium Isoptericola variabilis was identified, codon optimized (designated as I. variabilis-EPSPS*), and transferred into Zhonghua11, a widely used japonica rice cultivar. After systematic analysis of the transgene integration via PCR, Southern blot and flanking sequence isolation, three transgenic lines with only one intact I. variabilis-EPSPS* expression cassette integrated into intergenic regions were identified. Seed test results showed that the glyphosate tolerance of the transgenic rice was about 240 times that of wild type on plant medium. The glyphosate tolerance of transgenic rice lines was further evaluated based on comprehensive agronomic performances in the field with T3 and T5generations in a 2-year assay, which showed that they were rarely affected by glyphosate even when the dosage was 8400 g ha−1. To our knowledge, this is the first demonstration of the development of glyphosate-tolerant rice lines based on a comprehensive analysis of agronomic performances in the field. Taken together, the results suggest that the selected glyphosate-tolerant rice lines are highly tolerant to glyphosate and have the possibility of commercial release. I. variabilis-EPSPS* also can be a promising candidate gene in other species for developing glyphosate-tolerant crops. PMID:27625652

  6. Development of Novel Glyphosate-Tolerant Japonica Rice Lines: A Step Toward Commercial Release.

    PubMed

    Cui, Ying; Huang, Shuqing; Liu, Ziduo; Yi, Shuyuan; Zhou, Fei; Chen, Hao; Lin, Yongjun

    2016-01-01

    Glyphosate is the most widely used herbicide for its low cost and high efficiency. However, it is rarely applied directly in rice field due to its toxicity to rice. Therefore, glyphosate-tolerant rice can greatly decrease the cost of rice production and provide a more effective weed management strategy. Although, several approaches to develop transgenic rice with glyphosate tolerance have been reported, the agronomic performances of these plants have not been well evaluated, and the feasibility of commercial production has not been confirmed yet. Here, a novel glyphosate-tolerant gene cloned from the bacterium Isoptericola variabilis was identified, codon optimized (designated as I. variabilis-EPSPS (*)), and transferred into Zhonghua11, a widely used japonica rice cultivar. After systematic analysis of the transgene integration via PCR, Southern blot and flanking sequence isolation, three transgenic lines with only one intact I. variabilis-EPSPS (*) expression cassette integrated into intergenic regions were identified. Seed test results showed that the glyphosate tolerance of the transgenic rice was about 240 times that of wild type on plant medium. The glyphosate tolerance of transgenic rice lines was further evaluated based on comprehensive agronomic performances in the field with T3 and T5generations in a 2-year assay, which showed that they were rarely affected by glyphosate even when the dosage was 8400 g ha(-1). To our knowledge, this is the first demonstration of the development of glyphosate-tolerant rice lines based on a comprehensive analysis of agronomic performances in the field. Taken together, the results suggest that the selected glyphosate-tolerant rice lines are highly tolerant to glyphosate and have the possibility of commercial release. I. variabilis-EPSPS (*) also can be a promising candidate gene in other species for developing glyphosate-tolerant crops.

  7. Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats.

    PubMed

    Beveridge, T J R; Smith, H R; Porrino, L J

    2013-05-01

    Baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, has been used clinically to treat muscle spasticity, rigidity and pain. More recently, interest in the use of baclofen as an addiction medicine has grown, with promising preclinical cocaine and amphetamine data and demonstrated clinical benefit from alcohol and nicotine studies. Few preclinical investigations, however, have utilized chronic dosing of baclofen, which is important given that tolerance can occur to many of its effects. Thus the question of whether chronic treatment of baclofen maintains the efficacy of acute doses is imperative. The neural substrates that underlie the effects of baclofen, particularly those after chronic treatment, are also not known. In the present study, therefore, rats were treated with either a) vehicle, b) acute baclofen (5 mg/kg) or c) chronic baclofen (5 mg/kg, t.i.d. for 5 days). The effects of acute and chronic baclofen administration, compared to vehicle, were assessed using locomotor activity and changes in brain glucose metabolism (a measure of functional brain activity). Acute baclofen significantly reduced locomotor activity (horizontal and total distance traveled), while chronic baclofen failed to affect locomotor activity. Acute baclofen resulted in significantly lower rates of local cerebral glucose utilization throughout many areas of the brain, including the prefrontal cortex, caudate putamen, septum and hippocampus. The majority of these functional effects, with the exception of the caudate putamen and septum, were absent in animals chronically treated with baclofen. Despite the tolerance to the locomotor and functional effects of baclofen following repeated treatment, these persistent effects on functional activity in the caudate putamen and septum may provide insights into the way in which baclofen alters the reinforcing effects of abused substances such as cocaine, alcohol, and methamphetamine both in humans and animal models.

  8. Effects of acute NH3 air pollution on N-sensitive and N-tolerant lichen species.

    PubMed

    Paoli, Luca; Maslaňáková, Ivana; Grassi, Alice; Bačkor, Martin; Loppi, Stefano

    2015-12-01

    Lichens are sensitive to the presence of ammonia (NH3) in the environment. However, in order to use them as reliable indicators in biomonitoring studies, it is necessary to establish unequivocally the occurrence of certain symptoms following the exposure to NH3 in the environment. In this paper, we simulated an episode of acute air pollution due to the release of NH3. The biological effects of acute air pollution by atmospheric NH3 have been investigated using N-sensitive (Flavoparmelia caperata) and N-tolerant (Xanthoria parietina) species. Lichen samples were exposed to ecologically relevant NH3 concentrations for 8 weeks, simulating three areas of impact: a control area (2 μg/m(3)), an area of intermediate impact (2-35 μg/m(3)) and an area of high impact (10-315 μg/m(3)), with a peak of pollution reached between the fourth and fifth week. Ammonia affected both the photobiont and the mycobiont in F. caperata, while in X. parietina only the photosynthetic performance of the photobiont was altered after exposure to the highest concentration. In the photobiont of F. caperata we recorded chlorophyll degradation as indicated by OD435/415 ratio, decrease of the photosynthetic performance (as reflected by the maximum quantum yield of primary photochemistry FV/FM and the performance index PIABS); in the mycobiont, ergosterol reduction, membrane lipid peroxidation (as reflected by the increase of thiobarbituric acid reactive substances), alteration (decrease) of the secondary metabolite usnic acid. No effects were detected on caperatic acid and dehydrogenase activity. In X. parietina, the only signal determined by NH3 was the alteration of FV/FM and the performance index PIABS. The results suggest that physiological parameters in N-sensitive lichens well reflect the effects of NH3 exposure and can be applied as early indicators in monitoring studies.

  9. Carbohydrate and carbon metabolite accumulation responses in leaves of ozone tolerant and ozone susceptible spinach plants after acute ozone exposure.

    PubMed

    Robinson, J M; Rowland, R A

    1996-11-01

    The objective of this study was to determine whether exposure of plants to ozone (O3) increased the foliar levels of glucose, glucose sources, e.g., sucrose and starch, and glucose-6-phosphate (G6P), because in leaf cells, glucose is the precursor of the antioxidant, L-ascorbate, and glucose-6-phosphate is a source of NADPH needed to support antioxidant capacity. A further objective was to establish whether the response of increased levels of glucose, sucrose, starch and G6P in leaves could be correlated with a greater degree of plant tolerance to O3. Four commercially available Spinacia oleracea varieties were screened for tolerance or susceptibility to detrimental effects of O3 employing one 6.5 hour acute exposure to 25O nL O3 L(-1) air during the light. One day after the termination of ozonation (29 d post emergence), leaves of the plants were monitored both for damage and for gas exchange characteristics. Cultivar Winter Bloomsdale (cv Winter) leaves were least damaged on a quantitative grading scale. The leaves of cv Nordic, the most susceptible, were approximately 2.5 times more damaged. Photosynthesis (Pn) rates in the ozonated mature leaves of cv Winter were 48.9% less, and in cv Nordic, 66.2% less than in comparable leaves of their non-ozonated controls. Stomatal conductance of leaves of ozonated plants was found not to be a factor in the lower Pn rates in the ozonated plants. At some time points in the light, leaves of ozonated cv Winter plants had significantly higher levels of glucose, sucrose, starch, G6P, G1P, pyruvate and malate than did leaves of ozonated cv Nordic plants. It was concluded that leaves of cv Winter displayed a higher tolerance to ozone mediated stress than those of cv Nordic, in part because they had higher levels of glucose and G6P that could be mobilized during diminished photosynthesis to generate antioxidants (e.g., ascorbate) and reductants (e.g., NADPH). Elevated levels of both pyruvate and malate in the leaves of ozonated cv

  10. Attenuation of a radiation-induced conditioned taste aversion after the development of ethanol tolerance

    SciTech Connect

    Hunt, W.A.; Rabin, B.M.

    1988-01-01

    An attempt to reduce a radiation-induced conditioned taste aversion (CTA) was undertaken by rendering animals tolerant to ethanol. Ethanol tolerance, developed over 5 days, was sufficient to block a radiation-induced taste aversion, as well as an ethanol-induced CTA. Several intermittent doses of ethanol, which did not induce tolerance but removed the novelty of the conditioning stimulus, blocked an ethanol-induced CTA but not the radiation-induced CTA. A CTA induced by doses of radiation up to 500 rads was attenuated. These data suggest that radioprotection developing in association with ethanol tolerance is a result of a physiological response to the chronic presence of ethanol not to the ethanol itself.

  11. Long-term consequences of chemotherapeutic agents on hematopoiesis: development of altered radiation tolerance.

    PubMed

    Kovacs, C J; Evans, M J; Hooker, J L; Johnke, R M

    1988-01-01

    The long-term effects of chemotherapeutic agents on subsequent radiation tolerance of the hematopoietic marrow were studied after a single injection of doxorubicin, 5-fluorouracil, or cyclophosphamide at a maximum tolerated dose. At designated intervals following drug treatment, drug-treated and age-matched control male B6D2F1 mice were exposed to 4.5 Gy of total-body irradiation, and the recovery kinetics of the stem cell (assayed at days 8 and 13 colony-forming spleen units) and progenitor (burst-forming erythroid units, and colony-forming erythroid and granulocyte/macrophage units) compartments were established. Response deficits were calculated for each compartment by comparison of treated and control recovery curves at 5 intervals over 32 weeks. Based on these response deficits, a number of conclusions were drawn: 1) There is selective drug specificity for the more primitive (13d) and mature (8d) CFUs subpopulations; 2) these sensitivities determine the temporal consequences of drug treatment on subsequent radiation tolerance in the marrow (e.g., acute, delayed, or long term); and 3) drugs that influence long-term radiation tolerance of the marrow are dose dependent and initially affect the more primitive stem cells. The data suggest that the initial lesion in the stem cell compartment, resulting in long-term enhancement of radiosensitivity, involves a major restriction (either in cell number or in genetic functionality) of the proliferative potential necessary for recovery from subsequent radiation insult.

  12. Development of Carbon and Sulphur Tolerant Anodes of Solid Oxide Fuel Cells

    DTIC Science & Technology

    2010-01-14

    ABSTRACT  The objective of the project is to develop carbon and sulfur tolerant anodes of solid oxide fuel cells ( SOFCs ). Due to the complicity...LSCM/YSZ) composite anode is investigated in detail for the direct utilization of ethanol and methane (the main component of natural gas) in SOFCs ...demonstrate that the Pd-impregnated LSCM/YSZ composite is a promising carbon-tolerant anode for natural gas fuel-based SOFCs . The electrochemical

  13. Preclinical animal acute toxicity studies of new developed MRI contrast agent based on gadolinium

    NASA Astrophysics Data System (ADS)

    Nam, I. F.; Zhuk, V. V.

    2015-04-01

    Acute toxicity test of new developed MRI contrast agent based on disodium salt of gadopentetic acid complex were carried out on Mus musculus and Sprague Dawley rats according to guidelines of preclinical studies [1]. Groups of six animals each were selected for experiment. Death and clinical symptoms of animals were recorded during 14 days. As a result the maximum tolerated dose (MTD) for female mice is 2.8 mM/kg of body weight, male mice - 1.4 mM/kg, female rats - 2.8 mM/kg, male rats - 5.6 mM/kg of body weight. No Observed Adverse Effect Dose (NOAEL) for female mice is 1.4 mM/kg, male mice - 0.7 mM/kg, male and female rats - 0.7 mM/kg. According to experimental data new developed MRI contrast agent based on Gd-DTPA complex is low-toxic.

  14. CO2-O2 Interactions in Extension of Tolerance to Acute Hypoxia

    NASA Technical Reports Server (NTRS)

    Lambertsen, C. J.; Gelfand, R.

    1996-01-01

    Advantageous and/or detrimental influences associated with purposeful deviations from atmospheric levels of O2 and CO2 are studied. Specific goals have been directed to simulating situations of emergency or accidental exposure to hypoxic (10% O2) environments. They included establishing dynamic effects of hypoxia with and without CO2 (rate of acute adaptation), and stable-state (equilibrium) effects on blood and brain oxygenation. They also included effects on the physiological parameters of respiration and blood gas composition which underlie brain oxygenation. For 10% O2, a complete experiment consisted of three identical rest-exercise phases of 32 minutes duration. Following a five minute air control period, each inspired gas was administered over the next 27 minutes. The test gases were room air control, 10% +/- 0.1% O2 with 4% +/- 0.1% CO2, and 10% +/- 0.1% O2. A minimum of 45 minutes separated each phase. Relative to inspiration of 10% O2, brain oxygenation is enhanced by addition of 4% CO2. This is accomplished by increasing the rate at which O2 in arterial blood is supplied to the brain circulation (well above even the normoxic level), and on relative improvement in the arterial pressure of O2.

  15. CO2-O2 interactions in extension of tolerance to acute hypoxia

    NASA Technical Reports Server (NTRS)

    Lambertsen, C. J.

    1995-01-01

    Objectives and results of experimental projects a re summarized. The scope of information desired included (1) physiological and performance consequences of exposures to simulated microgravity, in rest and graded physical activity, (2) separate influences of graded degrees of atmospheric hypercapnia and hypoxia, and (3) composite effects of hypoxia and hypercapnia. The research objectives were selected for close relevance to existing quantitative information concerning interactions of hypercapnia and hypoxia on respiratory and brain circulatory control. They include: (1) to determine influences of normoxic immersion on interrelations of pulmonary ventilation, arterial PCO2 and PO2, and brain blood flow, in rest and physical work; (2) to determine influence of normoxic immersion on respiratory reactivity to atmospheric hypercapnia at rest; (3) to determine influence of atmospheric hypoxia on respiratory reactivity to hypercapnia at rest and in work; and (4) to provide physiological baselines of data concerning adaptations in acute exposures to aid in investigation of rates of adaptation or deteriorations in physiological or performance capability during subsequent multi-day exposures. A list of publications related to the present grant period is included along with an appendix describing the Performance Measurement System (human perceptual, cognitive and psychomotor functions).

  16. Does acute lead (Pb) contamination influence membrane fatty acid composition and freeze tolerance in intertidal blue mussels in arctic Greenland?

    PubMed

    Thyrring, Jakob; Juhl, Bodil Klein; Holmstrup, Martin; Blicher, Martin E; Sejr, Mikael K

    2015-11-01

    In their natural habitats, organisms are exposed to multiple stressors. Heavy metal contamination stresses the cell membrane due to increased peroxidation of lipids. Likewise, sub-zero air temperatures potentially reduce membrane functionality in ectothermal animals. We tested if acute lead (Pb) exposure for 7 days would influence survival in intertidal blue mussels (Mytilus edulis) after exposure to realistic sub-zero air temperatures. A full factorial experiment with five tissue Pb concentrations between 0 and 3500 μg Pb/g and six sub-zero temperatures from 0 to -17 °C were used to test the hypothesis that sub-lethal effects of Pb may increase the lethality caused by freezing in blue mussels exposed to temperatures simulating Greenland winter conditions. We found a significant effect of temperature on mortality. However, the short-term exposure to Pb did not result in any effects of Pb, nor did we find interactions between Pb and temperature. We analysed the relative abundance of major phospholipid fatty acids (PLFAs) in the gill tissue, but we found no significant effect of Pb tissue concentration on PLFA composition. Results suggest that Pb accumulation has limited effects on freeze tolerance and does not induce membrane damage in terms of persistent lipid peroxidation.

  17. Overview of the U.S. DOE Accident Tolerant Fuel Development Program

    SciTech Connect

    Jon Carmack; Frank Goldner; Shannon M. Bragg-Sitton; Lance L. Snead

    2013-09-01

    The United States Fuel Cycle Research and Development Advanced Fuels Campaign has been given the responsibility to conduct research and development on enhanced accident tolerant fuels with the goal of performing a lead test assembly or lead test rod irradiation in a commercial reactor by 2022. The Advanced Fuels Campaign has defined fuels with enhanced accident tolerance as those that, in comparison with the standard UO2-Zircaloy system currently used by the nuclear industry, can tolerate loss of active cooling in the reactor core for a considerably longer time period (depending on the LWR system and accident scenario) while maintaining or improving the fuel performance during normal operations and operational transients, as well as design-basis and beyond design-basis events. This paper provides an overview of the FCRD Accident Tolerant Fuel program. The ATF attributes will be presented and discussed. Attributes identified as potentially important to enhance accident tolerance include reduced hydrogen generation (resulting from cladding oxidation), enhanced fission product retention under severe accident conditions, reduced cladding reaction with high-temperature steam, and improved fuel-cladding interaction for enhanced performance under extreme conditions. To demonstrate the enhanced accident tolerance of candidate fuel designs, metrics must be developed and evaluated using a combination of design features for a given LWR design, potential improvements to that design, and the design of an advanced fuel/cladding system. The aforementioned attributes provide qualitative guidance for parameters that will be considered for fuels with enhanced accident tolerance. It may be unnecessary to improve in all attributes and it is likely that some attributes or combination of attributes provide meaningful gains in accident tolerance, while others may provide only marginal benefits. Thus, an initial step in program implementation will be the development of quantitative

  18. Development of a New Scale to Measure Ambiguity Tolerance in Veterinary Students.

    PubMed

    Hammond, Jennifer A; Hancock, Jason; Martin, Margaret S; Jamieson, Susan; Mellor, Dominic J

    2017-01-01

    The ability to cope with ambiguity and feelings of uncertainty is an essential part of professional practice. Research with physicians has identified that intolerance of ambiguity or uncertainty is linked to stress, and some authors have hypothesized that there could be an association between intolerance of ambiguity and burnout. We describe the adaptation of the TAMSAD (Tolerance of Ambiguity in Medical Students and Doctors) scale for use with veterinary students. Exploratory factor analysis supports a uni-dimensional structure for the Ambiguity tolerance construct. Although internal reliability of the 29-item TAMSAD scale is reasonable (α=.50), an alternative 27-item scale (drawn from the original 41 items used to develop TAMSAD) shows higher internal reliability for veterinary students (α=.67). We conclude that there is good evidence to support the validity of this latter TAVS (Tolerance of Ambiguity in Veterinary Students) scale to study ambiguity tolerance in veterinary students.

  19. Preliminary data on ASP2215: tolerability and efficacy in acute myeloid leukemia patients.

    PubMed

    Thom, Claire

    2015-09-01

    Claire Thom speaks to Gemma Westcott, Commissioning Editor: Claire Thom joined Astellas in 2013 as the Therapeutic Area Head for Oncology in Global Development. In that role, she also serves as the STAR leader for Oncology for Astellas. Prior to Astellas, she spent 12 years with Takeda. Her last position was Senior Vice President, Portfolio Management, Drug Development Management and Medical Informatics and Strategic Operations within the Medical Division (the Division within Millennium responsible for oncology clinical drug development within Takeda). During her 4 years at Millennium, at various times, she had responsibility within the Medical Division for leading portfolio management, business operations (medical finance, annual and mid-range financial planning, space planning and operations, headcount resourcing, development goals process), clinical development operations (clinical operations, programming, data management, statistics, medical writing, clinical outsourcing), drug development management (project management), medical informatics (technology support for the division) and the strategic project management office for the division. Prior to joining Millennium, Claire Thom spent 18 months working in Osaka, Japan, during which she was responsible for developing the oncology strategy for Takeda that culminated in the acquisition of Millennium. Before going to Japan, she held positions of varying responsibility within the Takeda US development organization including the management of regulatory affairs, safety, biometrics and data management, clinical research and quality assurance. Claire Thom has particular expertise in organizational design and efficiency; she has successfully worked through integrations across multiple functions and redesigned business processes. She has a PharmD from University of Illinois (IL, USA) and over 20 years of pharmaceutical experience including positions in medical affairs and new product planning (over 11 years at Searle

  20. Minocycline can delay the development of morphine tolerance, but cannot reverse existing tolerance in the maintenance period of neuropathic pain in rats.

    PubMed

    Zhang, Xin; Wang, Jing; Yu, Tingting; Du, Dongping; Jiang, Wei

    2015-01-01

    Neuropathic pain is a challenge for physicians and basic science researchers, because it often does not respond to routine treatment. The administration of morphine has been considered one of the effective recommended treatments, but its wide application is limited because of the development of antinociceptive tolerance. In general, basic science studies focus on neuropathic pain and morphine tolerance separately. However, we tried to investigate the effect of microglial activation on morphine tolerance in spinal nerve ligation (SNL) rats during the maintenance period of neuropathic pain. This study produced the following results. The morphine tolerance model in neuropathic pain was established by repeated administration of morphine twice daily (10 mg/kg s.c) in the maintenance period of SNL rats. Minocycline, the microglial activation inhibitor, was given once daily (30 mg/kg, i.p.) at different time-points. The CD11b protein level was measured by western blot to monitor microglial activation. Rats' mechanical allodynia was assessed using the 50% paw withdrawal threshold, and the tail antinociception was determined using the percentage of the maximal possible antinociceptive effect. First, the repeated administration of morphine induced the development of antinociceptive tolerance during the maintenance period of neuropathic pain. Second, during the development of morphine tolerance, microglial activation, which is related to the analgesic effect of morphine, decreased in the first few days, but this pattern was reversed in the following days with the development of morphine tolerance. Third, the repeated administration of minocycline, a microglial activation inhibitor, did not influence the antinociceptive effect of a single dose of morphine. Fourth, the pre-administration of minocycline can delay the development of morphine tolerance, but repeated minocycline administration cannot reverse existing morphine tolerance. We concluded that microglial activation

  1. Development and assessment of the disposition index based on the oral glucose tolerance test in subjects with different glycaemic status.

    PubMed

    Santos, J L; Yévenes, I; Cataldo, L R; Morales, M; Galgani, J; Arancibia, C; Vega, J; Olmos, P; Flores, M; Valderas, J P; Pollak, F

    2016-06-01

    Insulin secretion and insulin sensitivity indexes are related by hyperbolic functions, allowing the calculation of the disposition index (DI) as the product of the acute insulin response (AIR) and the insulin sensitivity index (Si) from intravenous glucose tolerance test (IVGTT). Our objective was to develop an oral-DI based on the oral glucose tolerance test (OGTT) and to assess its association with glucose tolerance status. This research is structured in three studies. Study 1: OGTT were performed in 833 non-diabetic Chilean women (18-60 years) without family history of diabetes mellitus. Study 2: an independent group of n = 57 non-diabetic (18-46 years) without family history of diabetes mellitus carried out an OGTT and an abbreviated IVGTT. Study 3: a sample of 1674 Chilean adults (18-60 years) with different glycaemic status performed an OGTT. An adequate statistical fit for a rectangular hyperbola was found between the area under the curve of insulin-to-glucose ratio (AUCI/G-R) and the Matsuda ISI-COMP index (study 1). The oral-DI derived as AUCI/G-R × ISI-COMP was previously termed insulin-secretion-sensitivity index-2 (ISSI-2). ISSI-2 significantly correlated with DI from IVGTT (rho = 0.34; p = 0.009) (study 2). ISSI-2 shows important differences across groups of subjects with different glycaemic status (study 3). We have confirmed that ISSI-2 replicates the mathematical properties of DI, showing significant correlations with DI from the abbreviated MM-IVGTT. These results indicate that ISSI-2 constitutes a surrogate measure of insulin secretion relative to insulin sensitivity and emphasizes the pivotal role of impaired insulin secretion in the development of glucose homeostasis dysregulation.

  2. A strategic plan to accelerate development of acute stroke treatments.

    PubMed

    Marler, John R

    2012-09-01

    In order to reenergize acute stroke research and accelerate the development of new treatments, we need to transform the usual design and conduct of clinical trials to test for small but significant improvements in effectiveness, and treat patients as soon as possible after stroke onset when treatment effects are most detectable. This requires trials that include thousands of acute stroke patients. A plan to make these trials possible is proposed. There are four components: (1) free access to the electronic medical record; (2) a large stroke emergency network and clinical trial coordinating center connected in real time to hundreds of emergency departments; (3) a clinical trial technology development center; and (4) strategic leadership to raise funds, motivate clinicians to participate, and interact with politicians, insurers, legislators, and other national and international organizations working to advance the quality of stroke care.

  3. 77 FR 61417 - Guidance for Industry on Acute Bacterial Sinusitis: Developing Drugs for Treatment; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-09

    ...: Developing Drugs for Treatment; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice... entitled ``Acute Bacterial Sinusitis: Developing Drugs for Treatment.'' This guidance addresses FDA's... an indication for the treatment of acute bacterial sinusitis (ABS). This guidance finalizes...

  4. Acute myeloid leukaemia: optimal management and recent developments.

    PubMed

    Villela, Luis; Bolaños-Meade, Javier

    2011-08-20

    The current treatment of patients with acute myeloid leukaemia yields poor results, with expected cure rates in the order of 30-40% depending on the biological characteristics of the leukaemic clone. Therefore, new agents and schemas are intensively studied in order to improve patients' outcomes. This review summarizes some of these new paradigms, including new questions such as which anthracycline is most effective and at what dose. High doses of daunorubicin have shown better responses in young patients and are well tolerated in elderly patients. Monoclonal antibodies are promising agents in good risk patients. Drugs blocking signalling pathways could be used in combination with chemotherapy or in maintenance with promising results. Epigenetic therapies, particularly after stem cell transplantation, are also discussed. New drugs such as clofarabine and flavopiridol are reviewed and the results of their use discussed. It is clear that many new approaches are under study and hopefully will be able to improve on the outcomes of the commonly used '7+3' regimen of an anthracycline plus cytarabine with daunorubicin, which is clearly an ineffective therapy in the majority of patients.

  5. HLW Glass Studies: Development of Crystal-Tolerant HLW Glasses

    SciTech Connect

    Matyas, Josef; Huckleberry, Adam R.; Rodriguez, Carmen P.; Lang, Jesse B.; Owen, Antionette T.; Kruger, Albert A.

    2012-04-02

    In our study, a series of lab-scale crucible tests were performed on designed glasses of different compositions to further investigate and simulate the effect of Cr, Ni, Fe, Al, Li, and RuO2 on the accumulation rate of spinel crystals in the glass discharge riser of the HLW melter. The experimental data were used to expand the compositional region covered by an empirical model developed previously (Matyáš et al. 2010b), improving its predictive performance. We also investigated the mechanism for agglomeration of particles and impact of agglomerates on accumulation rate. In addition, the TL was measured as a function of temperature and composition.

  6. Progress towards developing neutron tolerant magnetostrictive and piezoelectric transducers

    NASA Astrophysics Data System (ADS)

    Reinhardt, Brian; Tittmann, Bernhard; Rempe, Joy; Daw, Joshua; Kohse, Gordon; Carpenter, David; Ames, Michael; Ostrovsky, Yakov; Ramuhalli, Pradeep; Montgomery, Robert; Chien, Hualte; Wernsman, Bernard

    2015-03-01

    Current generation light water reactors (LWRs), sodium cooled fast reactors (SFRs), small modular reactors (SMRs), and next generation nuclear plants (NGNPs) produce harsh environments in and near the reactor core that can severely tax material performance and limit component operational life. To address this issue, several Department of Energy Office of Nuclear Energy (DOE-NE) research programs are evaluating the long duration irradiation performance of fuel and structural materials used in existing and new reactors. In order to maximize the amount of information obtained from Material Testing Reactor (MTR) irradiations, DOE is also funding development of enhanced instrumentation that will be able to obtain in-situ, real-time data on key material characteristics and properties, with unprecedented accuracy and resolution. Such data are required to validate new multi-scale, multi-physics modeling tools under development as part of a science-based, engineering driven approach to reactor development. It is not feasible to obtain high resolution/microscale data with the current state of instrumentation technology. However, ultrasound-based sensors offer the ability to obtain such data if it is demonstrated that these sensors and their associated transducers are resistant to high neutron flux, high gamma radiation, and high temperature. To address this need, the Advanced Test Reactor National Scientific User Facility (ATR-NSUF) is funding an irradiation, led by PSU, at the Massachusetts Institute of Technology Research Reactor to test the survivability of ultrasound transducers. As part of this effort, PSU and collaborators have designed, fabricated, and provided piezoelectric and magnetostrictive transducers that are optimized to perform in harsh, high flux, environments. Four piezoelectric transducers were fabricated with either aluminum nitride, zinc oxide, or bismuth titanate as the active element that were coupled to either Kovar or aluminum waveguides and two

  7. Progress towards developing neutron tolerant magnetostrictive and piezoelectric transducers

    SciTech Connect

    Reinhardt, Brian; Tittmann, Bernhard; Rempe, Joy; Daw, Joshua; Kohse, Gordon; Carpenter, David; Ames, Michael; Ostrovsky, Yakov; Ramuhalli, Pradeep; Montgomery, Robert; Chien, Hualte; Wernsman, Bernard

    2015-03-31

    Current generation light water reactors (LWRs), sodium cooled fast reactors (SFRs), small modular reactors (SMRs), and next generation nuclear plants (NGNPs) produce harsh environments in and near the reactor core that can severely tax material performance and limit component operational life. To address this issue, several Department of Energy Office of Nuclear Energy (DOE-NE) research programs are evaluating the long duration irradiation performance of fuel and structural materials used in existing and new reactors. In order to maximize the amount of information obtained from Material Testing Reactor (MTR) irradiations, DOE is also funding development of enhanced instrumentation that will be able to obtain in-situ, real-time data on key material characteristics and properties, with unprecedented accuracy and resolution. Such data are required to validate new multi-scale, multi-physics modeling tools under development as part of a science-based, engineering driven approach to reactor development. It is not feasible to obtain high resolution/microscale data with the current state of instrumentation technology. However, ultrasound-based sensors offer the ability to obtain such data if it is demonstrated that these sensors and their associated transducers are resistant to high neutron flux, high gamma radiation, and high temperature. To address this need, the Advanced Test Reactor National Scientific User Facility (ATR-NSUF) is funding an irradiation, led by PSU, at the Massachusetts Institute of Technology Research Reactor to test the survivability of ultrasound transducers. As part of this effort, PSU and collaborators have designed, fabricated, and provided piezoelectric and magnetostrictive transducers that are optimized to perform in harsh, high flux, environments. Four piezoelectric transducers were fabricated with either aluminum nitride, zinc oxide, or bismuth titanate as the active element that were coupled to either Kovar or aluminum waveguides and two

  8. PVX-tolerant potato development using a nucleic acid-hydrolyzing recombinant antibody.

    PubMed

    Yang, J-G; Hwang, K-H; Kil, E-J; Park, J; Cho, S; Lee, Y-G; Auh, C-K; Rhee, Y; Lee, S

    2017-01-01

    3D8 scFv, a catalytic recombinant antibody developed in the MRL mouse, exhibits nucleic acid-hydrolyzing activity. Previous studies have demonstrated that tobacco plants harboring 3D8 scFv antibodies showed broad-spectrum resistance to infection by both DNA and RNA viruses. In this study, potatoes were transformed with the 3D8 scFv gene and screened by potato virus X (PVX) challenge. Starting with the T0 and T1 potato lines, PVX-tolerant T1 potatoes were identified in the field and characterized by ELISA and RT-PCR analysis. T2 potatoes were propagated for T3 generation and additional virus challenges in the field, and 44% of the 3D8 scFv T3 transgenic potatoes grown in GMO fields were found to be tolerant to PVX infection. Tubers from PVX-tolerant T3 lines were 60% bigger and 24% heavier, compared with tubers from PVX-susceptible transgenic lines and wild-type potatoes. Three-step virus challenge experiments and molecular characterization techniques were used for plants grown in growth chambers or fields to identify 3D8 scFv-transgenic, PVX-tolerant potatoes. These studies also revealed that the viral tolerance enabled by 3D8 scFv persisted during asexual propagation.

  9. Molecular breeding for developing drought tolerant and disease resistant maize in sub Saharan Africa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The International Maize and Wheat Improvement Center (CIMMYT), in collaboration with public and private partners, is working on developing and disseminating drought tolerant maize for sub Saharan Africa (SSA) using pedigree selection and molecular breeding. In this paper, we provide an overview of ...

  10. Development and analysis of the Software Implemented Fault-Tolerance (SIFT) computer

    NASA Technical Reports Server (NTRS)

    Goldberg, J.; Kautz, W. H.; Melliar-Smith, P. M.; Green, M. W.; Levitt, K. N.; Schwartz, R. L.; Weinstock, C. B.

    1984-01-01

    SIFT (Software Implemented Fault Tolerance) is an experimental, fault-tolerant computer system designed to meet the extreme reliability requirements for safety-critical functions in advanced aircraft. Errors are masked by performing a majority voting operation over the results of identical computations, and faulty processors are removed from service by reassigning computations to the nonfaulty processors. This scheme has been implemented in a special architecture using a set of standard Bendix BDX930 processors, augmented by a special asynchronous-broadcast communication interface that provides direct, processor to processor communication among all processors. Fault isolation is accomplished in hardware; all other fault-tolerance functions, together with scheduling and synchronization are implemented exclusively by executive system software. The system reliability is predicted by a Markov model. Mathematical consistency of the system software with respect to the reliability model has been partially verified, using recently developed tools for machine-aided proof of program correctness.

  11. 75 FR 52755 - Draft Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-27

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Acute Bacterial Skin and Skin... guidance for industry entitled ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for... the development of antimicrobial drugs for the treatment of acute bacterial skin and skin...

  12. Tolerance of developing salmonid eggs and fry to nitrate exposure

    USGS Publications Warehouse

    Kincheloe, John W.; Wedemeyer, Gary A.; Koch, David L.

    1979-01-01

    This paper reports on tests which show significant effects on early salmonid life stages of nitrates at levels commonly found in groundwaters in geographical areas that are influenced by fertilizer application. It has long been known, from fish cultural experience, that in certain site specific locations, chronic problems can be expected with salmonid egg development and early fry mortality. However, fingerlings which survive usually grow normally. A complete explanation is lacking although several environmental factors have been proposed to account for this phenomenon. One, which has so far received little attention, is that nitrate levels in the ground and surface waters of many areas have been increasing significantly over historical background levels. Ammonia, urea, and other potential sources of nitrate can enter natural waters from a variety of sources, such as domestic or industrial sewage, animal feedlots, or seepage and return flows from agricultural lands. The latter may be the largest contributor, since billions of tons of nitrate fertilizers are applied to agricultural crops on a worldwide basis each year. In addition, intensive forest management techniques include the aerial application of nitrate fertilizer to increase the yield of wood products, while range management practices call for use of nitrates to increase forage production. The nitrate that is not taken up by plants ultimately appears in ground or surface waters.

  13. Progress towards developing neutron tolerant magnetostrictive and piezoelectric transducers

    SciTech Connect

    Reinhardt, Brian; Tittmann, Bernhard; Rempe, Joy; Daw, Joshua; Kohse, Gordon; Carpenter, David; Ames, Micheal; Ostrovsky, Yakov; Ramuhalli, Pradeep; Montgomery, Robert; Chien, Hualte; Wernsman, Bernard

    2014-07-01

    Current generation light water reactors (LWRs), sodium cooled fast reactors (SFRs), small modular reactors (SMRs), and next generation nuclear plants (NGNPs) provide harsh environments in and near the core that can severely test material performance and limit their operational life. To address this issue, several Department of Energy Office of Nuclear Energy (DOE-NE) research programs are evaluating the long duration radiation performance of fuels and materials. In To reduce the amount of Material and Test Reactor (MTR) irradiations required, DOE is also funding development of enhanced instrumentation that will be able to obtain data, with unprecedented accuracy and resolution, that are required to validate new multi-scale multiphysics modeling tools . It is not feasible to obtain such data with the current state of instrumentation technology. To address this need, PSU and collaborators have started an experiment to test the potential for utilizing ultrasonic instruments in-pile. Ultrasonic sensors must be resistant to high neutron flux, high gamma radiation, and high temperature. PSU and collaborators have designed, fabricated, and started to irradiate piezoelectric and magnetostrictive transducers designed to perform in such harsh environments. Three piezoelectric transducers were fabricated with aluminum nitride, zinc oxide, and bismuth titanate as the active element. The transducers are coupled kovar and aluminum waveguides of which pulse-echo ultrasonic measurements are made in-situ. Two magnetostrictive transducers were fabricated with Remendur and Arnokrome as the active elements. These devices will be pulsed and monitored in-situ. (1) Selection of candidate sensor materials as well as optimization of test assembly parameters (2) High temperature benchmark testing and (3) initial data from the irradiation will be reported.

  14. Vagotomy affects the development of oral tolerance and increases susceptibility to develop colitis independently of the alpha-7 nicotinic receptor.

    PubMed

    Di Giovangiulio, Martina; Bosmans, Goele; Meroni, Elisa; Stakenborg, Nathalie; Florens, Morgane; Farro, Giovanna; Gomez-Pinilla, Pedro J; Matteoli, Gianluca; Boeckxstaens, Guy

    2016-06-14

    Vagotomy (VGX) increases the susceptibility to develop colitis suggesting a crucial role for the cholinergic anti-inflammatory pathway in the regulation of the immune responses. Since oral tolerance and the generation of regulatory T cells (Tregs) are crucial to preserve mucosal immune homeostasis, we studied the effect of vagotomy and the involvement of α7 nicotinic receptors (α7nAChR) at the steady state and during colitis. Therefore, the development of both oral tolerance and colitis (induced by dextran sulfate sodium (DSS) or via T cell transfer) was studied in vagotomized mice and in α7nAChR(-/-) mice. VGX, but not α7nAChR deficiency, prevented oral tolerance establishment. This effect was associated with reduced Treg conversion in the lamina propria and mesenteric lymphnodes. To the same extent, vagotomized mice, but not α7nAChR(-/-) mice, developed a more severe DSS colitis compared with control mice treated with DSS, associated with a decreased number of colonic Tregs. However, neither VGX nor absence of α7nAChR in recipient mice affected colitis development in the T cell transfer model. In line, deficiency of α7nAChR exclusively in T cells did not influence the development of colitis induced by T cell transfer. Our results indicate a key role for the vagal intestinal innervation in the development of oral tolerance and colitis, most likely by modulating induction of Tregs independently of α7nAChR.

  15. Vagotomy Affects the Development of Oral Tolerance and Increases Susceptibility to Develop Colitis Independently of α-7 Nicotinic Receptor

    PubMed Central

    Di Giovangiulio, Martina; Bosmans, Goele; Meroni, Elisa; Stakenborg, Nathalie; Florens, Morgane; Farro, Giovanna; Gomez-Pinilla, Pedro J; Matteoli, Gianluca; Boeckxstaens, Guy E

    2016-01-01

    Vagotomy (VGX) increases the susceptibility to develop colitis suggesting a crucial role for the cholinergic anti-inflammatory pathway in the regulation of the immune responses. Since oral tolerance and the generation of regulatory T cells (Tregs) are crucial to preserve mucosal immune homeostasis, we studied the effect of vagotomy and the involvement of α7 nicotinic receptors (α7nAChR) at the steady state and during colitis. Therefore, the development of both oral tolerance and colitis (induced by dextran sulfate sodium (DSS) or via T cell transfer) was studied in vagotomized mice and in α7nAChR-/- mice. VGX, but not α7nAChR deficiency, prevented oral tolerance establishment. This effect was associated with reduced Treg conversion in the lamina propria and mesenteric lymphnodes. To the same extent, vagotomized mice, but not α7nAChR-/- mice, developed a more severe DSS colitis compared with control mice treated with DSS, associated with a decreased number of colonic Tregs. However, neither VGX nor absence of α7nAChR in recipient mice affected colitis development in the T cell transfer model. In line, deficiency of α7nAChR exclusively in T cells did not influence the development of colitis induced by T cell transfer. Our results indicate a key role for the vagal intestinal innervation in the development of oral tolerance and colitis, most likely by modulating induction of Tregs independently of α7nAChR. PMID:27341335

  16. Postpartum Acute Liver Dysfunction: A Case of Acute Fatty Liver of Pregnancy Developing Massive Intrahepatic Calcification.

    PubMed

    Bhat, Khalid Javid; Shovkat, Rabia; Samoon, Hamad Jeelani

    2015-12-01

    The function of the liver is particularly affected by the unique physiologic milieu of the pregnancy. Pregnancy-related liver diseases encompass a spectrum of different etiologies that are related to gestation or one of its complications. Hepatic calcification, a rare entity, is usually associated with infectious, vascular, or neoplastic lesions in the liver. To the best of our knowledge, only one case of rapidly occurring pregnancy-related intrahepatic calcification has been documented in a patient with severe eclampsia or hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. Here we present a case of immediate "postpartum" acute fatty liver of pregnancy (AFLP) in a 23-year-old hypertensive primigravida, complicated by acute renal dysfunction who developed dense intrahepatic calcification in less than a month after the initial diagnosis. A multidisciplinary approach for the management was used, to which the patient responded aptly. This case illustrates the first description of intrahepatic calcification in AFLP syndrome and highlights some of the challenges met in making the final diagnosis.

  17. Development of an ADC radiation tolerance characterization system for the upgrade of the ATLAS LAr calorimeter

    NASA Astrophysics Data System (ADS)

    Liu, Hong-Bin; Chen, Hu-Cheng; Chen, Kai; Kierstead, James; Lanni, Francesco; Takai, Helio; Jin, Ge

    2017-02-01

    ATLAS LAr calorimeter will undergo its Phase-I upgrade during the long shutdown (LS2) in 2018, and a new LAr Trigger Digitizer Board (LTDB) will be designed and installed. Several commercial-off-the-shelf (COTS) multi-channel high-speed ADCs have been selected as possible backups of the radiation tolerant ADC ASICs for the LTDB. To evaluate the radiation tolerance of these backup commercial ADCs, we developed an ADC radiation tolerance characterization system, which includes the ADC boards, data acquisition (DAQ) board, signal generator, external power supplies and a host computer. The ADC board is custom designed for different ADCs, with ADC drivers and clock distribution circuits integrated on board. The Xilinx ZC706 FPGA development board is used as a DAQ board. The data from the ADC are routed to the FPGA through the FMC (FPGA Mezzanine Card) connector, de-serialized and monitored by the FPGA, and then transmitted to the host computer through the Gigabit Ethernet. A software program has been developed with Python, and all the commands are sent to the DAQ board through Gigabit Ethernet by this program. Two ADC boards have been designed for the ADC, ADS52J90 from Texas Instruments and AD9249 from Analog Devices respectively. TID tests for both ADCs have been performed at BNL, and an SEE test for the ADS52J90 has been performed at Massachusetts General Hospital (MGH). Test results have been analyzed and presented. The test results demonstrate that this test system is very versatile, and works well for the radiation tolerance characterization of commercial multi-channel high-speed ADCs for the upgrade of the ATLAS LAr calorimeter. It is applicable to other collider physics experiments where radiation tolerance is required as well. Supported by the U. S. Department of Energy (DE-SC001270)

  18. The expressed protein in glyphosate-tolerant soybean, 5-enolpyruvylshikimate-3-phosphate synthase from Agrobacterium sp. strain CP4, is rapidly digested in vitro and is not toxic to acutely gavaged mice.

    PubMed

    Harrison, L A; Bailey, M R; Naylor, M W; Ream, J E; Hammond, B G; Nida, D L; Burnette, B L; Nickson, T E; Mitsky, T A; Taylor, M L; Fuchs, R L; Padgette, S R

    1996-03-01

    The safety of 5-enolpyruvylshikimate-3-phosphate synthase enzyme derived from Agrobacterium sp. strain CP4 (CP4 EPSPS) was assessed. CP4 EPSPS is the only protein introduced by genetic manipulation that is expressed in glyphosate-tolerant soybeans, which are being developed to provide new weed-control options for farmers. Expression of this protein in plants imparts high levels of glyphosate tolerance. The safety of CP4 EPSPS was ascertained by evaluating both physical and functional characteristics. CP4 EPSPS degrades readily in simulated gastric and intestinal fluids, suggesting that this protein will be degraded in the mammalian digestive tract upon ingestion as a component of food or feed, There were no deleterious effects due to the acute administration of CP4 EPSPS to mice by gavage at a high dosage of 572 mg/kg body wt, which exceeds 1000-fold tha anticipated consumption level of food products potentially containing CP4 EPSPS protein. CP4 EPSPS does not pose any important allergen concerns because this protein does not possess characteristics typical of allergenic proteins. These data, in combination with seed compositional analysis and animal feeding studies, support the conclusion that glyphosate-tolerant soybean are as safe and nutritious as traditional soybeans currently being marketed.

  19. Acute pancreatitis: New developments and strategies for the hospitalist.

    PubMed

    Dick, John F; Gardner, Timothy B; Merrens, Edward J

    2016-10-01

    Acute pancreatitis (AP) remains the most common reason for hospital admission of all the gastrointestinal illnesses in the United States. Since the last narrative review in the Journal of Hospital Medicine in 2010, new developments in regard to diagnosis and classification, fluid resuscitation, antibiotic use, nutritional support, and management of complications have helped refine the approach and improve outcomes in this disease. Whereas there is still no proven pharmacologic therapy to specifically combat the inflammatory consequences of AP, recent interventions have led to increased survival, shorter length of stay, and more appropriate transfer criteria for pancreatitis patients. This case-oriented review will highlight these developments and emphasize the primary role of the hospitalist in managing AP over the course of the admission. It will focus on when to coordinate with subspecialists, how to deliver effective yet efficient hospitalized care, and how to optimize appropriate discharge planning. Journal of Hospital Medicine 2016;11:724-729. © 2016 Society of Hospital Medicine.

  20. Development of pressure containment and damage tolerance technology for composite fuselage structures in large transport aircraft

    NASA Technical Reports Server (NTRS)

    Smith, P. J.; Thomson, L. W.; Wilson, R. D.

    1986-01-01

    NASA sponsored composites research and development programs were set in place to develop the critical engineering technologies in large transport aircraft structures. This NASA-Boeing program focused on the critical issues of damage tolerance and pressure containment generic to the fuselage structure of large pressurized aircraft. Skin-stringer and honeycomb sandwich composite fuselage shell designs were evaluated to resolve these issues. Analyses were developed to model the structural response of the fuselage shell designs, and a development test program evaluated the selected design configurations to appropriate load conditions.

  1. Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer’s Disease

    PubMed Central

    Irwin, Ronald W.; Solinsky, Christine M.; Loya, Carlos M.; Salituro, Francesco G.; Rodgers, Kathleen E.; Bauer, Gerhard; Rogawski, Michael A.; Brinton, Roberta Diaz

    2015-01-01

    To develop allopregnanolone as a therapeutic for Alzheimer’s disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The

  2. Ubiquitination pathway as a target to develop abiotic stress tolerance in rice

    PubMed Central

    Dametto, Andressa; Buffon, Giseli; Dos Reis Blasi, Édina Aparecida; Sperotto, Raul Antonio

    2015-01-01

    Abiotic stresses may result in significant losses in rice grain productivity. Protein regulation by the ubiquitin/proteasome system has been studied as a target mechanism to optimize adaptation and survival strategies of plants to different environmental stresses. This article aimed at highlighting recent discoveries about the roles ubiquitination may play in the exposure of rice plants to different abiotic stresses, enabling the development of modified plants tolerant to stress. Responses provided by the ubiquitination process include the regulation of the stomatal opening, phytohormones levels, protein stabilization, cell membrane integrity, meristematic cell maintenance, as well as the regulation of reactive oxygen species and heavy metals levels. It is noticeable that ubiquitination is a potential means for developing abiotic stress tolerant plants, being an excellent alternative to rice (and other cultures) improvement programs. PMID:26236935

  3. Lipophilicity is a critical parameter that dominates the efficacy of metalloporphyrins in blocking the development of morphine antinociceptive tolerance through peroxynitrite mediated pathways

    PubMed Central

    Batinić-Haberle, Ines; Ndengele, Michael M.; Cuzzocrea, Salvatore; Rebouças, Júlio. S.; Spasojević, Ivan; Salvemini, Daniela

    2009-01-01

    Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, partly because reduced analgesic effectiveness with chronic opiate therapy (i.e., tolerance) leads to escalating doses and distressing side effects. Peroxynitrite mediated nitroxidative stress in the dorsal horn of the spinal cord plays a critical role in the induction and development of antinociceptive tolerance to morphine. This provides a valid pharmacological basis for developing peroxynitrite scavengers as potent adjuncts to opiates in the management of pain. The cationic Mn(III) ortho N-alkylpyridylporphyrins, MnTE-2-PyP5+ and MnTnHex-2-PyP5+, are among the most potent peroxynitrite scavengers with nearly identical scavenging rate constants (≫107 M−1 s−1). Yet, MnTnHex-2-PyP5+ is significantly more lipophilic, more bioavailable, and in turn, was 30-fold more effective in blocking the development of morphine antinociceptive tolerance than MnTE-2-PyP5+ using the hot plate test in a well characterized murine model. The hydrophilic MnTE-2-PyP5+ and the lipophilic MnTnHex-2-PyP5+ were 10-fold and 300-fold, respectively, more effective in inhibiting morphine tolerance than hydrophilic Fe(III) porphyrin, FeTM-4-PyP5+. Both Mn porphyrins decreased levels of TNF-α, IL-1β, and IL-6 to normal values. Neither of them affected acute morphine antinociceptive effect nor caused motor function impairment. Also neither was able to reverse already established morphine tolerance. We have recently shown that anionic porphyrin, Mn(III) tetrakis(4-carboxylatophenyl)porphyrin, MnTBAP is selective in removing ONOO− over O2•−, yet at ~ 2 orders of magnitude lower efficacy than MnTE-2-PyP5+ and MnTnHex-2-PyP5+, which in turn parallels up to 100-fold lower ability to reverse morphine tolerance. These data (1) support the role of peroxynitrite rather than superoxide as a major mechanism in blocking the development of morphine tolerance, and (2) show that lipophilicity is a

  4. Safety and tolerance data from the Belgian multicentre study of anisoylated plasminogen streptokinase activator complex versus heparin in acute myocardial infarction.

    PubMed

    Bossaert, L L

    1987-01-01

    In the European Multicentre Study (EMS), the safety and efficacy of a single 30U intravenous injection of anisoylated plasminogen streptokinase activator complex (APSAC) was studied in patients with acute myocardial infarction. The present study discusses the Belgian data on safety and tolerance from the EMS study. 87 patients were randomised to treatment with APSAC or heparin. The reperfusion rate was 60.5% (APSAC) versus 20.5% (heparin control), and reocclusion occurred in 21% of the reperfused APSAC patients. Drug-related adverse events consisted of bleeding problems (7 events in patients on APSAC and 1 event in a patient on heparin and moderate allergic reactions (12 events in 9 patients on APSAC and 1 event in a heparin patient). There was 1 drug-related death in the APSAC group (hypovolaemic shock due to central vein puncture during lytic state) which could have been avoided. It is concluded that thrombolytic treatment of acute myocardial infarction with APSAC is effective and safe, as long as the standard precautions for thrombolytic treatment are respected. Bleeding and allergic-type events are infrequent, usually well tolerated and easily treated.

  5. Road Map for Development of Crystal-Tolerant High Level Waste Glasses

    SciTech Connect

    Matyas, Josef; Vienna, John D.; Peeler, David; Fox, Kevin; Herman, Connie; Kruger, Albert A.

    2014-05-31

    This road map guides the research and development for formulation and processing of crystal-tolerant glasses, identifying near- and long-term activities that need to be completed over the period from 2014 to 2019. The primary objective is to maximize waste loading for Hanford waste glasses without jeopardizing melter operation by crystal accumulation in the melter or melter discharge riser. The potential applicability to the Savannah River Site (SRS) Defense Waste Processing Facility (DWPF) is also addressed in this road map.

  6. Previous Homologous and Heterologous Stress Exposure Induces Tolerance Development to Pulsed Light in Listeria monocytogenes

    PubMed Central

    Heinrich, Victoria; Zunabovic, Marija; Petschnig, Alice; Müller, Horst; Lassenberger, Andrea; Reimhult, Erik; Kneifel, Wolfgang

    2016-01-01

    As one of the emerging non-thermal technologies, pulsed light (PL) facilitates rapid, mild and residue-free microbial surface decontamination of food and food contact materials. While notable progress has been made in the characterization of the inactivation potential of PL, experimental data available on the tolerance development to the same (homologous) stress or to different (heterologous) stresses commonly applied in food manufacturing (e.g., acid, heat, salt) is rather controversial. The findings of the present study clearly indicate that both the homologous tolerance development against PL as well as the heterologous tolerance development from heat to PL can be triggered in Listeria monocytogenes. Further, conducted kinetic analysis confirmed that the conventionally applied log-linear model is not well suited to describe the inactivation of L. monocytogenes, when exposed to PL. Instead, the Weibull model as well as the log-linear + tail model were identified as suitable models. Transmission electron microscopic (TEM) approaches allow suggestions on the morphological alterations in L. monocytogenes cells after being subjected to PL. PMID:27092137

  7. Enhanced development of dispositional tolerance to methadone by desipramine given together with methadone

    SciTech Connect

    Liu, S.J.; Wang, R.I.H.

    1985-02-25

    Rats given 2-day oral administration of methadone (15 mg/kg, twice on day 1 and once on day 2) by gastric tube developed dispositional tolerance to methadone analgesia as demonstrated by a decrease in analgesic response and by an increase in methadone metabolism. The increased metabolism of methadone was evidenced by a decrease in brain concentration of /sup 14/C-methadone and increases in the percentages of total /sup 14/C in liver or urine as /sup 14/C-water-soluble metabolites (/sup 14/C-WSM) after the rats were challenged with a test dose of /sup 14/C-methadone. Two-day pretreatment with a combination of desipramine (DMI) (10 mg/kg, ip) and methadone (15 mg/kg, po) enhanced the development of dispositional tolerance to methadone analgesia which was evidenced by a greater decrease in the brain concentration of methadone and a greater increase in methadone metabolism as compared to those changes in rats pretreated with only methadone. Repeated treatment with DMI alone neither decreased the analgesic effect of methadone nor stimulated methadone metabolism. It is suggested that DMI given together with methadone promoted the induction of methadone metabolism in the liver by prolonging the enzyme-stimulating state of methadone, thus enhancing the development of dispositional tolerance to methadone. 20 references, 1 figure, 1 table.

  8. Repeated Applications of Thoracic Spine Thrust Manipulation do not Lead to Tolerance in Patients Presenting with Acute Mechanical Neck Pain: A Secondary Analysis

    PubMed Central

    Fernández-De-Las-Peñas, Cesar; Cleland, Joshua A; Huijbregts, Peter; Palomeque-Del-Cerro, Luis; González-Iglesias, Javier

    2009-01-01

    It has been demonstrated that patients receiving mobilization techniques do not exhibit tolerance to repeated applications. However, this phenomenon has not been investigated for thoracic manipulation. Our aim was to determine if patients receiving thoracic thrust manipulation exhibit tolerance to repeated applications in acute mechanical neck pain. Forty-five patients were randomly assigned to two groups. The control group received electro- and thermotherapy for 5 sessions, and the experimental group received the same program and also received a thoracic thrust manipulation once a week for 3 consecutive weeks. Outcome measures included neck pain and cervical mobility. Within-session change scores for pain and mobility during treatment sessions #1, 3, and 5 were examined with a one-way repeated measured ANOVA. A 2-way ANOVA with session as within-subject variable and group as between-subject variable was used to compare change scores for each visit between groups to ascertain if there were significant between-group differences in within-session changes for the experimental versus the control group. The ANOVA showed that for either group the 3 within-session change scores were not significantly different (P > 0.1). The 2-way ANOVA revealed significant differences between groups for both pain and neck mobility in within-session change scores (all, P < 0.001). Change scores in each session were superior in the experimental group as compared to those in the control group. The results suggest that patients receiving thoracic manipulation do not exhibit tolerance to repeated applications with regard to pain and mobility measures in acute mechanical neck pain. Further studies should investigate the dose-response relationship of thoracic thrust manipulation in this population. PMID:20046622

  9. Like parent, like child? Development of prejudice and tolerance towards immigrants.

    PubMed

    Miklikowska, Marta

    2016-02-01

    Although intergroup attitudes are assumed to develop due to the influence of parents, there is no longitudinal evidence supporting this claim. In addition, research on socialization of intergroup attitudes has omitted possible effects of adolescents on their parents. We also know little about the conditions under which intergroup attitudes are transmitted. This two-wave, 2 years apart, study of adolescents (N = 507) and their parents examined the relations between parents and adolescents' prejudice and tolerance from a longitudinal perspective. The study tested whether parental prejudice and tolerance would predict over-time changes in adolescents' attitudes and whether adolescents' prejudice and tolerance would elicit changes in parental attitudes. Additionally, it explored whether some of the effects would depend on perceived parental support. Results showed significant bidirectional influences between parents and adolescents' attitudes. In addition, adolescents who perceived their parents as supportive showed higher parent-adolescent correspondence in prejudice than youth with low parental support. These findings show that intergroup attitudes develop as a result of mutual influences between parents and adolescents. Hence, the unidirectional transmission model and previous research findings should be revisited. The results also suggest that parents' prejudice influence adolescents' attitudes to the extent that youth perceive their parents as supportive.

  10. Organic nitrates and nitrate tolerance--state of the art and future developments.

    PubMed

    Daiber, Andreas; Münzel, Thomas; Gori, Tommaso

    2010-01-01

    The hemodynamic and antiischemic effects of nitroglycerin (GTN) are lost upon chronic administration due to the rapid development of nitrate tolerance. The mechanism of this phenomenon has puzzled several generations of scientists, but recent findings have led to novel hypotheses. The formation of reactive oxygen and nitrogen species in the mitochondria and the subsequent inhibition of the nitrate-bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) appear to play a central role, at least for GTN, that is, bioactivated by ALDH-2. Importantly, these findings provide the opportunity to reconcile the two "traditional" hypotheses of nitrate tolerance, that is, the one postulating a decreased bioactivation and the concurrent one suggesting a role of oxidative stress. Furthermore, recent animal and human experimental studies suggest that the organic nitrates are not a homogeneous group but demonstrate a broad diversity with regard to induction of vascular dysfunction, oxidative stress, and other side effects. In the past, attempts to avoid nitrate-induced side effects have focused on administration schedules that would allow a "nitrate-free interval"; in the future, the role of co-therapies with antioxidant compounds and of activation of endogeneous protective pathways such as the heme oxygenase 1 (HO-1) will need to be explored. However, the development of new nitrates, for example, tolerance-free aminoalkyl nitrates or combination of nitrate groups with established cardiovascular drugs like ACE inhibitors or AT(1)-receptor blockers (hybrid molecules) may be of great clinical interest.

  11. Development of Sulfur and Carbon Tolerant Reforming Alloy Catalysts Aided by Fundamental Atomistics Insights

    SciTech Connect

    Suljo Linic

    2006-08-31

    Current hydrocarbon reforming catalysts suffer from rapid carbon and sulfur poisoning. Even though there is a tremendous incentive to develop more efficient catalysts, these materials are currently formulated using inefficient trial and error experimental approaches. We have utilized a novel hybrid experimental/theoretical approach, combining quantum Density Functional Theory (DFT) calculations and various state-of-the-art experimental tools, to formulate carbon tolerant reforming catalysts. We have employed DFT calculations to develop molecular insights into the elementary chemical transformations that lead to carbon poisoning of Ni catalysts. Based on the obtained molecular insights, we have identified, using DFT quantum calculation, Sn/Ni alloy as a potential carbon tolerant reforming catalyst. Sn/Ni alloy was synthesized and tested in steam reforming of methane, propane, and isooctane. We demonstrated that the alloy catalyst is carbon-tolerant under nearly stoichiometric steam-to-carbon ratios. Under these conditions, monometallic Ni is rapidly poisoned by sp2 carbon deposits. The research approach is distinguished by a few characteristics: (a) Knowledge-based, bottom-up approach, compared to the traditional trial and error approach, allows for a more efficient and systematic discovery of improved catalysts. (b) The focus is on exploring alloy materials which have been largely unexplored as potential reforming catalysts.

  12. Development of Sulfur and Carbon Tolerant Reforming Alloy Catalysts Aided Fundamental Atomistic Insights

    SciTech Connect

    Suljo Linic

    2008-12-31

    Current hydrocarbon reforming catalysts suffer from rapid carbon and sulfur poisoning. Even though there is a tremendous incentive to develop more efficient catalysts, these materials are currently formulated using inefficient trial and error experimental approaches. We have utilized a hybrid experimental/theoretical approach, combining quantum Density Functional Theory (DFT) calculations and various state-of-the-art experimental tools, to formulate carbon tolerant reforming catalysts. We have employed DFT calculations to develop molecular insights into the elementary chemical transformations that lead to carbon poisoning of Ni catalysts. Based on the obtained molecular insights, we have identified, using DFT quantum calculation, various Ni alloy catalysts as potential carbon tolerant reforming catalysts. The alloy catalysts were synthesized and tested in steam reforming and partial oxidation of methane, propane, and isooctane. We demonstrated that the alloy catalysts are much more carbon-tolerant than monometallic Ni catalysts under nearly stoichiometric steam-to-carbon ratios. Under these conditions, monometallic Ni is rapidly poisoned by sp2 carbon deposits. The research approach is distinguished by two characteristics: (a) knowledge-based, bottomup approach, compared to the traditional trial and error approach, allows for a more efficient and systematic discovery of improved catalysts. (b) the focus is on exploring alloy materials which have been largely unexplored as potential reforming catalysts.

  13. Brain acetylcholinesterase diurnal variations during the rapid development of tolerance to the hypothermic effect of ethanol

    SciTech Connect

    Wang, O.; Soliman, K.F.A. )

    1991-03-11

    Male Sprague-Dawley rats maintained under controlled environmental conditions were used. Acetylcholinesterase (AChE) activity was determined in the cerebral cortex, midbrain, hypothalamus, hippocampus, cerebellum, pons and medulla oblongata of saline control and ethanol-treated rats, either after a single dose at 06:0 or 18:00h, or after a second dose administered 24 hrs later at the same time scheduled. Results of this experiment indicate that repeated administration with ethanol was associated with the rapid development of tolerance to the hypothermic action of ethanol. A single injection of ethanol at 0600h resulted in a significant decrease in AChE activity in the hypothalamus, medulla, cerebellum, hippocampus and the cortex. However, ethanol administration at 18.00h was associated with significant increases in AChE activity in the same brain regions. The repeated administration of ethanol at 06.00h was associated with tolerance in AChE response to ethanol in the hypothalamus and hippocampus. However, there was no tolerance development in AChE activity in brain regions when ethanol was administered at 18.00h. The results indicate that chronotolerance to ethanol might be related to the brain cholinergic system.

  14. Brain cholinergic involvement during the rapid development of tolerance to morphine

    NASA Technical Reports Server (NTRS)

    Wahba, Z. Z.; Oriaku, E. T.; Soliman, S. F. A.

    1987-01-01

    The effect of repeated administration of morphine on the activities of the cholinergic enzymes, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), in specific brain regions were studied in rats treated with 10 mg/kg morphine for one or two days. Repeated administration of morphine was associated with a decline in the degree of analgesia produced and with a significant increase of AChE activity of the medulla oblongata. A single injection of morphine resulted in a significant decline in ChAT activity in the hypothalamus, cerebellum, and medulla oblongata regions. After two consecutive injections, no decline in ChAT was observed in these regions, while in the cerebral cortex the second administration elicited a significant decline. The results suggest that the development of tolerance to morphine may be mediated through changes in ChAT activity and lend support to the involvement of the central cholinergic system in narcotic tolerance.

  15. siRNA capsulated brain-targeted nanoparticles specifically knock down OATP2B1 in mice: a mechanism for acute morphine tolerance suppression

    PubMed Central

    Yang, Zi-Zhao; Li, Li; Wang, Lu; Xu, Ming-Cheng; An, Sai; Jiang, Chen; Gu, Jing-Kai; Wang, Zai-Jie Jim; Yu, Lu-Shan; Zeng, Su

    2016-01-01

    Regulating main brain-uptake transporter of morphine may restrict its tolerance generation, then modify its antinociception. In this study, more than 2 fold higher intracellular uptake concentrations for morphine and morphine-6-glucuronide (M6G) were observed in stable expression cells, HEK293-hOATP2B1 than HEK293-MOCK. Specifically, the Km value of morphine to OATP2B1 (57.58 ± 8.90 μM) is 1.4-time more than that of M6G (80.31 ± 21.75 μM); Cyclosporine A (CsA), an inhibitor of OATP2B1, can inhibit their intracellular accumulations with IC50 = 3.90 ± 0.50 μM for morphine and IC50 = 6.04 ± 0.86 μM for M6G, respectively. To further investigate the role of OATP2B1 in morphine brain transport and tolerance, the novel nanoparticles of DGL-PEG/dermorphin capsulated siRNA (OATP2B1) were applied to deliver siRNA into mouse brain. Along with OATP2B1 depressed, a main reduction was found for each of morphine or M6G in cerebrums or epencephalons of acute morphine tolerance mice. Furthermore, calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) in mouse prefrontal cortex (mPFC) underwent dephosphorylation at Thr286. In conclusion, OATP2B1 downregulation in mouse brain can suppress tolerance via blocking morphine and M6G brain transport. These findings might help to improve the pharmacological effects of morphine. PMID:27629937

  16. Rapid Crown Root Development Confers Tolerance to Zinc Deficiency in Rice

    PubMed Central

    Nanda, Amrit K.; Wissuwa, Matthias

    2016-01-01

    Zinc (Zn) deficiency is one of the leading nutrient disorders in rice (Oryza sativa). Many studies have identified Zn-efficient rice genotypes, but causal mechanisms for Zn deficiency tolerance remain poorly understood. Here, we report a detailed study of the impact of Zn deficiency on crown root development of rice genotypes, differing in their tolerance to this stress. Zn deficiency delayed crown root development and plant biomass accumulation in both Zn-efficient and inefficient genotypes, with the effects being much stronger in the latter. Zn-efficient genotypes had developed new crown roots as early as 3 days after transplanting (DAT) to a Zn deficient field and that was followed by a significant increase in total biomass by 7 DAT. Zn-inefficient genotypes developed few new crown roots and did not increase biomass during the first 7 days following transplanting. This correlated with Zn-efficient genotypes retranslocating a higher proportion of shoot-Zn to their roots, compared to Zn-inefficient genotypes. These latter genotypes were furthermore not efficient in utilizing the limited Zn for root development. Histological analyses indicated no anomalies in crown tissue of Zn-efficient or inefficient genotypes that would have suggested crown root emergence was impeded. We therefore conclude that the rate of crown root initiation was differentially affected by Zn deficiency between genotypes. Rapid crown root development, following transplanting, was identified as a main causative trait for tolerance to Zn deficiency and better Zn retranslocation from shoot to root was a key attribute of Zn-efficient genotypes. PMID:27066060

  17. Approaches to prevent acute bacterial meningitis in developing countries.

    PubMed Central

    Wright, P. F.

    1989-01-01

    Endemic acute bacterial meningitis of childhood appears to be neglected as a cause of morbidity and mortality in developing countries, probably because it has been overshadowed by the dramatic epidemics of meningococcal disease in sub-Saharan Africa. The available data based on reviews of hospitalized patients suggest that endemic meningitis is mostly a disease of young infants, Streptococcus pneumoniae and Haemophilus influenzae type b being the most important etiologic agents. The epidemiological pattern appears to be different in developing countries, compared with northern Europe or the USA, and closely resembles the early age of onset and high incidence of meningitis observed among the native American populations in Alaska. The mortality from meningitis appears to be much higher in developing countries than in industrialized countries. The availability of vaccines against the pneumococcus and haemophilus, particularly those in which the bacterial polysaccharide is conjugated to a protein, promises protection against systemic bacterial infection from these organisms. The assessment of the efficacy of such vaccines will have to include a close examination of meningitis as an outcome. It is suggested that before such vaccines become available careful clinical and epidemiological studies of meningitis will help both to define the impact of this disease and how to design an intervention strategy. PMID:2611973

  18. Development of a Lubricant Therapy to Prevent Development of Osteoarthritis after Acute Injury of Synovial Joints

    DTIC Science & Technology

    2015-10-01

    AD______________ AWARD NUMBER: W81XWH-14-1-0562 TITLE: Development of a Lubricant Therapy to Prevent Development of Osteoarthritis after Acute...Injury of Synovial Joints PRINCIPAL INVESTIGATOR: Robert L. Sah RECIPIENT: Dr. Prem Yadav, Ph.D. REPORT DATE: October 2015 TYPE OF REPORT...PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE October 2015 2. REPORT TYPE Annual 3. DATES COVERED 30 Sep 2014 - 29 Sep 2015 4

  19. Prenatal allospecific NK cell tolerance hinges on instructive allorecognition through the activating receptor during development

    PubMed Central

    Alhajjat, Amir M.; Strong, Beverly S.; Lee, Amanda E.; Turner, Lucas E.; Wadhwani, Ram K.; Ortaldo, John R.; Heusel, Jonathan W.; Shaaban, Aimen F.

    2015-01-01

    Little is known about how the prenatal interaction between NK cells and alloantigens shapes the developing NK cell repertoire towards tolerance or immunity. Specifically, the effect on NK cell education arising from developmental co-recognition of alloantigens by activating and inhibitory receptors with shared specificity is uncharacterized. Using a murine prenatal transplantation model, we examined the manner in which this seemingly conflicting input affects NK cell licensing and repertoire formation in mixed hematopoietic chimeras. We found that prenatal NK cell tolerance arose from the elimination of phenotypically “hostile” NK cells that express an allospecific activating receptor without co-expressing any allospecific inhibitory receptors. Importantly, the checkpoint for the system appeared to occur centrally within the bone marrow during the final stage of NK cell maturation and hinged on the instructive recognition of allogeneic ligand by the activating receptor rather than through the inhibitory receptor as classically proposed. Residual non-deleted hostile NK cells expressing only the activating receptor exhibited an immature, anergic phenotype but retained the capacity to upregulate inhibitory receptor expression in peripheral sites. However, the potential for this adaptive change to occur was lost in developmentally mature chimeras. Collectively, these findings illuminate the intrinsic process in which developmental allorecognition through the activating receptor regulates the emergence of durable NK cell tolerance and establishes a new paradigm to fundamentally guide future investigations of prenatal NK cell allospecific education. PMID:26136432

  20. Low-temperature tolerance and genetic potential in wheat (Triticum aestivum L.): response to photoperiod, vernalization, and plant development.

    PubMed

    Limin, Allen E; Fowler, D Brian

    2006-07-01

    It is frequently observed that winter habit types are more low-temperature (LT) tolerant than spring habit types. This raises the question of whether this is due to pleiotropic effects of the vernalization loci or to the linkage of LT-tolerance genes to these vernalization loci. Reciprocal near-isogenic lines (NILs) for alleles at the Vrn-A1 locus, Vrn-A1 and vrn-A1, determining spring and winter habit respectively, in two diverse genetic backgrounds of wheat (Triticum aestivum L.) were used to separate the effects of vernalization, photoperiod, and development on identical, or near identical, genetic backgrounds. The vrn-A1 allele in the winter lines allowed full expression of genotype dependent LT tolerance potential. The winter allele (vrn-A1) in a very cold tolerant genetic background resulted in 11 degrees C, or a 2.4-fold, greater LT tolerance compared to the spring allele. Similarly, the delay in development caused by short-day (SD) versus long-day (LD) photoperiod in the identical spring habit NIL resulted in an 8.5 degrees C or 2.1-fold, increase in LT tolerance. The duration of time in early developmental stages was shown to underlie full expression of genetic LT-tolerance potential. Therefore, pleiotropic effects of the vernalization loci can explain the association of LT tolerance and winter habit irrespective of either the proposed closely linked Fr-A1 or the more distant Fr-A2 LT-tolerance QTLs. Plant development progressively reduced LT-acclimation ability, particularly after the main shoot meristem had advanced to the double ridge reproductive growth stage. The Vrn-1 genes, or other members of the flowering induction pathway, are discussed as possible candidates for involvement in LT-tolerance repression.

  1. Development of an electronic database for Acute Pain Service outcomes

    PubMed Central

    Love, Brandy L; Jensen, Louise A; Schopflocher, Donald; Tsui, Ban CH

    2012-01-01

    BACKGROUND: Quality assurance is increasingly important in the current health care climate. An electronic database can be used for tracking patient information and as a research tool to provide quality assurance for patient care. OBJECTIVE: An electronic database was developed for the Acute Pain Service, University of Alberta Hospital (Edmonton, Alberta) to record patient characteristics, identify at-risk populations, compare treatment efficacies and guide practice decisions. METHOD: Steps in the database development involved identifying the goals for use, relevant variables to include, and a plan for data collection, entry and analysis. Protocols were also created for data cleaning quality control. The database was evaluated with a pilot test using existing data to assess data collection burden, accuracy and functionality of the database. RESULTS: A literature review resulted in an evidence-based list of demographic, clinical and pain management outcome variables to include. Time to assess patients and collect the data was 20 min to 30 min per patient. Limitations were primarily software related, although initial data collection completion was only 65% and accuracy of data entry was 96%. CONCLUSIONS: The electronic database was found to be relevant and functional for the identified goals of data storage and research. PMID:22518364

  2. Roles of central catecholamine and hypothalamic neuropeptide Y genome in the development of tolerance to phenylpropanolamine-mediated appetite suppression.

    PubMed

    Hsieh, Yih-Shou; Yang, Shun-Fa; Chiou, Hui-Ling; Kuo, Dong-Yih

    2007-10-01

    Phenylpropanolamine (PPA) is an appetite suppressant. Repeated treatment with PPA can decrease food intake on initial days, but on subsequent days, food intake gradually returns to normal (tolerant effect). In an attempt to investigate the underlying mechanisms of PPA tolerance, the authors examined the roles of catecholamine (CAT) and hypothalamic neuropeptide Y (NPY) genome. Results revealed that pretreatment with either bupropion, a CAT transporter inhibitor, or a-methylparatyrosine, a tyrosine hydroxylase inhibitor, modulated the effect of PPA tolerance. Moreover, results also revealed that the alteration in NPY messenger RNA level coincided with the change of feeding behavior during PPA treatment and that infusions of NPY antisense oligonucleotide into the cerebroventricle abolished the effect of PPA tolerance. These findings suggest that cerebral CAT and hypothalamic NPY genome are involved in the development of tolerance to PPA-induced appetite suppression.

  3. 77 FR 60126 - Guidance for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-02

    ...; Formerly 2008N-0004] Guidance for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment... Media: Developing Drugs for Treatment.'' This guidance addresses FDA's current thinking regarding the... treatment of acute bacterial otitis media (ABOM). This guidance finalizes the revised draft guidance of...

  4. Place-aversion conditioned by phencyclidine in rats: development of tolerance and pharmacologic antagonism.

    PubMed

    Iwamoto, E T

    The pharmacologic properties of phencyclidine were assessed in adult, male rats using a three-chambered, place-conditioning apparatus. Phencyclidine hydrochloride (PCP), at doses of 0.5 to 4 mg/kg, produced a dose-related place-aversion after three drug/environment pairings. During the place-conditioning procedure, 4 mg/kg of PCP significantly increased spontaneous locomotor activity compared to saline-control. Tolerance to PCP-induced place-aversion developed after four daily administrations of 4 mg/kg of PCP. d-Butaclamol, 0.4 mg/kg, given 1 min before each of the three conditioning-doses of PCP decreased the development of the place-aversion induced by PCP. 1-Butaclamol was without significant effect. Spiroperidol, 0.06 mg/kg, completely blocked the development of PCP place-aversion. Spiroperidol and the stereoisomers of butaclamol did not have significant place-conditioning activity when administered alone in the place-conditioning paradigm. The data suggest that PCP induces place-aversion in rats in the place-conditioning model, and that tolerance to this effect develops within 4 days. Furthermore, since d-butaclamol or spiroperidol, but not 1-butaclamol, antagonized this effect of PCP, PCP-induced place-aversion may be mediated in part by a dopaminergic mechanism.

  5. The Development of Design Tools for Fault Tolerant Quantum Dot Cellular Automata Based Logic

    NASA Technical Reports Server (NTRS)

    Armstrong, Curtis D.; Humphreys, William M.

    2003-01-01

    We are developing software to explore the fault tolerance of quantum dot cellular automata gate architectures in the presence of manufacturing variations and device defects. The Topology Optimization Methodology using Applied Statistics (TOMAS) framework extends the capabilities of the A Quantum Interconnected Network Array Simulator (AQUINAS) by adding front-end and back-end software and creating an environment that integrates all of these components. The front-end tools establish all simulation parameters, configure the simulation system, automate the Monte Carlo generation of simulation files, and execute the simulation of these files. The back-end tools perform automated data parsing, statistical analysis and report generation.

  6. Fault Tolerant Magnetic Bearing Testing and Conical Magnetic Bearing Development for Extreme Temperature Environments

    NASA Technical Reports Server (NTRS)

    Keith, Theo G., Jr.; Clark, Daniel

    2004-01-01

    During the six month tenure of the grant, activities included continued research of hydrostatic bearings as a viable backup-bearing solution for a magnetically levitated shaft system in extreme temperature environments (1000 F), developmental upgrades of the fault-tolerant magnetic bearing rig at the NASA Glenn Research Center, and assisting in the development of a conical magnetic bearing for extreme temperature environments, particularly turbomachinery. It leveraged work from the ongoing Smart Efficient Components (SEC) and the Turbine-Based Combined Cycle (TBCC) program at NASA Glenn Research Center. The effort was useful in providing technology for more efficient and powerful gas turbine engines.

  7. PREDICTING THE ACUTE BEHAVIORAL EFFECTS OF TOLUENE INHALED FOR 24 HRS IN RATS: DOSE METRICS, METABOLISM AND BEHAVIORAL TOLERANCE

    EPA Science Inventory

    Purpose: Recent research on the acute effects of volatile organic compounds (VOCs) suggests that extrapolation from short (~ 1 h) to long durations (up to 4 h) is improved by using estimates of brain toluene concentration ( Br[ToI)] instead of cumulative inhaled dose (C x t) as a...

  8. Development of N-version software samples for an experiment in software fault tolerance

    NASA Technical Reports Server (NTRS)

    Lauterbach, L.

    1987-01-01

    The report documents the task planning and software development phases of an effort to obtain twenty versions of code independently designed and developed from a common specification. These versions were created for use in future experiments in software fault tolerance, in continuation of the experimental series underway at the Systems Validation Methods Branch (SVMB) at NASA Langley Research Center. The 20 versions were developed under controlled conditions at four U.S. universities, by 20 teams of two researchers each. The versions process raw data from a modified Redundant Strapped Down Inertial Measurement Unit (RSDIMU). The specifications, and over 200 questions submitted by the developers concerning the specifications, are included as appendices to this report. Design documents, and design and code walkthrough reports for each version, were also obtained in this task for use in future studies.

  9. An oral lipid challenge and acute intake of caffeinated coffee additively decrease glucose tolerance in healthy men.

    PubMed

    Beaudoin, Marie-Soleil; Robinson, Lindsay E; Graham, Terry E

    2011-04-01

    Lipid-induced insulin resistance has been investigated primarily with i.v. infusions, and caffeine-induced insulin resistance, with alkaloid caffeine. The effects of orally consumed lipids and coffee have not been established and to our knowledge have never been simultaneously investigated. The goals of this study were to determine whether an oral lipid challenge and caffeinated coffee would disrupt glucose homeostasis and to characterize their respective incretin responses. It was hypothesized that oral ingestion of saturated lipids would impair glucose tolerance and that caffeinated coffee would further hinder glucose management. Ten young, healthy males participated in 5 trials in a randomized, cross-over design. At time 0 h, they underwent an oral fat tolerance test (OFTT: 1 g lipid/kg body weight) or consumed water, followed 5 h later by caffeinated (5 mg/kg) coffee, decaffeinated coffee, or water. At 6 h, volunteers underwent an oral glucose tolerance test (OGTT). Consumption of the OFTT increased glucose concentrations (P < 0.05) after a subsequent OGTT. At 7 h, caffeinated coffee produced the highest glucose concentrations (P < 0.05). Glucagon-like peptide-1 active (GLP-1a) and glucose-dependent insulinotropic polypeptide (GIP) were both increased for up to 6 h in all OFTT trials (P < 0.05). Compared to all other treatments, caffeinated and decaffeinated coffee produced higher GLP-1a response at 6.25 h (P < 0.05), whereas only caffeinated coffee increased GIP secretion (P < 0.05). These results show that oral consumption of lipids and caffeinated coffee can independently and additively decrease glucose tolerance. Incretin hormones could explain at least in part this impaired glucose homeostasis.

  10. Acute movement disorders in children: experience from a developing country.

    PubMed

    Goraya, Jatinder Singh

    2015-03-01

    We describe acute movement disorders in 92 children, aged 5 days to 15 years, from an Indian tertiary hospital. Eighty-nine children had hyperkinetic movement disorders, with myoclonus in 25, dystonia in 21, choreoathetosis in 19, tremors in 15, and tics in 2. Tetany and tetanus were seen in 5 and 2 children, respectively. Hypokinetic movement disorders included acute parkinsonism in 3 children. Noninflammatory and inflammatory etiology were present in 60 and 32 children, respectively. Benign neonatal sleep myoclonus in 16 and opsoclonus myoclonus syndrome in 7 accounted for the majority of myoclonus cases. Vitamin B12 deficiency in 13 infants was the most common cause of tremors. Rheumatic fever and encephalitis were the most common causes of acute choreoathetosis. Acute dystonia had metabolic etiology in 6 and encephalitis and drugs in 3 each. Psychogenic movement disorders were seen in 4 cases only, although these patients may be underreported.

  11. Calcium-acting drugs modulate expression and development of chronic tolerance to nicotine-induced antinociception in mice.

    PubMed

    Damaj, M I

    2005-11-01

    Initial studies in our laboratory suggested that tolerance to nicotine is thought to involve neuronal adaptation not only at the level of the drug-receptor interaction but at postreceptor events such as calcium-dependent second messengers. The present study was undertaken to investigate the hypothesis that L-type calcium channels and calcium-dependent calmodulin protein kinase II are involved in the development and expression of nicotine tolerance. To that end, the effects of modulation of L-type calcium channels (through the use of inhibitors or activators) as well as calcium-dependent calmodulin protein kinase II inactivation were studied in a mouse model of tolerance where mice were infused with nicotine in minipumps (24 mg/kg/day) for 14 days. In addition, the activity of calcium-dependent calmodulin protein kinase II in the lumbar spinal cord region obtained from nicotine-tolerant mice was measured. Our data showed that chronic administration of L-type calcium channel antagonists nimodipine (1 and 5 mg/kg) and verapamil (10 mg/kg) prevented the development of tolerance to nicotine-induced antinociception. In contrast, chronic exposure of BAYK8644 [(+/-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester], a calcium channel activator, enhanced nicotine's tolerance. Moreover, a significant increase in both dependent and independent calcium-dependent calmodulin protein kinase II activity was seen in the spinal cord in nicotine-tolerant mice. Finally, spinal administration of 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenylpiperazine (KN-62), a calcium-dependent calmodulin protein kinase II antagonist, reduced the expression of tolerance to nicotine-induced antinociception in mice. In conclusion, our data indicate that calcium-dependent mechanisms such as L-type calcium channels and calcium-dependent calmodulin protein kinase II activation are involved in the expression and development of nicotine

  12. Development of stress tolerant Saccharomyces cerevisiae strains by metabolic engineering: New aspects from cell flocculation and zinc supplementation.

    PubMed

    Cheng, Cheng; Zhang, Mingming; Xue, Chuang; Bai, Fengwu; Zhao, Xinqing

    2017-02-01

    Budding yeast Saccharomyces cerevisiae is widely studied for the production of biofuels from lignocellulosic biomass. However, economic production is currently challenged by the repression of cell growth and compromised fermentation performance of S. cerevisiae strains in the presence of various environmental stresses, including toxic level of final products, inhibitory compounds released from the pretreatment of cellulosic feedstocks, high temperature, and so on. Therefore, it is important to improve stress tolerance of S. cerevisiae to these stressful conditions to achieve efficient and economic production. In this review, the latest advances on development of stress tolerant S. cerevisiae strains are summarized, with the emphasis on the impact of cell flocculation and zinc addition. It was found that cell flocculation affected ethanol tolerance and acetic acid tolerance of S. cerevisiae, and addition of zinc to a suitable level improved stress tolerance of yeast cells to ethanol, high temperature and acetic acid. Further studies on the underlying mechanisms by which cell flocculation and zinc status affect stress tolerance will not only enrich our knowledge on stress response and tolerance mechanisms of S. cerevisiae, but also provide novel metabolic engineering strategies to develop robust yeast strains for biofuels production.

  13. Bacterial Infections, Alloimmunity, and Transplantation Tolerance

    PubMed Central

    Ahmed, Emily B.; Daniels, Melvin; Alegre, Maria-Luisa; Chong, Anita S.

    2010-01-01

    Transplantation of solid organs across histocompatibility barriers in the absence of immunosuppression is invariably followed by acute allograft rejection. Although several immunosuppressive regimens have been developed to prevent allograft rejection, these global immunosuppressive agents effectively inhibit all T cells leaving the host vulnerable to infections. Thus a major goal in transplantation immunology is to induce donor-specific tolerance that results in the extended suppression of allograft-specific immune responses, while leaving the remainder of the immune system competent to fight infections and malignancies. Initial successes in identifying approaches that successfully induce transplantation tolerance in experimental models have led to a newer research focus of identifying potential barriers to the induction of such tolerance as well as events that may reverse established allograft tolerance. Both clinical and experimental studies have identified bacterial infections as a possible trigger of allograft rejection. Recently, experimental models of transplantation tolerance have identified that bacterial signals can promote acute allograft rejection either by preventing the induction of transplantation tolerance or by reversing tolerance after it has been stably established. This review summarizes experimental and clinical literature supporting the hypothesis that bacterial infections and innate immunity can qualitatively and quantitatively alter adaptive alloreactivity through effects on innate immune responses. PMID:21126661

  14. Protected Graft Copolymer Excipient Leads to a Higher Acute Maximum Tolerated Dose and Extends Residence Time of Vasoactive Intestinal Peptide Significantly Better than Sterically Stabilized Micelles

    PubMed Central

    Reichstetter, Sandra; Castillo, Gerardo M.; Rubinstein, Israel; Nishimoto-Ashfield, Akiko; Lai, ManShun; Jones, Cynthia C.; Banjeree, Aryamitra; Lyubimov, Alex; Bloedow, Duane C.; Bogdanov, Alexei; Bolotin, Elijah M.

    2013-01-01

    Purpose To determine and compare pharmacokinetics and toxicity of two nanoformulations of Vasoactive Intestinal Peptide (VIP). Methods VIP was formulated using a micellar (Sterically Stabilized Micelles, SSM) and a polymer-based (Protected Graft Copolymer, PGC) nanocarrier at various loading percentages. VIP binding to the nanocarriers, pharmacokinetics, blood pressure, blood chemistry, and acute maximum tolerated dose (MTD) of the formulations after injection into BALB/c mice were determined. Results Both formulations significantly extend in vivo residence time compared to unformulated VIP. Formulation toxicity is dependent on loading percentage, showing major differences between the two carrier types. Both formulations increase in vivo potency of unformulated VIP and show acute MTDs at least 140 times lower than unformulated VIP, but still at least 100 times higher than the anticipated highest human dose, 1–5 μg/kg. These nanocarriers prevented a significant drop in arterial blood pressure compared to unformulated VIP. Conclusions While both carriers enhance in vivo residence time compared to unformulated VIP and reduce the drop in blood pressure immediately after injection, PGC is the excipient of choice to extend residence time and improve the safety of potent therapeutic peptides such as VIP. PMID:23224976

  15. A comparison of acute and chronic toxicity tests used to examine the temporal stability of a gradient in copper tolerance of Hediste diversicolor from the Fal estuary, Cornwall, UK.

    PubMed

    Burlinson, F C; Lawrence, A J

    2007-01-01

    The aim of this study was to use two different toxicity tests to verify the existence of a gradient in tolerance along Rostronguet Creek. Hediste diversicolor was collected from five populations in the Fal estuary previously shown to vary in copper tolerance. Exposure to 4 mgL(-1) of copper in an acute assay demonstrated that Mylor Creek worms were sensitive (LT(50) 86 h) and the tolerance of Rostronguet Creek worms increased moving upstream from the mouth of the creek (LT(50)s 100-258 h). There was no significant difference in tolerance between Mylor worms and worms from the mouth of Rostronguet Creek. This is in agreement with a previous study [Grant, A., Hateley, J.G., Jones, N.V., 1989. Mapping the ecological impact of heavy metals on the estuarine polychaete Nereis diversicolor using inherited metal tolerance. Marine Pollution Bulletin 20, 235-238] and demonstrates temporal stability of the gradient. Copper tolerance was also measured using a chronic toxicity test run for 90 d using step-wise increases in challenge concentration. A significant difference in tolerance was shown between populations from Mylor Creek and those at the mouth of Rostronguet Creek, which has not been reported previously. Experimental protocol was therefore an important factor in detecting population variation in tolerance.

  16. Ascorbate biosynthesis and its involvement in stress tolerance and plant development in rice (Oryza sativa L.).

    PubMed

    Höller, Stefanie; Ueda, Yoshiaki; Wu, Linbo; Wang, Yunxia; Hajirezaei, Mohammad-Reza; Ghaffari, Mohammad-Reza; von Wirén, Nicolaus; Frei, Michael

    2015-08-01

    Ascorbic acid (AsA) biosynthesis and its implications for stress tolerance and plant development were investigated in a set of rice knock-out (KO) mutants for AsA biosynthetic genes and their wild-types. KO of two isoforms of GDP-D-mannose epimerase (OsGME) reduced the foliar AsA level by 20-30%, and KO of GDP-L-galactose phosphorylase (OsGGP) by 80%, while KO of myo-inositol oxygenase (OsMIOX) did not affect foliar AsA levels. AsA concentration was negatively correlated with lipid peroxidation in foliar tissue under ozone stress and zinc deficiency, but did not affect the sensitivity to iron toxicity. Lack of AsA reduced the photosynthetic efficiency as represented by the maximum carboxylation rate of Rubisco (Vmax), the maximum electron transport rate (Jmax) and the chlorophyll fluorescence parameter ΦPSII. Mutants showed lower biomass production than their wild-types, especially when OsGGP was lacking (around 80% reductions). All plants except for KO mutants of OsGGP showed distinct peaks in foliar AsA concentrations during the growth, which were consistent with up-regulation of OsGGP, suggesting that OsGGP plays a pivotal role in regulating foliar AsA levels during different growth stages. In conclusion, our data demonstrate multiple roles of AsA in stress tolerance and development of rice.

  17. [Efficacy and tolerability of morniflumate in acute otitis in infants: results of a randomized study versus placebos].

    PubMed

    Portmann, M; Portmann, D; Rohou, S; Pollet, M; Colson, J; Cuvelier, A; Fournier, J L; Jeannerot, F; Marx, J; Menet, V

    1990-01-01

    In a randomized double-blind placebo-controlled, parallel group study, 79 infants with acute otitis media received treatment with suppositories containing either Nifluril (400 mg daily, morniflumate) or placebo for five days. Both groups of patients also received amoxicilline (50 mg/kg daily) for eight days. The combination of Nifluril with antibiotic therapy gave significantly greater relief from abnormalities of the tympanic membrane (after two days treatment), inflammation of the throat and nasal congestion than did antibiotic therapy alone. Overall clinical assessment confirmed a significantly greater recover rate in the Nifluril group compared with the placebo group. Very few side effects were recorded, limited to diarrhoea, without any drug interruption. Nifluril may be recommended as an effective safe adjuvant to the antibiotic treatment of acute otitis media in infants.

  18. Development of high alcohol tolerant organisms. I. Strain selection and screening. Annual report, 31 July 1981-1 August 1982

    SciTech Connect

    Bayne, P.D.

    1982-12-01

    The principal objective of this study is the selection and development of an alcohol tolerant microorganism strain which will allow less water to be removed from the fermented beer, thus allowing the more energy efficient production of fuel alcohol. The program resulted in the selection of an outstanding strain of Zymomonas (B-10) for further evaluation in pilot scale fermentations and development by both mutagenesis and continuous selection. One culture strain of yeast and a number of mutant and variant strains of yeast await further evaluation for possible use as high alcohol tolerant strains in the production of power alcohol. Most important of all, the results of this investigation suggest a genetic basis, not a biochemical one, for strain differences in alcohol tolerance. It is our belief that a rational program of mass mutagenesis and screening will afford superior strains just as in the development of antibiotic yields. The automation and standardization of these mutagenic and selective regimes will allow larger samples to be screened and detect tolerance differences with greater sensitivity. Elimination of carbon diversion and increasing ethanol production rates and yields appear to be possible from the preliminary work conducted. Where several natural lines yield more tolerant strains by these procedures, genetic crossing, possibly using in vitro genetic chemical methods to circumvent natural barrier mechanisms, such as polyploidy, could result in derivatives with even greater tolerance.

  19. Change in functional selectivity of morphine with the development of antinociceptive tolerance

    PubMed Central

    Macey, T A; Bobeck, E N; Suchland, K L; Morgan, M M; Ingram, S L

    2015-01-01

    BACKGROUND AND PURPOSE Opioids, such as morphine, are the most effective treatment for pain but their efficacy is diminished with the development of tolerance following repeated administration. Recently, we found that morphine activated ERK in opioid-tolerant but not in naïve rats, suggesting that morphine activation of μ-opioid receptors is altered following repeated morphine administration. Here, we have tested the hypothesis that μ-opioid receptor activation of ERK in the ventrolateral periaqueductal gray (vlPAG) is dependent on dynamin, a protein implicated in receptor endocytosis. EXPERIMENTAL APPROACH Rats were made tolerant to repeated microinjections of morphine into the vlPAG. The effects of dynamin on ERK activation and antinociception were assessed by microinjecting myristoylated dominant-negative dynamin peptide (Dyn-DN) or a scrambled control peptide into the vlPAG. Microinjection of a fluorescent dermorphin analogue (DERM-A594) into the vlPAG was used to monitor μ-opioid receptor internalization. KEY RESULTS Morphine did not activate ERK and Dyn-DN administration had no effect on morphine-induced antinociception in saline-pretreated rats. In contrast, morphine-induced ERK activation in morphine-pretreated rats that was blocked by Dyn-DN administration. Dyn-DN also inhibited morphine antinociception. Finally, morphine reduced DERM-A594 internalization only in morphine-tolerant rats indicating that μ-opioid receptors were internalized and unavailable to bind DERM-A594. CONCLUSIONS AND IMPLICATIONS Repeated morphine administration increased μ-opioid receptor activation of ERK signalling via a dynamin-dependent mechanism. These results demonstrate that the balance of agonist signalling to G-protein and dynamin-dependent pathways is altered, effectively changing the functional selectivity of the agonist-receptor complex. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other

  20. Acute cholecystitis developed immediately after thoracic kyphoplasty -A case report-

    PubMed Central

    An, Sang-Bum; Yim, Jiyeon; Kim, Eunjung; Shin, Jae-Hyuck; Lee, Sang Chul

    2012-01-01

    Postoperative acute cholecystitis is a rare complication of orthopaedic surgery and is unrelated to the biliary tract. In particular, in the case of immediate postoperative state after surgery such as kyphoplasty at the thoracic vertebra, symptoms related to inflammation mimic those of abdominal origin, so the diagnosis and the treatment of acute cholecystitis can be delayed leading to a fatal outcome. It is important that physicians should be aware of the postoperative patient's condition in order to make an early diagnosis and determine treatment. PMID:23060986

  1. Antiradiation Vaccine: Technology Development- Radiation Tolerance,Prophylaxis, Prevention And Treatment Of Clinical Presentation After Heavy Ion Irradiation.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Slava; Jones, Jeffrey

    Introduction: Research in the field of biological effects of heavy charged particles is necessary for both heavy-ion therapy (hadrontherapy) and protection from the exposure to galactic cosmic radiation in long-term manned space missions.[Durante M. 2004] In future crew of long-term manned missions could operate in exremely high hadronic radiation areas of space and will not survive without effective radiation protection. An Antiradiation Vaccine (AV) must be an important part of a countermeasures regimen for efficient radiation protection purposes of austronauts-cosmonauts-taukonauts: immune-prophylaxis and immune-therapy of acute radiation toxic syndromes developed after heavy ion irradiation. New technology developed (AV) for the purposes of radiological protection and improvement of radiation tolerance and it is quite important to create protective immune active status which prevent toxic reactions inside a human body irradiated by high energy hadrons.[Maliev V. et al. 2006, Popov D. et al.2008]. High energy hadrons produce a variety of secondary particles which play an important role in the energy deposition process, and characterise their radiation qualities [Sato T. et al. 2003] Antiradiation Vaccine with specific immune-prophylaxis by an anti-radiation vaccine should be an important part of medical management for long term space missions. Methods and experiments: 1. Antiradiation vaccine preparation standard, mixture of toxoid form of Radiation Toxins [SRD-group] which include Cerebrovascular RT Neurotoxin, Cardiovascular RT Neurotoxin, Gastrointestinal RT Neurotoxin, Hematopoietic RT Hematotoxin. Radiation Toxins of Radiation Determinant Group isolated from the central lymph of gamma-irradiated animals with Cerebrovascular, Cardiovascular, Gastro-intestinal, Hematopoietic forms of ARS. Devices for radiation are "Panorama", "Puma". 2. Heavy ion exposure was accomplished at Department of Research Institute of Nuclear Physics, Dubna, Russia. The heavy ions

  2. Advanced Durability and Damage Tolerance Design and Analysis Methods for Composite Structures: Lessons Learned from NASA Technology Development Programs

    NASA Technical Reports Server (NTRS)

    Harris, Charles E.; Starnes, James H., Jr.; Shuart, Mark J.

    2003-01-01

    Aerospace vehicles are designed to be durable and damage tolerant. Durability is largely an economic life-cycle design consideration whereas damage tolerance directly addresses the structural airworthiness (safety) of the vehicle. However, both durability and damage tolerance design methodologies must address the deleterious effects of changes in material properties and the initiation and growth of microstructural damage that may occur during the service lifetime of the vehicle. Durability and damage tolerance design and certification requirements are addressed for commercial transport aircraft and NASA manned spacecraft systems. The state-of-the-art in advanced design and analysis methods is illustrated by discussing the results of several recently completed NASA technology development programs. These programs include the NASA Advanced Subsonic Technology Program demonstrating technologies for large transport aircraft and the X-33 hypersonic test vehicle demonstrating technologies for a single-stage-to-orbit space launch vehicle.

  3. Acute toxoplasmosis-etiological factor for development of Hodgkin's lymphoma?

    PubMed

    Snopkova, Svatava; Pohanka, Miroslav; Polak, Pavel; Havlickova, Katerina; Jarkovsky, Jiři; Moulis, Mojmir; Stroblova, Hana; Husa, Petr

    2013-12-01

    The case of an HIV-positive man treated for acute toxoplasmosis with no traces of malignancy is reported. A second lymph node extirpation was performed after 5 months, which identified the presence of Hodgkin and Reed-Sternberg (HRS) cells. This case suggests that toxoplasmosis may cause changes in the regulation of surrounding cells and induce neoplastic proliferation.

  4. ROAD MAP FOR DEVELOPMENT OF CRYSTAL-TOLERANT HIGH LEVEL WASTE GLASSES

    SciTech Connect

    Fox, K.; Peeler, D.; Herman, C.

    2014-05-15

    The U.S. Department of Energy (DOE) is building a Tank Waste Treatment and Immobilization Plant (WTP) at the Hanford Site in Washington to remediate 55 million gallons of radioactive waste that is being temporarily stored in 177 underground tanks. Efforts are being made to increase the loading of Hanford tank wastes in glass while meeting melter lifetime expectancies and process, regulatory, and product quality requirements. This road map guides the research and development for formulation and processing of crystaltolerant glasses, identifying near- and long-term activities that need to be completed over the period from 2014 to 2019. The primary objective is to maximize waste loading for Hanford waste glasses without jeopardizing melter operation by crystal accumulation in the melter or melter discharge riser. The potential applicability to the Savannah River Site (SRS) Defense Waste Processing Facility (DWPF) will also be addressed in this road map. The planned research described in this road map is motivated by the potential for substantial economic benefits (significant reductions in glass volumes) that will be realized if the current constraints (T1% for WTP and TL for DWPF) are approached in an appropriate and technically defensible manner for defense waste and current melter designs. The basis of this alternative approach is an empirical model predicting the crystal accumulation in the WTP glass discharge riser and melter bottom as a function of glass composition, time, and temperature. When coupled with an associated operating limit (e.g., the maximum tolerable thickness of an accumulated layer of crystals), this model could then be integrated into the process control algorithms to formulate crystal-tolerant high-level waste (HLW) glasses targeting high waste loadings while still meeting process related limits and melter lifetime expectancies. The modeling effort will be an iterative process, where model form and a broader range of conditions, e.g., glass

  5. Role of Abscisic Acid in the Induction of Desiccation Tolerance in Developing Seeds of Arabidopsis thaliana

    PubMed Central

    Meurs, Cor; Basra, Amarjit S.; Karssen, Cees M.; van Loon, Leendert C.

    1992-01-01

    In contrast to wild-type seeds of Arabidopsis thaliana and to seeds deficient in (aba) or insensitive to (abi3) abscisic acid (ABA), maturing seeds of recombinant (aba,abi3) plants fail to desiccate, remain green, and lose viability upon drying. These double-mutant seeds acquire only low levels of the major storage proteins and are deficient in several low mol wt polypeptides, both soluble and bound, and some of which are heat stable. A major heat-stable glycoprotein of more than 100 kilodaltons behaves similarly; during seed development, it shows a decrease in size associated with the abi3 mutation. In seeds of the double mutant from 14 to 20 days after pollination, the low amounts of various maturation-specific proteins disappear and many higher mol wt proteins similar to those occurring during germination are induced, but no visible germination is apparent. It appears that in the aba,abi3 double mutant seed development is not completed and the program for seed germination is initiated prematurely in the absence of substances protective against dehydration. Seeds may be made desiccation tolerant by watering the plants with the ABA analog LAB 173711 or by imbibition of isolated immature seeds, 11 to 15 days after pollination, with ABA and sucrose. Whereas sucrose stimulates germination and may protect dehydration-sensitive structures from desiccation damage, ABA inhibits precocious germination and is required to complete the program for seed maturation and the associated development of desiccation tolerance. ImagesFigure 1Figure 2Figure 4Figure 5Figure 6Figure 8 PMID:16668818

  6. Acute Myeloid Leukaemia of Donor Cell Origin Developing 17 Years after Allogenic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukaemia

    PubMed Central

    Jiménez, Pilar; Alvarez, J. Carlos; Garrido, Pilar; Lorente, J. Antonio; Palacios, Jorge; Ruiz-Cabello, Francisco

    2012-01-01

    Donor cell leukaemia (DCL) is a rare complication of allogenic hematopoietic cell transplantation (HCT). We report the case of a female patient with acute promyelocytic leukaemia (APL), FAB type M3, who developed acute myeloid leukaemia (AML) type M5 of donor origin 17 years after allogenic bone marrow transplantation (BMT) from her HLA-matched sister. Morphology and immunophenotyping showed differences with the initial leukaemia, and short tandem repeat (STR) analysis confirmed donor-type haematopoiesis. Interphase fluorescence in situ hybridisation (FISH) showed an 11q23 deletion. Given that the latency period between transplant and development of leukaemia was the longest reported to date, we discuss the mechanisms underlying delayed leukaemia onset. PMID:23675279

  7. Preinduction of HSP70 promotes hypoxic tolerance and facilitates acclimatization to acute hypobaric hypoxia in mouse brain

    PubMed Central

    Zhang, Kuan; Zhao, Tong; Huang, Xin; Liu, Zhao-hui; Xiong, Lei; Li, Ming-ming; Wu, Li-ying; Zhao, Yong-qi

    2008-01-01

    It has been shown that induction of HSP70 by administration of geranylgeranylacetone (GGA) leads to protection against ischemia/reperfusion injury. The present study was performed to determine the effect of GGA on the survival of mice and on brain damage under acute hypobaric hypoxia. The data showed that the mice injected with GGA survived significantly longer than control animals (survival time of 9.55 ± 3.12 min, n = 16 vs. controls at 4.28 ± 4.29 min, n = 15, P < 0.005). Accordingly, the cellular necrosis or degeneration of the hippocampus and the cortex induced by sublethal hypoxia for 6 h could be attenuated by preinjection with GGA, especially in the CA2 and CA3 regions of the hippocampus. In addition, the activity of nitric oxide synthase (NOS) of the hippocampus and the cortex was increased after exposure to sublethal hypoxia for 6 h but could be inhibited by the preinjection of GGA. Furthermore, the expression of HSP70 was significantly increased at 1 h after GGA injection. These results suggest that administration of GGA improved survival rate and prevented acute hypoxic damage to the brain and that the underlying mechanism involved induction of HSP70 and inhibition of NOS activity. PMID:19105051

  8. High Temperature, Permanent Magnet Biased, Fault Tolerant, Homopolar Magnetic Bearing Development

    NASA Technical Reports Server (NTRS)

    Palazzolo, Alan; Tucker, Randall; Kenny, Andrew; Kang, Kyung-Dae; Ghandi, Varun; Liu, Jinfang; Choi, Heeju; Provenza, Andrew

    2008-01-01

    This paper summarizes the development of a magnetic bearing designed to operate at 1,000 F. A novel feature of this high temperature magnetic bearing is its homopolar construction which incorporates state of the art high temperature, 1,000 F, permanent magnets. A second feature is its fault tolerance capability which provides the desired control forces with over one-half of the coils failed. The construction and design methodology of the bearing is outlined and test results are shown. The agreement between a 3D finite element, magnetic field based prediction for force is shown to be in good agreement with predictions at room and high temperature. A 5 axis test rig will be complete soon to provide a means to test the magnetic bearings at high temperature and speed.

  9. Development and evaluation of a Fault-Tolerant Multiprocessor (FTMP) computer. Volume 2: FTMP software

    NASA Technical Reports Server (NTRS)

    Lala, J. H.; Smith, T. B., III

    1983-01-01

    The software developed for the Fault-Tolerant Multiprocessor (FTMP) is described. The FTMP executive is a timer-interrupt driven dispatcher that schedules iterative tasks which run at 3.125, 12.5, and 25 Hz. Major tasks which run under the executive include system configuration control, flight control, and display. The flight control task includes autopilot and autoland functions for a jet transport aircraft. System Displays include status displays of all hardware elements (processors, memories, I/O ports, buses), failure log displays showing transient and hard faults, and an autopilot display. All software is in a higher order language (AED, an ALGOL derivative). The executive is a fully distributed general purpose executive which automatically balances the load among available processor triads. Provisions for graceful performance degradation under processing overload are an integral part of the scheduling algorithms.

  10. Exogenous application of molybdenum affects the expression of CBF14 and the development of frost tolerance in wheat.

    PubMed

    Al-Issawi, Mohammed; Rihan, Hail Z; Woldie, Wondwossen Abate; Burchett, Stephen; Fuller, Michael P

    2013-02-01

    Wheat is able to cold acclimate in response to low temperatures and thereby increase its frost tolerance and the extent of this acclimation is greater in winter genotypes compared to spring genotypes. Such up-regulation of frost tolerance is controlled by Cbf transcription factors. Molybdenum (Mo) application has been shown to enhance frost tolerance of wheat and this study aimed to investigate the effect of Mo on the development of frost tolerance in winter and spring wheat. Results showed that Mo treatment increased the expression of Cbf14 in wheat under non-acclimating condition but did not alter frost tolerance. However, when Mo was applied in conjunction with exposure of plants to low temperature, Mo increased the expression of Cbf14 and enhanced frost tolerance in both spring and winter genotypes but the effect was more pronounced in the winter genotype. It was concluded that the application of Mo could be useful in situations where enhanced frost resistance is required. Further studies are proposed to elucidate the effect of exogenous of applications of Mo on frost resistance in spring and winter wheat at different growth stages.

  11. Chronic overexpression of cerebral Epo improves the ventilatory response to acute hypoxia during the postnatal development.

    PubMed

    Caravagna, Céline; Gasser, Edith M Schneider; Ballot, Orlane; Joseph, Vincent; Soliz, Jorge

    2015-08-01

    Clinicians observed that the treatment of premature human newborns for anemia with erythropoietin (Epo) also improved their respiratory autonomy. This observation is in line with our previous in vitro studies showing that acute and chronic Epo stimulation enhances fictive breathing of brainstem-spinal cord preparations of postnatal day 3-4 mice during hypoxia. Furthermore, we recently reported that the antagonization of the cerebral Epo (by using the soluble Epo receptor; sEpoR) significantly reduced the basal ventilation and the hypoxic ventilatory response of 10 days old mice. In this study, we used transgenic (Tg21) mice to investigate the effect of the chronic cerebral Epo overexpression on the modulation of the normoxic and hypoxic ventilatory drive during the post-natal development. Ventilation was evaluated by whole body plethysmography at postnatal ages 3 (P3), 7 (P7), 15 (P15) and 21 (P21). In addition Epo quantification was performed by RIA and mRNA EpoR was evaluated by qRT-PCR. Our results showed that compared to control animals the chronic Epo overexpression stimulates the hypoxic (but not the normoxic) ventilation assessed as VE/VO2 at the ages of P3 and P21. More interestingly, we observed that at P7 and P15 the chronic Epo stimulation of ventilation was attenuated by the down regulation of the Epo receptor in brainstem areas. We conclude that Epo, by stimulating ventilation in brainstem areas crucially helps tolerating physiological (e.g., high altitude) and/or pathological (e.g., respiratory disorders, prematurity, etc.) oxygen deprivation at postnatal ages.

  12. Development of an Animal Model of Thoracolumbar Burst Fracture Induced Acute Spinal Cord Injury

    DTIC Science & Technology

    2015-05-01

    AWARD NUMBER: W81XWH-14-2-0013 TITLE: DEVELOPMENT OF AN ANIMAL MODEL OF THORACOLUMBAR BURST FRACTURE - INDUCED ACUTE SPINAL CORD INJURY...2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER DEVELOPMENT OF AN ANIMAL MODEL OF THORACOLUMBAR BURST FRACTURE -INDUCED ACUTE SPINAL CORD INJURY 5b...leads to permanent disability following traumatic spine injury. A dramatic increase in blast related spinal burst fracture has been observed in

  13. Chronic and acute inspiratory muscle loading augment the effect of a 6-week interval program on tolerance of high-intensity intermittent bouts of running.

    PubMed

    Tong, Tom K; Fu, Frank H; Eston, Roger; Chung, Pak-Kwong; Quach, Binh; Lu, Kui

    2010-11-01

    This study examined the hypothesis that chronic (training) and acute (warm-up) loaded ventilatory activities applied to the inspiratory muscles (IM) in an integrated manner would augment the training volume of an interval running program. This in turn would result in additional improvement in the maximum performance of the Yo-Yo intermittent recovery test in comparison with interval training alone. Eighteen male nonprofessional athletes were allocated to either an inspiratory muscle loading (IML) group or control group. Both groups participated in a 6-week interval running program consisting of 3-4 workouts (1-3 sets of various repetitions of selected distance [100-2,400 m] per workout) per week. For the IML group, 4-week IM training (30 inspiratory efforts at 50% maximal static inspiratory pressure [P0] per set, 2 sets·d-1, 6 d·wk-1) was applied before the interval program. Specific IM warm-up (2 sets of 30 inspiratory efforts at 40% P0) was performed before each workout of the program. For the control group, neither IML was applied. In comparison with the control group, the interval training volume as indicated by the repeatability of running bouts at high intensity was approximately 27% greater in the IML group. Greater increase in the maximum performance of the Yo-Yo test (control: 16.9 ± 5.5%; IML: 30.7 ± 4.7% baseline value) was also observed after training. The enhanced exercise performance was partly attributable to the greater reductions in the sensation of breathlessness and whole-body metabolic stress during the Yo-Yo test. These findings show that the combination of chronic and acute IML into a high-intensity interval running program is a beneficial training strategy for enhancing the tolerance to high-intensity intermittent bouts of running.

  14. Molecular cloning of glucose transporter 1 in grouper Epinephelus coioides and effects of an acute hyperglycemia stress on its expression and glucose tolerance.

    PubMed

    Liu, Hongyu; Dong, Xiaohui; Chi, Shuyan; Yang, Qihui; Zhang, Shuang; Chen, Liqiao; Tan, Beiping

    2017-02-01

    The glucose transporter family proteins play pivotal roles in glucose metabolism. In this study, we successfully cloned the orange spotted grouper (Epinephelus coioides) glucose transporter 1 (EcGlut1) gene (GenBank accession: JQ623903). The full-length EcGlut1 cDNA was 2126 bp with a 1476 bp ORF, a 437bp5'-UTR and 223bp3'-UTR. EcGlut1 is predicted to encode a 491 amino acid protein with a MW of 53.9 kDa, a pI of 8.66 and a Pfam domain. Bioinformatics analysis revealed that EcGlut1 was evolutionally conserved between fishes with 80-89 % amino acid identities. EcGlut1 was expressed predominantly in heart and liver and at lower levels in muscle, intestine, stomach and brain. We also investigated the effect of acute hyperglycemia stress on EcGlut1 expression. In glucose tolerance test, changes in EcGlut1 mRNA expression in response to glucose injection and glucose metabolism-related indictors were assessed at the same time. Glucose injection significantly suppressed EcGlut1 mRNA expression in liver at 12 h and in brain at 24 h postinjection (P < 0.05). EcGlut1 mRNA levels in heart were increased at 6 h (P < 0.05). Plasma glucose level increased significantly and reached its maximum at 3 h postinjection (P < 0.05). The spatiotemporal expression of EcGlut1 and glucose metabolism suggested that orange spotted grouper might rely on fat anabolism to reduce acute hyperglycemia stress and the delayed transcription of EcGlut1 gene might be one reason for glucose intolerance in E. coioides.

  15. Pretreatment with low doses of acenocoumarol inhibits the development of acute ischemia/reperfusion-induced pancreatitis.

    PubMed

    Warzecha, Z; Sendur, P; Ceranowicz, P; Dembinski, M; Cieszkowski, J; Kusnierz-Cabala, B; Tomaszewska, R; Dembinski, A

    2015-10-01

    Coagulative disorders are known to occur in acute pancreatitis and are related to the severity of this disease. Various experimental and clinical studies have shown protective and therapeutic effect of heparin in acute pancreatitis. Aim of the present study was to determine the influence of acenocoumarol, a vitamin K antagonist, on the development of acute pancreatitis. Studies were performed on male Wistar rats weighing 250 - 270 g. Acenocoumarol at the dose of 50, 100 or 150 μg/kg/dose or vehicle were administered once a day for 7 days before induction of acute pancreatitis. Acute pancreatitis was induced in rats by pancreatic ischemia followed by reperfusion. The severity of acute pancreatitis was assessed after 5-h reperfusion. Pretreatment with acenocoumarol given at the dose of 50 or 100 μg/kg/dose reduced morphological signs of acute pancreatitis. These effects were accompanied with a decrease in the pancreatitis-evoked increase in serum activity of lipase and serum concentration of pro-inflammatory interleukin-1β. Moreover, the pancreatitis-evoked reductions in pancreatic DNA synthesis and pancreatic blood flow were partially reversed by pretreatment with acenocoumarol given at the dose of 50 and 100 μg/kg/dose. Administration of acenocoumarol at the dose of 150 μg/kg/dose did not exhibit any protective effect against ischemia/reperfusion-induced pancreatitis. We concluded that pretreatment with low doses of acenocoumarol reduces the severity of ischemia/reperfusion-induced acute pancreatitis.

  16. Spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the STAT3-NMDA receptor pathway in rats.

    PubMed

    Hu, Fen; Cui, Yu; Guo, Ruixian; Chen, Jingfu; Guo, Runming; Shen, Ning; Hua, Xiaoxiao; Mo, Liqiu; Feng, Jianqiang

    2014-08-01

    Leptin, an adipokine synthesized mainly by non‑neuronal tissues, has been reported to contribute to the pathogenesis of neuropathic pain. It has been hypothesized that morphine tolerance and neuropathic pain share some common pathological mechanisms. The present study was designed to examine whether spinal leptin is implicated in the development of morphine antinociceptive tolerance, and whether spinal leptin induces the activation of signal transducer and activator of transcription 3 (STAT3) signaling pathway and the NR1 subunit of N‑methyl‑D‑aspartate (NMDA) receptor, in morphine antinociceptive tolerance in rats. The results demonstrated that intrathecal (i.t.) administration of a leptin antagonist (LA) prevented the development of morphine antinociceptive tolerance in rats. Further studies revealed that the levels of the spinal leptin and the leptin receptor (Ob‑R) were time‑dependently increased following chronic morphine treatment. Mechanistic examination indicated that chronic morphine triggered activation of the STAT3 pathway and an increase in the expression of the NR1 subunit of the NMDA receptor, which was ameliorated by i.t. administration of AG490 [a Janus kinase (JAK)‑STAT inhibitor]. The increased activation of STAT3 and the NR1 subunit was markedly attenuated by i.t. treatment with LA. In addition, the spinal administration of AG490 or MK‑801 (a non‑competitive NMDA receptor inhibitor) blocked the development of morphine antinociceptive tolerance. Taken together, these results have demonstrated, for the first time, to the best of our knowledge, that spinal leptin contributes to the development of morphine antinociceptive tolerance by activating the spinal STAT3‑NMDA receptor pathway.

  17. Splenic CD11clowCD45RBhigh dendritic cells derived from endotoxin-tolerant mice attenuate experimental acute liver failure

    PubMed Central

    Zhang, Sai-Nan; Yang, Nai-Bin; Ni, Shun-Lan; Dong, Jin-Zhong; Shi, Chun-Wei; Li, Shan-Shan; Zhang, Sheng-Guo; Tang, Xin-Yue; Lu, Ming-Qin

    2016-01-01

    Endotoxin tolerance (ET) is suggested to attenuate the severity of acute liver failure (ALF) in mice, possibly through both innate and adaptive immunity. However, the involvement of regulatory dendritic cells (DCregs) in ET has not been fully elucidated. In this study, their effect on ALF in mice was investigated. Splenic DCregs from ET-exposed mice (ET-DCregs) showed lower expression levels of CD40, CD80, and MHC-II markers and stronger inhibition of allogenic T cells and regulation of IL-10 and IL-12 secretion than splenic DCregs from normal mice (nDCregs). Moreover, the mRNA and protein levels of TNF-α and P65 in splenic ET-DCregs were significantly lower than those in the splenic nDCregs. The survival rate was significantly increased and liver injury was mitigated in mice with ALF treated with splenic ET-DCregs. In addition, A20 expression was decreased in the liver of ALF mice, but elevated after infusion of splenic nDCregs and ET-DCregs, and a much higher elevation was observed after infusing the latter cells. The functionality of splenic DCregs was altered after ET exposure, contributing to protection of the livers against D-GalN/LPS-induced ALF. PMID:27625297

  18. Praxis and the role development of the acute care nurse practitioner.

    PubMed

    Kilpatrick, Kelley

    2008-06-01

    Acute care nurse practitioner roles have been introduced in many countries. The acute care nurse practitioner provides nursing and medical care to meet the complex needs of patients and their families using a holistic, health-centred approach. There are many pressures to adopt a performance framework and execute activities and tasks. Little time may be left to explore domains of advanced practice nursing and develop other forms of knowledge. The primary objective of praxis is to integrate theory, practice and art, and facilitate the recognition and valuing of different types of knowledge through reflection. With this framework, the acute care nurse practitioner assumes the role of clinician and researcher. Praxis can be used to develop the acute care nurse practitioner role as an advanced practice nursing role. A praxis framework permeates all aspects of the acute care nurse practitioner's practice. Praxis influences how relationships are structured with patients, families and colleagues in the work setting. Decision-makers at different levels need to recognize the contribution of praxis in the full development of the acute care nurse practitioner role. Different strategies can be used by educators to assist students and practitioners to develop a praxis framework.

  19. Recent developments in epigenetics of acute and chronic kidney diseases.

    PubMed

    Reddy, Marpadga A; Natarajan, Rama

    2015-08-01

    The growing epidemic of obesity and diabetes, the aging population as well as prevalence of drug abuse has led to significant increases in the rates of the closely associated acute and chronic kidney diseases, including diabetic nephropathy. Furthermore, evidence shows that parental behavior and diet can affect the phenotype of subsequent generations via epigenetic transmission mechanisms. These data suggest a strong influence of the environment on disease susceptibility and that, apart from genetic susceptibility, epigenetic mechanisms need to be evaluated to gain critical new information about kidney diseases. Epigenetics is the study of processes that control gene expression and phenotype without alterations in the underlying DNA sequence. Epigenetic modifications, including cytosine DNA methylation and covalent post-translational modifications of histones in chromatin, are part of the epigenome, the interface between the stable genome and the variable environment. This dynamic epigenetic layer responds to external environmental cues to influence the expression of genes associated with disease states. The field of epigenetics has seen remarkable growth in the past few years with significant advances in basic biology, contributions to human disease, as well as epigenomics technologies. Further understanding of how the renal cell epigenome is altered by metabolic and other stimuli can yield novel new insights into the pathogenesis of kidney diseases. In this review, we have discussed the current knowledge on the role of epigenetic mechanisms (primarily DNAme and histone modifications) in acute and chronic kidney diseases, and their translational potential to identify much needed new therapies.

  20. Growth and development alter susceptibility to acute renal injury.

    PubMed

    Zager, Richard A; Johnson, Ali C M; Naito, Masayo; Lund, Steve R; Kim, Nayeon; Bomsztyk, Karol

    2008-09-01

    Many of the studies of acute renal injury have been conducted in young mice usually during their rapid growth phase; yet, the impact of age or growth stage on the degree of injury is unknown. To address this issue, we studied three forms of injury (endotoxemic-, glycerol-, and maleate-induced) in mice ranging in age from adolescence (3 weeks) to maturity (16 weeks). The severity of injury within each model significantly correlated with weight and age. We also noticed a progressive age-dependent reduction in renal cholesterol content, a potential injury modifier. As the animals grew and aged they also exhibited stepwise decrements in the mRNAs of HMG CoA reductase and the low density lipoprotein receptor, two key cholesterol homeostatic genes. This was paralleled by decreased amounts of RNA polymerase II and the transcription factor SREBP1/2 at the reductase and lipoprotein receptor gene loci as measured by chromatin immunoprecipitation. Our study shows that the early phase of mouse growth can profoundly alter renal susceptibility to diverse forms of experimental acute renal injury.

  1. Comparative Analysis of Expression Profiles of Panicle Development among Tolerant and Sensitive Rice in Response to Drought Stress

    PubMed Central

    Wei, Haibin; Chen, Chen; Ma, Xiaosong; Zhang, Yu; Han, Jing; Mei, Hanwei; Yu, Shunwu

    2017-01-01

    Water deficit caused a serious threat to crops, especially panicle development at reproductive growth phase. We investigated grain yield components and gene expression profiles of panicle among tolerant and sensitive rice in response to drought stress. Panicle morphologies exhibited that secondary branches per panicle were more severely affected as compared to primary branches per panicle. Moreover, grain weight per panicle showed significant decrease for both tolerant and sensitive varieties except for MILT1444. Expression profile analysis revealed that 783 differentially expressed genes (DEGs) were identified to be drought-induced from young panicles in 2 cm length. Hierarchical clustering indicated that 76.8% of DEGs were up-regulated for all six rice varieties, and the percentage of down-regulated genes was higher in sensitive group than tolerant group. Biological process category revealed that the shared Gene Ontology (GO) terms were involved in response to abiotic stimulus and stress, whereas the specific GO terms in tolerant group were identified as regulation of biological quality, homeostatic process, cell growth, anatomical structure morphogenesis and development, and the unique terms in sensitive varieties were identified as lipid metabolic process and secondary metabolic process. Furthermore, the gene-based association analysis narrowed down list of DEGs, and four genes common to all six varieties were selected as candidate for breeders. Together, we found several shared and distinct biological processes between tolerant and sensitive varieties, and candidate stress-responsive genes. These findings provided insight into functional mechanisms regulating drought stress response in panicle development and may also help to crop tolerant improvement.

  2. Development of a more fish-tolerant turbine runner, advanced hydropower turbine project

    SciTech Connect

    Cook, T.C.; Hecker, G.E.; Faulkner, H.B.; Jansen, W.

    1997-02-01

    Alden Research Laboratory, Inc. (ARL) and Northern Research and Engineering Corporation (NREC) conducted a research program to develop a turbine runner which will minimize fish injury and mortality at hydroelectric projects. ARL?NREC have developed a runner shape which minimizes the number of blade leading edges, reduces the pressure versus time and the velocity versus distance gradients within the runner, minimizes or eliminates the clearance between the runner and runner housing, and maximizes the size of the flow passages, all with minimal penalty on turbine efficiency. An existing pump impeller provided the starting point for developing the fish tolerant turbine runner. The Hidrostal pump is a single bladed combined screw/centrifugal pump which has been proven to transport fish with minimal injury. The focus of the ARL/NREC research project was to develop a new runner geometry which is effective in downstream fish passage and hydroelectric power generation. A flow of 1,000 cfs and a head in the range of 75 ft to 100 ft were selected for conceptual design of the new runner. Conceptual design of the new runner began with a re-evaluation of studies which have been previously conducted to identify probable sources of injury to fish passing through hydraulic turbines. Criteria relative to hydraulic characteristics which are favorable for fish passage were prepared based on a reassessment of the available information. Important criteria used to develop the new runner design included low pressure change rates, minimum absolute pressures, and minimum shear. Other criteria which are reflected in the runner design are a minimum number of blades (only two), minimum total length of leading edges, and large flow passages. 86 figs., 5 tabs.

  3. Tolerating Zero Tolerance?

    ERIC Educational Resources Information Center

    Moore, Brian N.

    2010-01-01

    The concept of zero tolerance dates back to the mid-1990s when New Jersey was creating laws to address nuisance crimes in communities. The main goal of these neighborhood crime policies was to have zero tolerance for petty crime such as graffiti or littering so as to keep more serious crimes from occurring. Next came the war on drugs. In federal…

  4. Solution ELISA as a platform of choice for development of robust, drug tolerant immunogenicity assays in support of drug development.

    PubMed

    Mikulskis, Alvydas; Yeung, Dave; Subramanyam, Meena; Amaravadi, Lakshmi

    2011-02-28

    Humanized monoclonal antibody therapeutics are in many ways indistinguishable from the anti-therapeutic/anti-drug antibodies generated in humans. Therefore, immunogenicity assessments to such therapeutics pose unique challenges in clinical trials especially when significant drug interference is encountered. There are several technology platforms based on the bridging immunogenicity assay format, which have been successfully used for detection and quantification of anti-drug antibodies (ADA) in serum or plasma samples. Enzyme-Linked Immunosorbent Assay (ELISA) and Electrochemiluminescent (ECL) immunoassay formats are among the most popular technology platforms. Pretreatment of samples with acid can also be used to lower drug interference. While ECL technology platform offered many advantages over traditional solid-phase ELISA methods, reliance on a single (or limited) vendor source became a significant concern within the biopharmaceutical industry especially for immunogenicity assays that need to be implemented over a period of many years in support of a single drug development program. We describe herein a systematic evaluation of solid-phase ELISA, GYROS, AlphaLISA, ECL Immunoassay, and solution ELISA platforms for detection of anti-drug antibodies with the goal of selection and development of a robust technology platform that meets the desired performance characteristics for most immunogenicity assays and can be easily implemented in a typical immunoassay laboratory. As part of this effort the Design of Experiments (DOE) approach was utilized in optimization of sample acid treatment conditions in order to improve drug tolerance in the evaluated assay platforms. After the initial evaluation of various technology platforms, a solution ELISA format was chosen for further development to support clinical trials for a humanized therapeutic antibody. As part of the assay development, flexible use of digoxigenin and 6-(2,4-dinitrophenyl) aminohexanoic acid (DNP) for

  5. 78 FR 63220 - Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-23

    ... HUMAN SERVICES Food and Drug Administration Guidance for Industry on Acute Bacterial Skin and Skin... guidance for industry entitled ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for... drugs to treat acute bacterial skin and skin structure infections (ABSSSI). This guidance finalizes...

  6. [The conditioned-reflex mechanism of the development of tolerance for and dependence on narcotic agents].

    PubMed

    Tsibul'skiĭ, V L; Belyĭ, V P

    1992-01-01

    At the beginning the term "tolerance" determinations, given in different source of literature, have been considered. Further, the history of conditioned of tolerance and abuse creation from psycho-active drugs have been discussed. The hart of the article contains the critical points of the current representation of neurophysiological theory in the field of behavior, interaction mechanisms between live systems and drugs. The point of view, dominating in pharmacology science that tolerance is the direct result of drug substances intervention into the organism, has been opposed. Separation of primary and secondary physiological effects of drugs, allowed to the authors to conclude that the dominant role belongs to the state living system and to the presence of necessities during the motivation creations for the second drug use and to the tolerance changing.

  7. Role of Homocysteine in the Ischemic Stroke and Development of Ischemic Tolerance

    PubMed Central

    Lehotský, Ján; Tothová, Barbara; Kovalská, Maria; Dobrota, Dušan; Beňová, Anna; Kalenská, Dagmar; Kaplán, Peter

    2016-01-01

    tolerance and recognition of the co-morbid risk factors would result in development of new avenues for exploration of novel therapeutics against ischemia and stroke. PMID:27932944

  8. Interplay between reactive oxygen species and hormones in the control of plant development and stress tolerance.

    PubMed

    Xia, Xiao-Jian; Zhou, Yan-Hong; Shi, Kai; Zhou, Jie; Foyer, Christine H; Yu, Jing-Quan

    2015-05-01

    As a consequence of a sessile lifestyle, plants are continuously exposed to changing environmental conditions and often life-threatening stresses caused by exposure to excessive light, extremes of temperature, limiting nutrient or water availability, and pathogen/insect attack. The flexible coordination of plant growth and development is necessary to optimize vigour and fitness in a changing environment through rapid and appropriate responses to such stresses. The concept that reactive oxygen species (ROS) are versatile signalling molecules in plants that contribute to stress acclimation is well established. This review provides an overview of our current knowledge of how ROS production and signalling are integrated with the action of auxin, brassinosteroids, gibberellins, abscisic acid, ethylene, strigolactones, salicylic acid, and jasmonic acid in the coordinate regulation of plant growth and stress tolerance. We consider the local and systemic crosstalk between ROS and hormonal signalling pathways and identify multiple points of reciprocal control, as well as providing insights into the integration nodes that involve Ca(2+)-dependent processes and mitogen-activated protein kinase phosphorylation cascades.

  9. Identification of desiccation tolerance transcripts potentially involved in rape (Brassica napus L.) seeds development and germination.

    PubMed

    Lang, Sirui; Liu, Xiaoxia; Ma, Gang; Lan, QinYing; Wang, Xiaofeng

    2014-10-01

    To investigate regulatory processes and protective mechanisms leading to desiccation tolerance (DT) in seeds, cDNA amplified fragment length polymorphism (cDNA-AFLP) in conjunction with 128 primer combinations was used to detect differential gene expression in rape seeds in response to DT during seed development and germination. We obtained approximately 8000 transcript-derived fragments (TDFs), of which 394 TDFs with differential expression patterns ("sustained expression", "up-regulated", "couple with seed DT", and "down-regulated") were excised from gels and re-amplified by polymerase chain reaction (PCR). After sequencing and comparison with the National Center for Biotechnology Information database, 176 TDFs presented significant similarity with known genes that could be classified into the following categories: metabolism and energy, stress resistance and defense, storage, signal transduction, and other functional categories. Using semiquantitative reverse-transcription PCR and real-time PCR approaches, the significance of the differences was further confirmed in fresh seeds and dehydrated seeds. The genes that encode superoxide dismutase, peroxiredoxin, caleosin, oleosin S3, steroleosin, late embryogenesis abundant protein, glutathione reductase, β-glucosidase, S23 transcriptional repressor, and some heat-shock proteins could be associated with DT. The results of this study will aid in the identification of candidate genes for future experiments that seek to understand seed DT.

  10. Preliminary work toward the development of a dimensional tolerance standard for rapid prototyping

    NASA Technical Reports Server (NTRS)

    Kennedy, W. J.

    1996-01-01

    Rapid prototyping is a new technology for building parts quickly from CAD models. It works by slicing a CAD model into layers, then by building a model of the part one layer at a time. Since most parts can be sliced, most parts can be modeled using rapid prototyping. The layers themselves are created in a number of different ways - by using a laser to cure a layer of an epoxy or a resin, by depositing a layer of plastic or wax upon a surface, by using a laser to sinter a layer of powder, or by using a laser to cut a layer of paper. Rapid prototyping (RP) is new, and a standard part for use in comparing dimensional tolerances has not yet been chosen and accepted by ASTM (the American Society for Testing Materials). Such a part is needed when RP is used to build parts for investment casting or for direct use. The objective of this project was to start the development of a standard part by using statistical techniques to choose the features of the part which show curl - the vertical deviation of a part from its intended horizontal plane.

  11. Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development.

    PubMed

    Mosconi, E; Rekima, A; Seitz-Polski, B; Kanda, A; Fleury, S; Tissandie, E; Monteiro, R; Dombrowicz, D D; Julia, V; Glaichenhaus, N; Verhasselt, V

    2010-09-01

    Allergic asthma is a chronic lung disease resulting from an inappropriate T helper (Th)-2 response to environmental antigens. Early tolerance induction is an attractive approach for primary prevention of asthma. Here, we found that breastfeeding by antigen-sensitized mothers exposed to antigen aerosols during lactation induced a robust and long-lasting antigen-specific protection from asthma. Protection was more profound and persistent than the one induced by antigen-exposed non-sensitized mothers. Milk from antigen-exposed sensitized mothers contained antigen-immunoglobulin (Ig) G immune complexes that were transferred to the newborn through the neonatal Fc receptor resulting in the induction of antigen-specific FoxP3(+) CD25(+) regulatory T cells. The induction of oral tolerance by milk immune complexes did not require the presence of transforming growth factor-beta in milk in contrast to tolerance induced by milk-borne free antigen. Furthermore, neither the presence of IgA in milk nor the expression of the inhibitory FcgammaRIIb in the newborn was required for tolerance induction. This study provides new insights on the mechanisms of tolerance induction in neonates and highlights that IgG immune complexes found in breast milk are potent inducers of oral tolerance. These observations may pave the way for the identification of key factors for primary prevention of immune-mediated diseases such as asthma.

  12. Can crops tolerate acid rain

    SciTech Connect

    Kaplan, J.K.

    1989-11-01

    This brief article describes work by scientists at the ARS Air Quality-Plant Growth and Development Laboratory in Raleigh, North Carolina, that indicates little damage to crops as a result of acid rain. In studies with simulated acid rain and 216 exposed varieties of 18 crops, there were no significant injuries nor was there reduced growth in most species. Results of chronic and acute exposures were correlated in sensitive tomato and soybean plants and in tolerant winter wheat and lettuce plants. These results suggest that 1-hour exposures could be used in the future to screen varieties for sensitivity to acid rain.

  13. Development of a Native Escherichia coli Induction System for Ionic Liquid Tolerance

    PubMed Central

    Frederix, Marijke; Hütter, Kimmo; Leu, Jessica; Batth, Tanveer S.; Turner, William J.; Rüegg, Thomas L.; Blanch, Harvey W.; Simmons, Blake A.; Adams, Paul D.; Keasling, Jay D.; Thelen, Michael P.; Dunlop, Mary J.; Petzold, Christopher J.; Mukhopadhyay, Aindrila

    2014-01-01

    The ability to solubilize lignocellulose makes certain ionic liquids (ILs) very effective reagents for pretreating biomass prior to its saccharification for biofuel fermentation. However, residual IL in the aqueous sugar solution can inhibit the growth and function of biofuel-producing microorganisms. In E. coli this toxicity can be partially overcome by the heterologous expression of an IL efflux pump encoded by eilA from Enterobacter lignolyticus. In the present work, we used microarray analysis to identify native E. coli IL-inducible promoters and develop control systems for regulating eilA gene expression. Three candidate promoters, PmarR’, PydfO’, and PydfA’, were selected and compared to the IPTG-inducible PlacUV5 system for controlling expression of eilA. The PydfA’ and PmarR’ based systems are as effective as PlacUV5 in their ability to rescue E. coli from typically toxic levels of IL, thereby eliminating the need to use an IPTG-based system for such tolerance engineering. We present a mechanistic model indicating that inducible control systems reduce target gene expression when IL levels are low. Selected-reaction monitoring mass spectrometry analysis revealed that at high IL concentrations EilA protein levels were significantly elevated under the control of PydfA’ and PmarR’ in comparison to the other promoters. Further, in a pooled culture competition designed to determine fitness, the strain containing pPmarR’-eilA outcompeted strains with other promoter constructs, most significantly at IL concentrations above 150 mM. These results indicate that native promoters such as PmarR’ can provide effective systems for regulating the expression of heterologous genes in host engineering and simplify the development of industrially useful strains. PMID:24983352

  14. Considerations in the Development of a Sound Tolerance Interview and Questionnaire Instrument.

    PubMed

    Sherlock, LaGuinn P; Formby, Craig

    2017-02-01

    Most clinicians approach the objective fitting of hearing aids with three goals in mind: audibility, comfort, and tolerance. When these three amplification goals have been met, the hearing aid user is more likely to adapt to and perceive benefit from hearing aid use. However, problems related to the loudness of sounds and reduced sound tolerance, which may or may not be reported by the aided user, can adversely impact adaptation to amplification and the individual's quality of life. Although there are several standardized questionnaires available to evaluate hearing aid benefit and satisfaction, there is no standardized questionnaire or interview tool for evaluating reduced sound tolerance and the related impact on hearing aid use. We describe a 36-item tool, the Sound Tolerance Questionnaire (STQ), consisting of six sections, including experience with hearing aids, sound sensitivity/intolerance, medical and noise exposure histories, coexisting tinnitus problems, and a final question to differentiate the primary and secondary problems related to sound intolerance, tinnitus, and hearing loss. In its current format as a research tool, the STQ was sensitive in pinpointing vague sound tolerance complaints not reported by the study participants in eligibility screening by Formby et al. A refined version of the STQ, the Sound Tolerance Interview and Questionnaire Instrument (STIQI), structured as a two-part tool, is presented in the appendix for prospective clinical use. The STIQI has potential utility to delineate factors contributing to loudness complaints and/or reduced sound tolerance in individuals considering hearing aid use, as well as those who have been unsuccessful hearing aid users secondary to loudness complaints or sound intolerance. The STIQI, when validated and refined, also may hold promise for predicting hearing aid benefit and/or assessing treatment-related change over time of hearing aid use or interventions designed to remediate problems of loudness

  15. Supraspinal Inactivation of Mitochondrial Superoxide Dismutase is a Source of Peroxynitrite in the Development of Morphine Antinociceptive Tolerance

    PubMed Central

    Doyle, Timothy; Bryant, Leesa; Batinic-Haberle, Ines; Little, Joshua; Cuzzocrea, Salvatore; Masini, Emanuela; Spasojevic, Ivan; Salvemini, Daniela

    2010-01-01

    Effective treatment of chronic pain with morphine is limited by decreases in the drug’s analgesic action with chronic administration (antinociceptive tolerance). Because opioids are mainstays of pain management, restoring their efficacy has great clinical importance. We have recently reported that formation of peroxynitrite (ONOO−, PN) in the dorsal horn of the spinal cord plays a critical role in the development of morphine antinociceptive tolerance and have further documented that nitration and enzymatic inactivation of mitochondrial superoxide dismutase (MnSOD) at that site provides a source for this nitroxidative species. We now report for the first time that antinociceptive tolerance is also associated with the inactivation of MnSOD at supraspinal sites. Inactivation of MnSOD led to nitroxidative stress as evidenced by increased levels of products of oxidative DNA damage and activation of the nuclear factor poly (ADP-ribose) polymerase in whole brain homogenates. Co-administration of morphine with potent Mn porphyrin-based peroxynitrite scavengers, (MnTE-2-PyP5+ and MnTnHex-2-PyP5+) (1) restored the enzymatic activity of MnSOD, (2) attenuated PN derived nitroxidative stress, and (3) blocked the development of morphine induced antinociceptive tolerance. The more lipophilic analogue, MnTnHex-2-PyP5+ was able to cross the blood brain barrier at higher levels than its lipophylic counterpart MnTE-2-PyP5+ and was about 30 fold more efficacious. Collectively, these data suggest that peroxynitrite mediated enzymatic inactivation of supraspinal MnSOD provides a source of nitroxidative stress, which in turn contributes to central sensitization associated with the development of morphine antinociceptive tolerance. These results support our general contention that PN-targeted therapeutics may have potential as adjuncts to opiates in pain management. PMID:19607887

  16. An Assessment of Genetic Diversity and Drought Tolerance in Argan Tree (Argania spinosa) Populations: Potential for the Development of Improved Drought Tolerance.

    PubMed

    Chakhchar, Abdelghani; Haworth, Matthew; El Modafar, Cherkaoui; Lauteri, Marco; Mattioni, Claudia; Wahbi, Said; Centritto, Mauro

    2017-01-01

    individuals and then developing varieties with enhanced drought tolerance to enable the maintenance of argan production as climate change results in more frequent and severe drought events in Northern Africa.

  17. An Assessment of Genetic Diversity and Drought Tolerance in Argan Tree (Argania spinosa) Populations: Potential for the Development of Improved Drought Tolerance

    PubMed Central

    Chakhchar, Abdelghani; Haworth, Matthew; El Modafar, Cherkaoui; Lauteri, Marco; Mattioni, Claudia; Wahbi, Said; Centritto, Mauro

    2017-01-01

    individuals and then developing varieties with enhanced drought tolerance to enable the maintenance of argan production as climate change results in more frequent and severe drought events in Northern Africa. PMID:28303146

  18. Development of tolerance after repeated administration of a selective muscarinic M1 antagonist biperiden in healthy human volunteers.

    PubMed

    Salin-Pascual, R J; Granados-Fuentes, D; Galicia-Polo, L; Nieves, E; Gillin, J C

    1993-02-01

    The muscarinic antagonist biperiden produces a dose-dependent inhibition of (REM) sleep on acute administration. The present study addressed the possibility of pharmacological tolerance after repeated biperiden administration. Six healthy volunteers were studied under sleep laboratory conditions in the following situations: one acclimatization, night, two baseline (that were averaged), 4 nights of biperiden administration, and 4 nights of placebo recovery administration. Six milligrams of biperiden and placebo were administered in identical capsules. Volunteers and technicians were blind to the order of the administration of the capsules. REM sleep time was reduced during the first and the second night, but was not significantly different in comparison with baseline by the third night. During placebo recovery nights, REM sleep time was not different from baseline. REM sleep latency was increased during the first and second nights of biperiden administration, but tolerance to this effect was observed by the third night. On placebo nights a dramatic shortening of REM latency was observed. The present findings support the hypothesis that anticholinergic drugs, even a selective M1 antagonist such as biperiden, induce tolerance soon after administration. A similar effect has been reported with scopolamine, a nonselective muscarinic antagonist, but the main difference is that biperiden withdrawal was not followed by an REM sleep rebound. The observed effect on REM sleep latency during placebo administration may be related to a supersensitivity to muscarinic M-1 receptors that trigger the first REM sleep period. Because short REM latency has been the main finding in the sleep of depressed patients, some implications of the present findings are discussed.

  19. Efficacy and tolerability of an ectoine mouth and throat spray compared with those of saline lozenges in the treatment of acute pharyngitis and/or laryngitis: a prospective, controlled, observational clinical trial.

    PubMed

    Müller, Dörte; Lindemann, Torben; Shah-Hosseini, Kija; Scherner, Olaf; Knop, Markus; Bilstein, Andreas; Mösges, Ralph

    2016-09-01

    The aim of this observational trial was to evaluate the efficacy and tolerability of a mouth and throat spray containing ectoine in the treatment of acute pharyngitis and/or laryngitis. The outcome was compared with control treatment using saline lozenges. This study was designed as a prospective, controlled, non-randomized, observational multicenter clinical trial and was conducted in Germany. The study population consisted of 95 patients. The decision for treatment with either spray or lozenges was based on the patients' preference for pharyngeal or oral application. Investigators assessed symptoms specific to acute pharyngitis/laryngitis and determined the pharyngitis symptom score. Both patients and investigators evaluated the tolerability and efficacy of the treatment applied. Treatment with the spray showed higher efficacy, 1.95 ± 0.81 versus 1.68 ± 0.67 (investigators) and 1.97 ± 0.88 versus 1.57 ± 0.69 (patients, p < 0.05). Treatment with the spray resulted in significantly greater reduction of cervical lymph node swelling (p < 0.05), ∆ spray = 0.44 ± 0.62, ∆ lozenges = 0.21 ± 0.62. The lozenges showed some advantage in relieving cough, ∆ lozenges = 0.62 ± 0.94 versus ∆ spray = 0.44 ± 0.85. Both patients and investigators rated the tolerability of both medical devices as "good" to "very good". Adverse events of mild to moderate severity were either possibly related or not related to the medical devices used. No serious adverse events occurred. Taken together, while the tolerability was consistent in both treatment groups, the ectoine-based spray showed superior efficacy in treating acute pharyngitis and/or laryngitis.

  20. Application of Acute Maximal Exercise to Enhance Mechanisms Underlying Blood Pressure Regulation and Orthostatic Tolerance After Exposure to Simulated Microgravity

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Engelke, K. A.; Doerr, D. F.

    1999-01-01

    Development of orthostatic hypotension and intolerance in astronauts who return to earth following a spaceflight mission represents a significant operational concern to NASA. Reduced plasma volume, vascular resistance, and baroreflex responsiveness following exposure to actual and ground-based analogs of microgravity have been associated with orthostatic instability, suggesting that these mechanisms may contribute alone or in combination to compromise of blood pressure regulation after spaceflight. It therefore seems reasonable that development of procedures designed to reverse or restore the effects of microgravity on regulatory mechanisms of blood volume, vascular resistance and cardiac function should provide some protection against postflight orthostatic intolerance. Several investigations have provided evidence that a single bout of exhaustive dynamic exercise enhances functions of mechanisms responsible for blood pressure stability. Therefore, the purpose of our research project was to conduct a series of experiments using ground-based analogs of reduced gravity (i.e., prolonged restriction to the upright standing posture) in human subjects to investigate the hypothesis that a single bout of dynamic maximal exercise would restore blood volume, vascular resistance and cardiac function and improve blood pressure stability.

  1. Medical student and junior doctors' tolerance of ambiguity: development of a new scale.

    PubMed

    Hancock, Jason; Roberts, Martin; Monrouxe, Lynn; Mattick, Karen

    2015-03-01

    The practice of medicine involves inherent ambiguity, arising from limitations of knowledge, diagnostic problems, complexities of treatment and outcome and unpredictability of patient response. Research into doctors' tolerance of ambiguity is hampered by poor conceptual clarity and inadequate measurement scales. We aimed to create and pilot a measurement scale for tolerance of ambiguity in medical students and junior doctors that addresses the limitations of existing scales. After defining tolerance of ambiguity, scale items were generated by literature review and expert consultation. Feedback on the draft scale was sought and incorporated. 411 medical students and 75 foundation doctors in Exeter, UK were asked to complete the scale. Psychometric analysis enabled further scale refinement and comparison of scale scores across subgroups. The pilot study achieved a 64% response rate. The final 29 item version of the Tolerance of Ambiguity in Medical Students and Doctors (TAMSAD) scale had good internal reliability (Cronbach's α 0.80). Tolerance of ambiguity was higher in foundation year 2 doctors than first, third and fourth year medical students (-5.23, P = 0.012; -5.98, P = 0.013; -4.62, P = 0.035, for each year group respectively). The TAMSAD scale offers a valid and reliable alternative to existing scales. Further work is required in different settings and in longitudinal studies but this study offers intriguing provisional insights.

  2. Development of equipment parameter tolerances for the ultrasonic inspection of steel components: Application to components up to 3 inches thick

    SciTech Connect

    Green, E.R.; Doctor, S.R.; Hockey, R.L.; Diaz, A.A. )

    1992-06-01

    This report documents work performed at Pacific Northwest Laboratory on the effect of frequency domain equipment interactions on the reliability of ultrasonic inservice inspection. The primary focus of this work is to provide information to the United States Nuclear Regulatory Commission on the acceptability of equipment parameter tolerances as given in the American Society of Mechanical Engineers (ASME) Boiler and Pressure Vessel Code Section 11 Appendix 8. Mathematical models were developed for the entire ultrasonic inspection system including sound propagation through the inspection sample. The models were used to determine worst-case inspection scenarios for thin sections (piping), and these worst-case inspection scenarios were then used in sensitivity studies to determine the suitability of equipment parameter tolerances. Ultrasonics literature was reviewed to find worst-case inspection scenarios outside the scope of the model used, but none that were significantly worse were found. Experiments were performed to confirm the important modeling results. Methods for reducing parameter sensitivity such as the use of a phase insensitive receive were also investigated. The model predicted that ASME Code tolerances for equipment bandwidth are acceptable, but tolerances for center frequency are too broad to provide reliable inspection of worst-case defects using narrow band systems. Experiments confirmed the basic trends predicted by the model, but the model seems to be conservative in that it shows greater sensitivity than is found empirically.

  3. Predicting the acute behavioral effects in rats inhaling toluene for up to 24 hrs: Inhaled vs, internal dose metrics and tolerance.

    EPA Science Inventory

    The acute toxicity of toluene, a model volatile organic compound (VOC), depends on the concentration (C) and duration (t) of exposure, and guidelines for acute exposures have traditionally used extrelationships to extrapolate protective and/or effective concentrations across dura...

  4. The SIFT computer and its development. [Software Implemented Fault Tolerance for aircraft control

    NASA Technical Reports Server (NTRS)

    Goldberg, J.

    1981-01-01

    Software Implemented Fault Tolerance (SIFT) is an aircraft control computer designed to allow failure probability of less than 10 to the -10th/hour. The system is based on advanced fault-tolerance computing and validation methodology. Since confirmation of reliability by observation is essentially impossible, system reliability is estimated by a Markov model. A mathematical proof is used to justify the validity of the Markov model. System design is represented by a hierarchy of abstract models, and the design proof comprises mathematical proofs that each model is, in fact, an elaboration of the next more abstract model.

  5. From immunosuppression to tolerance.

    PubMed

    Adams, David H; Sanchez-Fueyo, Alberto; Samuel, Didier

    2015-04-01

    The past three decades have seen liver transplantation becoming a major therapeutic approach in the management of end-stage liver diseases. This is due to the dramatic improvement in survival after liver transplantation as a consequence of the improvement of surgical and anaesthetic techniques, of post-transplant medico-surgical management and of prevention of disease recurrence and other post-transplant complications. Improved use of post-transplant immunosuppression to prevent acute and chronic rejection is a major factor in these improved results. The liver has been shown to be more tolerogenic than other organs, and matching of donor and recipients is mainly limited to ABO blood group compatibility. However, long-term immunosuppression is required to avoid severe acute and chronic rejection and graft loss. With the current immunosuppression protocols, the risk of acute rejection requiring additional therapy is 10-40% and the risk of chronic rejection is below 5%. However, the development of histological lesions in the graft in long-term survivors suggest atypical forms of graft rejection may develop as a consequence of under-immunosuppression. The backbone of immunosuppression remains calcineurin inhibitors (CNI) mostly in association with steroids in the short-term and mycophenolate mofetil or mTOR inhibitors (everolimus). The occurrence of post-transplant complications related to the immunosuppressive therapy has led to the development of new protocols aimed at protecting renal function and preventing the development of de novo cancer and of dysmetabolic syndrome. However, there is no new class of immunosuppressive drugs in the pipeline able to replace current protocols in the near future. The aim of a full immune tolerance of the graft is rarely achieved since only 20% of selected patients can be weaned successfully off immunosuppression. In the future, immunosuppression will probably be more case oriented aiming to protect the graft from rejection and at

  6. Developing drug strategies for the neuroprotective treatment of acute ischemic stroke.

    PubMed

    Tuttolomondo, Antonino; Pecoraro, Rosaria; Arnao, Valentina; Maugeri, Rosario; Iacopino, Domenico Gerardo; Pinto, Antonio

    2015-01-01

    Developing new treatment strategies for acute ischemic stroke in the last twenty years has offered some important successes, but also several failures. Most trials of neuroprotective therapies have been uniformly negative to date. Recent research has reported how excitatory amino acids act as the major excitatory neurotransmitters in the cerebral cortex and hippocampus. Furthermore, other therapeutic targets such as free radical scavenger strategies and the anti-inflammatory neuroprotective strategy have been evaluated with conflicting data in animal models and human subjects with acute ischemic stroke. Whereas promising combinations of neuroprotection and neurorecovery, such as citicoline, albumin and cerebrolysin have been tested with findings worthy of further evaluation in larger randomized clinical trials. Understanding the complexities of the ischemic cascade is essential to developing pharmacological targets for acute ischemic stroke in neuroprotective or flow restoration therapeutic strategies.

  7. Development of Cardiovascular Indices of Acute Pain Responding in Infants: A Systematic Review

    PubMed Central

    Waxman, Jordana A.; Pillai Riddell, Rebecca R.; Tablon, Paula; Schmidt, Louis A.; Pinhasov, Angelina

    2016-01-01

    Background. Cardiovascular indices of pain are pervasive in the hospital setting. However, no prospective research has examined the development of cardiac responses to acutely painful procedures in the first year of life. Objectives. Our main goal was to synthesize existing evidence regarding the development of cardiovascular responses to acutely painful medical procedures over the first year of life in preterm and term born infants. Methods. A systematic search retrieved 6994 articles to review against inclusion criteria. A total of 41 studies were included in the review. Results. In response to acutely painful procedures, most infants had an increase in mean heart rate (HR) that varied in magnitude both across and within gestational and postnatal ages. Research in the area of HR variability has been inconsistent, limiting conclusions. Conclusions. Longitudinal research is needed to further understand the inherent variability of cardiovascular pain responses across and within gestational and postnatal ages and the causes for the variability. PMID:27445630

  8. Medical Student and Junior Doctors' Tolerance of Ambiguity: Development of a New Scale

    ERIC Educational Resources Information Center

    Hancock, Jason; Roberts, Martin; Monrouxe, Lynn; Mattick, Karen

    2015-01-01

    The practice of medicine involves inherent ambiguity, arising from limitations of knowledge, diagnostic problems, complexities of treatment and outcome and unpredictability of patient response. Research into doctors' tolerance of ambiguity is hampered by poor conceptual clarity and inadequate measurement scales. We aimed to create and pilot a…

  9. Environmental Factors Involved in the Development of Tolerance to Behavior Effects of Delta-9-Tetrahydrocannabinol.

    DTIC Science & Technology

    1976-08-01

    Squirrel monkeys were trained under a variety of behavioral procedures, and then Delta- 9 - tetrahydrocannabinol was administered daily until tolerance...effects of Delta- 9 - tetrahydrocannabinol . Three classes of experiments were performed. The first group of experiments examined the roles of behavioral

  10. Environmental Factors Involved in the Development of Tolerance to Behavioral Effects of Delta-9-Tetrahydrocannabinol

    DTIC Science & Technology

    1975-08-01

    tolerance seems a reliable outcome when simple motor responses are maintained by schedules of positive reinforcement (e.g., Carlini, 1968; Ferr~ro and...when simple responses are maintained by schedules of positive reinforcement . On the other hand, when procedures that employ "unlearned" (elicited

  11. Involvement of moesin in the development of morphine analgesic tolerance through P-glycoprotein at the blood-brain barrier.

    PubMed

    Kobori, Takuro; Fujiwara, Shuhei; Miyagi, Kei; Harada, Shinichi; Nakamoto, Kazuo; Nakagawa, Takayuki; Takahashi, Hideo; Narita, Minoru; Tokuyama, Shogo

    2014-01-01

    Altered expression of P-glycoprotein (P-gp), a drug efflux transporter expressed by brain capillary endothelial cells (BCECs), may contribute to the development of opioid analgesic tolerance, as demonstrated by cumulative evidence from research. However, the detailed mechanism by which chronic morphine treatment increases P-gp expression remains unexplained. Ezrin/radixin/moesin (ERM) are scaffold proteins that are known to regulate the plasma membrane localization of some drug transporters such as P-gp in peripheral tissues, although a few reports suggest its role in the central nervous system as well. In this study, we investigated the involvement of ERM in the development of morphine analgesic tolerance through altered P-gp expression in BCECs. Repeated treatment with morphine (10 mg/kg/day, s.c. for 5 days) decreased its analgesic effect in the tail-flick test and increased P-gp protein expression in BCECs, as determined by Western blotting. Furthermore, moesin protein expression increased in the same fraction whereas that of ezrin decreased; no change was observed in the radixin expression. Furthermore, immunoprecipitation and immunofluorescence assays revealed interaction between moesin and P-gp molecules, along with co-localization, in BCECs. In conclusion, an increase in moesin expression may contribute to the increased expression of P-gp in BCECs, leading to the development of morphine analgesic tolerance.

  12. The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.

    PubMed

    Hartings, Jed A; Shuttleworth, C William; Kirov, Sergei A; Ayata, Cenk; Hinzman, Jason M; Foreman, Brandon; Andrew, R David; Boutelle, Martyn G; Brennan, K C; Carlson, Andrew P; Dahlem, Markus A; Drenckhahn, Christoph; Dohmen, Christian; Fabricius, Martin; Farkas, Eszter; Feuerstein, Delphine; Graf, Rudolf; Helbok, Raimund; Lauritzen, Martin; Major, Sebastian; Oliveira-Ferreira, Ana I; Richter, Frank; Rosenthal, Eric S; Sakowitz, Oliver W; Sánchez-Porras, Renán; Santos, Edgar; Schöll, Michael; Strong, Anthony J; Urbach, Anja; Westover, M Brandon; Winkler, Maren Kl; Witte, Otto W; Woitzik, Johannes; Dreier, Jens P

    2016-01-01

    A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão's historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

  13. [Importance of bone scanning and osteoscintimetry for assessing development of acute haematogenic childhood osteomyelitis (author's transl)].

    PubMed

    Fotter, R; Höllwarth, M

    1980-01-01

    Bone scanning with 99m-Tc-MDP is generally used for the early diagnosis of acute haematogenic childhood osteomyelitis. The combination of this method with radionuclide osteoscintimetry and the evaluation of the relative uptake ratio supply objective criteria for assessing the development of the disease. They permit statements as to the morphological and functional aspects of the disease and thus facilitate clinical assessment.

  14. Myeloid Sarcoma in an Eyelid That Developed during Chemotherapy for Acute Myeloid Leukemia

    PubMed Central

    Kang, Hyera; Takahashi, Yasuhiro; Takahashi, Emiko; Kakizaki, Hirohiko

    2016-01-01

    An 80-year-old female presented with a mass in the left upper eyelid margin that had developed during chemotherapy for acute myeloid leukemia. The mass was elastic, hard, and pinkish, with a relatively smooth surface but without madarosis. The histopathological findings corresponded to a myeloid sarcoma. No blast cells were shown in the peripheral blood at the time of biopsy, and she subsequently underwent an azacitidine injection regimen. The size of the eyelid tumor decreased 3 months after the biopsy, when the course of azacitidine injections was completed. However, acute myeloid leukemia recurred, and the patient died PMID:26889156

  15. Risk Factors for the Development of Intra-Abdominal Fungal Infections in Acute Pancreatitis

    PubMed Central

    Schwender, Brian J.; Gordon, Stuart R.; Gardner, Timothy B.

    2015-01-01

    Objectives Intra-abdominal fungal infections (AFI) complicating acute pancreatitis arise in the context of pancreatic necrosis. Our goal was to determine which risk factors contribute to AFI in patients with acute pancreatitis. Methods Records were reviewed from 479 non-transfer patients admitted to our medical center with acute pancreatitis from 1985–2009. Using multivariable regression models, risk factors for AFI were identified. Results Out of 479 patients admitted with acute pancreatitis, 17 patients were subsequently found to have an AFI and 3 of these patients expired. The mean length of stay for patients with an AFI was 24 days and 76% were admitted to the intensive care unit. Patients with AFI were more likely to have received prophylactic antibiotics on admission (OR 1.7, 95% C.I. 1.2–2.3), TPN within 7 days of admission (OR 1.4, 95% C.I. 1.1–1.7) or to have necrosis on CT scan within 7 days of admission (OR 1.4, 95% C.I. 1.1–1.7). Multivariable regression models identified admission antibiotic use (OR 1.6, 95% C.I. 1.4–1.8) as the strongest predictor of AFI. Conclusion Admission antibiotics are the biggest risk factor for the development of intra-abdominal fungal infections in acute pancreatitis. Prophylactic antibiotics to prevent infected necrosis should therefore be discouraged. PMID:25872170

  16. Pancreatitis developing in the context of acute hepatitis: a literature review.

    PubMed

    Khedmat, Hossein; Ghamar-Chehreh, Mohammad Ebrahim; Agah, Shahram; Aghaei, Aghdas

    2015-03-20

    Despite strong evidence suggestive of associations between hepatic diseases and pancreas injury, a potential relationship between acute hepatitis and acute pancreatitis has not been a matter of review; which we focused on in the current paper. Some of the main findings of this review article are: fulminant hepatitis failure represents the highest incident rate of hepatitis-related acute pancreatitis; so a screening program might be indicative in these patients. Specific characteristics of HAV-related pancreatitis are that it is a benign condition with no reported mortality; and a male preponderance in the incidence, with females developing in older ages and having shown the signs of both conditions simultaneously. The incidence of acute pancreatitis in HBV infection is the lowest, but the mortality was the highest. HEV-related acute pancreatitis was most likely to represent pseudocysts and there was an apparent ethnic-priority with Indian descents, the only reported cases in the literature. Hepatitis-related pancreatitis in liver transplant recipients was most frequent in HBV infected patients; and in IFN-induced pancreatitis, cessation of the drug was most effective in treatment, with no catastrophic event reported.

  17. Comprehensive scanning of somatic mitochondrial DNA alterations in acute leukemia developing from myelodysplastic syndromes.

    PubMed

    Linnartz, Bjoern; Anglmayer, Roswitha; Zanssen, Stefanie

    2004-03-15

    Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by ineffective hematopoiesis resulting in refractory cytopenias. Transformation resulting in acute myeloblastic leukemia is the final stage in the multistep process of MDS evolution. Functional relevant mutations of mitochondrial DNA (mtDNA) have been related to sideroblastic anemia and MDS. To investigate the role of mtDNA in malignant transformation to acute leukemia, we used high-resolution techniques such as single-strand conformational polymorphism and fluorescence sequencing for investigation of the whole mitochondrial genome from blood cells of 10 patients with MDS. Functionally relevant point mutations in mitochondrial RNA and polypeptide-encoding genes were detected in 50% of patients with MDS. Their increasing mutation load connects MDS and the developing acute myeloid leukemias. Several point mutations of mtDNA, including secondary point mutations for Leber's hereditary optic neuropathy, occur in one bone marrow and may synergically affect bone marrow stem cells by an apoptotic pathway.

  18. Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801

    NASA Astrophysics Data System (ADS)

    Trujillo, Keith A.; Akil, Huda

    1991-01-01

    The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.

  19. Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice

    PubMed Central

    Lauro, Filomena; Giancotti, Luigino Antonio; Ilari, Sara; Dagostino, Concetta; Gliozzi, Micaela; Morabito, Chiara; Malafoglia, Valentina; Raffaeli, William; Muraca, Maurizio; Goffredo, Bianca M.; Mollace, Vincenzo; Muscoli, Carolina

    2016-01-01

    Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5–50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy. PMID:27227548

  20. Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice.

    PubMed

    Lauro, Filomena; Giancotti, Luigino Antonio; Ilari, Sara; Dagostino, Concetta; Gliozzi, Micaela; Morabito, Chiara; Malafoglia, Valentina; Raffaeli, William; Muraca, Maurizio; Goffredo, Bianca M; Mollace, Vincenzo; Muscoli, Carolina

    2016-01-01

    Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5-50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy.

  1. Development of an ischemic tolerance model in a PC12 cell line

    PubMed Central

    Maric, Dragan; Ruetzler, Christl; Barker, Jeffery L; Hallenbeck, John M

    2006-01-01

    Although ischemic tolerance has been described in a variety of primary cell culture systems, no similar in vitro models have been reported with any cell line. A model of ischemic preconditioning in the rat pheochromocytoma PC12 cell line is described here. When compared to nonpreconditioned cells, preexposure of PC12 cells to 6 hours of oxygen and glucose deprivation (OGD) significantly increased cell viability after 15 hours of OGD 24 hours later. Flow cytometry analysis of cells labeled with specific markers for apoptosis, Annexin V, and Hoechst 33342, and of DNA content, revealed that apoptosis is involved in OGD-induced PC12 cell death and that preconditioning of the cells mainly counteracts the effect of apoptosis. Immunocytochemistry of caspase-3, a central executioner in the apoptotic process, further confirmed the activation of apoptotic pathways in OGD-induced PC12 cell death. This model may be useful to investigate the cellular mechanisms involved in neuronal transient tolerance following ischemia. PMID:15647748

  2. Populus euphratica XTH overexpression enhances salinity tolerance by the development of leaf succulence in transgenic tobacco plants.

    PubMed

    Han, Yansha; Wang, Wei; Sun, Jian; Ding, Mingquan; Zhao, Rui; Deng, Shurong; Wang, Feifei; Hu, Yue; Wang, Yang; Lu, Yanjun; Du, Liping; Hu, Zanmin; Diekmann, Heike; Shen, Xin; Polle, Andrea; Chen, Shaoliang

    2013-11-01

    Populus euphratica is a salt-tolerant tree species that develops leaf succulence after a prolonged period of salinity stress. In the present study, a putative xyloglucan endotransglucosylase/hydrolase gene (PeXTH) from P. euphratica was isolated and transferred to tobacco plants. PeXTH localized exclusively to the endoplasmic reticulum and cell wall. Plants overexpressing PeXTH were more salt tolerant than wild-type tobacco with respect to root and leaf growth, and survival. The increased capacity for salt tolerance was due mainly to the anatomical and physiological alterations caused by PeXTH overexpression. Compared with the wild type, PeXTH-transgenic plants contained 36% higher water content per unit area and 39% higher ratio of fresh weight to dry weight, a hallmark of leaf succulence. However, the increased water storage in the leaves in PeXTH-transgenic plants was not accompanied by greater leaf thickness but was due to highly packed palisade parenchyma cells and fewer intercellular air spaces between mesophyll cells. In addition to the salt dilution effect in response to NaCl, these anatomical changes increased leaf water-retaining capacity, which lowered the increase of salt concentration in the succulent tissues and mesophyll cells. Moreover, the increased number of mesophyll cells reduced the intercellular air space, which improved carbon economy and resulted in a 47-78% greater net photosynthesis under control and salt treatments (100-150 mM NaCl). Taken together, the results indicate that PeXTH overexpression enhanced salt tolerance by the development of succulent leaves in tobacco plants without swelling.

  3. A Formal Method for Developing Provably Correct Fault-Tolerant Systems Using Partial Refinement and Composition

    DTIC Science & Technology

    2009-01-01

    which is defined in Table 5. Verify the ASW Properties. The property checker Salsa [8] easily verifies that the specification of the ASW’s normal behavior... Salsa to check the fault-tolerant specification FT for all properties listed in Table 4. All but P2 were shown to be invariants. Thus the required...Conf., 2000. 8. R. Bharadwaj and S. Sims. Salsa : Combining constraint solvers with BDDs for automatic invariant checking. In Proc. Tools and Algorithms

  4. A Formal Method for Developing Provably Correct Fault-Tolerant Systems Using Partial Refinement and Composition

    DTIC Science & Technology

    2009-01-01

    constructs the state invariant H1, which is defined in Table 5. Verify the ASW Properties. The property checker Salsa [8] easily verifies that the...as auxiliary invariants, we used Salsa to check the fault-tolerant specification FT for all properties listed in Table 4. All but P2 were shown to be...Proc. 19th Digital Avionics Sys. Conf., 2000. 8. R. Bharadwaj and S. Sims. Salsa : Combining constraint solvers with BDDs for automatic invariant

  5. Engineering the future. Development of transgenic plants with enhanced tolerance to adverse environments.

    PubMed

    Zurbriggen, Matias D; Hajirezaei, Mohammad-Reza; Carrillo, Nestor

    2010-01-01

    Environmental stresses - especially drought and salinity - and iron limitation are the primary causes of crop yield losses. Therefore, improvement of plant stress tolerance has paramount relevance for agriculture, and vigorous efforts are underway to design stress-tolerant crops. Three aspects of this ongoing research are reviewed here. First, attempts have been made to strengthen endogenous plant defences, which are characterised by intertwined, hierarchical gene networks involved in stress perception, signalling, regulation and expression of effector proteins, enzymes and metabolites. The multigenic nature of this response requires detailed knowledge of the many actors and interactions involved in order to identify proper intervention points, followed by significant engineering of the prospective genes to prevent undesired side-effects. A second important aspect refers to the effect of concurrent stresses as plants normally meet in the field (e.g., heat and drought). Recent findings indicate that plant responses to combined environmental hardships are somehow unique and cannot be predicted from the addition of the individual stresses, underscoring the importance of programming research within this conceptual framework. Finally, the photosynthetic microorganisms from which plants evolved (i.e., algae and cyanobacteria) deploy a totally different strategy to acquire stress tolerance, based on the substitution of stress-vulnerable targets by resistant isofunctional proteins that could take over the lost functions under adverse conditions. Reintroduction of these ancient traits in model and crop plants has resulted in increased tolerance to environmental hardships and iron starvation, opening a new field of opportunities to increase the endurance of crops growing under suboptimal conditions.

  6. Repeated injections of orexin-A developed behavioral tolerance to its analgesic effects in rats

    PubMed Central

    Ghasemi, Elmira; Heidari-Oranjaghi, Nima; Azhdari-Zarmehri, Hassan; Sadegh, Mehdi

    2015-01-01

    Objective(s): Reduction of pharmacological effectiveness or tolerance appears following repeated administration of many analgesic drugs. We investigated tolerance to anti-nociceptive effects of orexin-A, an endogenous potent analgesic peptide using the hot-plate test. Materials and Methods: Orexin-A was microinjected ICV (intracerebroventricular) with an interval of 12 hr for 7 continuous days and its anti-nociceptive responses were measured on days 1, 4 and 7 using the hot-plate test following the first day of administration. Orexin-A was used at a dose of 100 pmol to induce analgesic effects. Results: ICV administration of orexin-A produced an effective anti-nociception on the first day of experiment as measured by hot-plate 5, 15, and 30 min after the injection, in comparison with both baselines (hot-plate test one day before the beginning of orexin-A administration and control, saline-administrated group). However, repeated administration of orexin-A on the following days revealed a significant reduction in this analgesic effect during day 4 to day 7. However, to rule out any associative tolerance resulting from learning related to experimental procedures and/or environmental cues, a single injection of orexin-A was administrated to animals of control group (which were receiving saline during 7 days of experiments) and the analgesic effect was observed. Conclusion: These results, for the first time, indicated the appearance of tolerance to anti-nociceptive effects of orexin-A, following repeated administrations of this agent. PMID:26877847

  7. A serial histologic study of the development and progression of acute pancreatitis in the rat.

    PubMed Central

    Rao, S. S.; Watt, I. A.; Donaldson, L. A.; Crocket, A.; Joffe, S. N.

    1981-01-01

    This study was undertaken for the purpose of a serial investigation of the development and progression of the light-microscopic changes of acute pancreatitis and histologic criteria for evaluating pancreatitis. Acute pancreatitis, similar to that found in man, was induced in rats with the use of a closed duodenal loop technique (n = 36). Control rats underwent a laparotomy with mobilization of the duodenum (n = 12). Animals were killed every 2 hours for 24 hours, and a detailed and independent histologic evaluation was made of each. Focal acinar necrosis proceeding to a vasculitis appeared within 2--4 hours before the infiltration of inflammatory cells. Thereafter, the extent of acinar necrosis closely reflected the vasculitis with the later development of the acute inflammation. By the sixteenth hour, these changes were graded as moderate pancreatitis, and by 24 hours the process represented severe hemorrhagic pancreatitis. Vascular changes and acinar necrosis preceded the inflammatory cell infiltrate. The pancreatitis has been quantitated into minimal, moderate, or severe by assessing the severity of edema, acute inflammatory infiltrate, and changes in the vessels, ducts, and acini. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:7223862

  8. Development and Validation of a Risk-Adjustment Tool in Acute Asthma

    PubMed Central

    Tsai, Chu-Lin; Clark, Sunday; Sullivan, Ashley F; Camargo, Carlos A

    2009-01-01

    Objective To develop and prospectively validate a risk-adjustment tool in acute asthma. Data Sources Data were obtained from two large studies on acute asthma, the Multicenter Airway Research Collaboration (MARC) and the National Emergency Department Safety Study (NEDSS) cohorts. Both studies involved >60 emergency departments (EDs) and were performed during 1996–2001 and 2003–2006, respectively. Both included patients aged 18–54 years presenting to the ED with acute asthma. Study Design Retrospective cohort studies. Data Collection Clinical information was obtained from medical record review. The risk index was derived in the MARC cohort and then was prospectively validated in the NEDSS cohort. Principle Findings There were 3,515 patients in the derivation cohort and 3,986 in the validation cohort. The risk index included nine variables (age, sex, current smoker, ever admitted for asthma, ever intubated for asthma, duration of symptoms, respiratory rate, peak expiratory flow, and number of beta-agonist treatments) and showed satisfactory discrimination (area under the receiver operating characteristic curve, 0.75) and calibration (p=.30 for Hosmer–Lemeshow test) when applied to the validation cohort. Conclusions We developed and validated a novel risk-adjustment tool in acute asthma. This tool can be used for health care provider profiling to identify outliers for quality improvement purposes. PMID:19619246

  9. Sulfur tolerant anode materials

    SciTech Connect

    Not Available

    1988-02-01

    The goal of this program is the development of a molten carbonate fuel cell (MCFC) anode which is more tolerant of sulfur contaminants in the fuel than the current state-of-the-art nickel-based anode structures. This program addresses two different but related aspects of the sulfur contamination problem. The primary aspect is concerned with the development of a sulfur tolerant electrocatalyst for the fuel oxidation reaction. A secondary issue is the development of a sulfur tolerant water-gas-shift reaction catalyst and an investigation of potential steam reforming catalysts which also have some sulfur tolerant capabilities. These two aspects are being addressed as two separate tasks.

  10. Nitrate tolerance.

    PubMed

    Parker, J O

    1987-11-16

    The organic nitrates are the most widely used agents in the management of patients with angina pectoris. When initially administered by the oral route, the nitrates produce profound changes in systemic hemodynamics and significant and prolonged improvement in exercise duration. It has been shown that during short periods of regular oral nitrate administration, the hemodynamic, antiischemic and antianginal effects of the nitrates are greatly reduced. Thus, when initially administered, oral isosorbide dinitrate prolongs exercise duration for a period of several hours, but during sustained 4-times-daily therapy, exercise tolerance is improved for only 2 hours after administration. Studies with transdermal preparations of isosorbide dinitrate and nitroglycerin also show improvement during short-term administration for up to 8 hours, but after several days of once-daily therapy, the effects of these agents are similar to placebo. It is apparent that nitrate tolerance is a clinically relevant problem. Although tolerance develops rapidly during nitrate therapy, it is reversed promptly during nitrate-free periods. Oral nitrates maintain their antianginal effects when given 2 or 3 times daily with provision of a nitrate-free period. Studies are currently underway to investigate the effects of intermittent administration schedules with transdermal nitrate preparations.

  11. Development and preliminary validation of an integrated efficacy-tolerability composite measure for the evaluation of analgesics.

    PubMed

    Katz, Nathaniel P; Mou, Joy; Trudeau, Jeremiah; Xiang, Jim; Vorsanger, Gary; Orman, Camille; Kim, Myoung

    2015-07-01

    The goal of this analysis was to develop and evaluate integrated measures of benefit and tolerability of analgesic drugs in clinical trials. We evaluated an efficacy-tolerability composite (ETC) measure combining different cutoff values for daily pain reduction (≥20%, ≥30%, or ≥50% pain reduction) and adverse events (AEs) (no AE, no or mild AEs, no or mild drug-related AEs). Nine ETC cutoff values (3 × 3) were tested using data from a randomized double-blind trial comparing tapentadol extended release (ER) (n = 310), oxycodone controlled release (CR) (n = 322), and placebo (n = 314) in subjects with chronic low back pain. Efficacy-tolerability composite scores were calculated as the mean number of days a subject met the ETC criterion divided by the number of days the subject was expected to be in study; ETC scores were then averaged in each treatment group. For all 9 ETC measures, validity was demonstrated by significant correlation of ETC scores with patients' Global Impression of change and with change from baseline in pain scores. Tapentadol ER ETC scores were statistically significantly higher than oxycodone CR ETC scores for 4 of the ETC measures. "No/mild drug-related AE and ≥20% pain reduction" demonstrated the best overall validity (correlation with patients' global impression of change) and responsiveness (discrimination between treatment groups), yielding a higher standardized effect size for tapentadol ER compared with placebo (0.19 [95% confidence interval: 0.031-0.346]) and with oxycodone CR (0.23 [95% confidence interval: 0.070-0.383]) than other cutoff values. Thus, we have identified herein a composite measure that seems to be a valid and responsive measure of the overall efficacy and tolerability of analgesics in clinical trials.

  12. MOAtox: A comprehensive mode of action and acute aquatic toxicity database for predictive model development.

    PubMed

    Barron, M G; Lilavois, C R; Martin, T M

    2015-04-01

    The mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, the development of quantitative structure activity relationship (QSAR) and other models has been limited by the availability of comprehensive high quality MOA and toxicity databases. The current study developed a dataset of MOA assignments for 1213 chemicals that included a diversity of metals, pesticides, and other organic compounds that encompassed six broad and 31 specific MOAs. MOA assignments were made using a combination of high confidence approaches that included international consensus classifications, QSAR predictions, and weight of evidence professional judgment based on an assessment of structure and literature information. A toxicity database of 674 acute values linked to chemical MOA was developed for fish and invertebrates. Additionally, species-specific measured or high confidence estimated acute values were developed for the four aquatic species with the most reported toxicity values: rainbow trout (Oncorhynchus mykiss), fathead minnow (Pimephales promelas), bluegill (Lepomis macrochirus), and the cladoceran (Daphnia magna). Measured acute toxicity values met strict standardization and quality assurance requirements. Toxicity values for chemicals with missing species-specific data were estimated using established interspecies correlation models and procedures (Web-ICE; http://epa.gov/ceampubl/fchain/webice/), with the highest confidence values selected. The resulting dataset of MOA assignments and paired toxicity values are provided in spreadsheet format as a comprehensive standardized dataset available for predictive aquatic toxicology model development.

  13. Dissecting the Mechanism of T Cell Tolerance for More Effective Breast Cancer Vaccine Development

    DTIC Science & Technology

    2004-08-01

    comprising amino acids 420-429 (PDSLRDLSVF) of neu. We also determined that RNEU420-429 is naturally processed and presented by tumor cells and is the...the natural RNEU4 20-4 2 9 epitope, both wild-type RNEU4 2 0 -42 9 and the heteroclitic variant RNEU 420-429A2 were used to vaccinate mice. Dendritic...Cancer Res. 2001, May 1;61(9):3689-97. 9. Sakaguchi S. Naturally arising CD4÷ regulatory t cells for immunologic self-tolerance and negative control

  14. Development of radiation tolerant components for the Quench Protection System at CERN

    NASA Astrophysics Data System (ADS)

    Bitterling, O.; Denz, R.; Steckert, J.; Uznanski, S.

    2016-01-01

    This paper describes the results of irradiation campaigns with the high resolution Analog to Digital Converter (ADC) ADS1281. This ADC will be used as part of a revised quench detection circuit for the 600 A corrector magnets at the CERN Large Hadron Collider (LHC) . To verify the radiation tolerance of the ADC an irradiation campaign using a proton beam, applying doses up to 3,4 kGy was conducted. The resulting data and an analysis of the found failure modes is discussed in this paper. Several mitigation measures are described that allow to reduce the error rate to levels acceptable for operation as part of the LHC QPS.

  15. Acute kidney injury: risk factors and management challenges in developing countries

    PubMed Central

    Ponce, Daniela; Balbi, Andre

    2016-01-01

    Acute kidney injury (AKI) is a major global health problem in both developed and developing nations, negatively affecting patient morbidity and responsible for an estimated 1.4 million deaths per year. Although the International Society of Nephrology set a goal of eliminating preventable deaths from AKI by 2025, implementation of this program in developing countries presents major challenges not only because of the lack of resources but also because of the scarce data addressing the epidemiology and causes of AKI in developing countries, the limited health care resources to diagnose and treat AKI, and the poor awareness of the impact of AKI on patient outcomes. PMID:27578995

  16. Development and Psychometric Evaluation of Child Acute Stress Measures in Spanish and English

    PubMed Central

    Kassam-Adams, Nancy; Gold, Jeffrey I.; Montaño, Zorash; Kohser, Kristen L.; Cuadra, Anai; Muñoz, Cynthia; Armstrong, F. Daniel

    2015-01-01

    Clinicians and researchers need tools for accurate early assessment of children’s acute stress reactions and acute stress disorder (ASD). There is a particular need for independently validated Spanish-language measures. The current study reports on 2 measures of child acute stress (a self-report checklist and a semi-structured interview), describing the development of the Spanish version of each measure and psychometric evaluation of both the Spanish and English versions. Children between the ages of 8 to 17 years who had experienced a recent traumatic event completed study measures in Spanish (n = 225) or in English (n = 254). Results provide support for reliability (internal consistency of the measures in both languages ranges from .83 to .89; cross-language reliability of the checklist is .93) and for convergent validity (with later PTSD symptoms, and with concurrent anxiety symptoms). Comparing checklist and interview results revealed a strong association between severity scores within the Spanish and English samples. Checklist-interview differences in evaluating the presence of ASD appear to be linked to different content coverage for dissociation symptoms. Future studies should further assess the impact of differing assessment modes, content coverage, and the use of these measures in children with diverse types of acute trauma exposure in English- and Spanish-speaking children. PMID:23371337

  17. Development of acute exposure guideline levels for airborne exposures to hazardous substances.

    PubMed

    Krewski, Daniel; Bakshi, Kulbir; Garrett, Roger; Falke, Ernest; Rusch, George; Gaylor, David

    2004-04-01

    Hazardous substances can be released into the atmosphere due to industrial and transportation accidents, fires, tornadoes, earthquakes, and terrorists, thereby exposing workers and the nearby public to potential adverse health effects. Various enforceable guidelines have been set by regulatory agencies for worker and ambient air quality. However, these exposure levels generally are not applicable to rare lifetime acute exposures, which possibly could occur at high concentrations. Acute exposure guideline levels (AEGLs) provide estimates of concentrations for airborne exposures for an array of short durations that possibly could cause mild (AEGL-1), severe, irreversible, potentially disabling adverse health effects (AEGL-2), or life threatening effects (AEGL-3). These levels can be useful for emergency responders and planners in reducing or eliminating potential risks to the public. Procedures and methodologies for deriving AEGLs are reviewed in this paper that have been developed in the United States, with direct input from international representatives of OECD member-countries, by the National Advisory Committee for Acute Exposure Guidelines for Hazardous Substances and reviewed by the National Research Council. Techniques are discussed for the extrapolation of effects across different exposure durations. AEGLs provide a viable approach for assisting in the prevention, planning, and response to acute airborne exposures to toxic agents.

  18. Development and Initial Psychometric Evaluation of the Post-Acute Acuity Rating for Children

    PubMed Central

    O'Brien, Jane E.; Dumas, Helene M.

    2015-01-01

    The Post-Acute Acuity Rating for Children (PAARC) is the first known acuity rating intended to reflect medical severity based on age, reason for admission, diagnoses, dependence in activities of daily living, and technology reliance for children admitted to post-acute care rehabilitation hospitals. Content validity was tested using an expert panel scoring the Content Validity Index (CVI). Concurrent validity was examined using clinician's opinion of acuity at admission, the Complexity Index, and All Patient Refined Diagnosis Related Group (APR-DRG) codes. Predictive validity was examined with acute care readmission within 30 days. Interrater reliability was assessed using admission histories from closed cases. Content validity was established and concurrent validity was moderate to high with clinician opinion (rho = .76, p < .001), the Complexity Index (rho = .76, p < .001), and APR-DRGs (rho = .349, p = .001). Predictive validity was moderate (rho = .504, p = .005) and returns to acute care within 30 days. Interrater reliability was excellent (ICC = 0.97; 95% CI = 0.92–0.90, p < .001). Experts agreed that the PAARC's content is relevant, simple, and representative of the population. The PAARC measured well against indicators of medical complexity for pediatric outpatient care and medical record coding and was reliable between raters. This work supports proceeding with additional development and validity testing of the PAARC. PMID:26609433

  19. Development of Toxicological Risk Assessment Models for Acute and Chronic Exposure to Pollutants.

    PubMed

    Reichwaldt, Elke S; Stone, Daniel; Barrington, Dani J; Sinang, Som C; Ghadouani, Anas

    2016-08-31

    Alert level frameworks advise agencies on a sequence of monitoring and management actions, and are implemented so as to reduce the risk of the public coming into contact with hazardous substances. Their effectiveness relies on the detection of the hazard, but with many systems not receiving any regular monitoring, pollution events often go undetected. We developed toxicological risk assessment models for acute and chronic exposure to pollutants that incorporate the probabilities that the public will come into contact with undetected pollution events, to identify the level of risk a system poses in regards to the pollutant. As a proof of concept, we successfully demonstrated that the models could be applied to determine probabilities of acute and chronic illness types related to recreational activities in waterbodies containing cyanotoxins. Using the acute model, we identified lakes that present a 'high' risk to develop Day Away From Work illness, and lakes that present a 'low' or 'medium' risk to develop First Aid Cases when used for swimming. The developed risk models succeeded in categorising lakes according to their risk level to the public in an objective way. Modelling by how much the probability of public exposure has to decrease to lower the risks to acceptable levels will enable authorities to identify suitable control measures and monitoring strategies. We suggest broadening the application of these models to other contaminants.

  20. Development of Toxicological Risk Assessment Models for Acute and Chronic Exposure to Pollutants

    PubMed Central

    Reichwaldt, Elke S.; Stone, Daniel; Barrington, Dani J.; Sinang, Som C.; Ghadouani, Anas

    2016-01-01

    Alert level frameworks advise agencies on a sequence of monitoring and management actions, and are implemented so as to reduce the risk of the public coming into contact with hazardous substances. Their effectiveness relies on the detection of the hazard, but with many systems not receiving any regular monitoring, pollution events often go undetected. We developed toxicological risk assessment models for acute and chronic exposure to pollutants that incorporate the probabilities that the public will come into contact with undetected pollution events, to identify the level of risk a system poses in regards to the pollutant. As a proof of concept, we successfully demonstrated that the models could be applied to determine probabilities of acute and chronic illness types related to recreational activities in waterbodies containing cyanotoxins. Using the acute model, we identified lakes that present a ‘high’ risk to develop Day Away From Work illness, and lakes that present a ‘low’ or ‘medium’ risk to develop First Aid Cases when used for swimming. The developed risk models succeeded in categorising lakes according to their risk level to the public in an objective way. Modelling by how much the probability of public exposure has to decrease to lower the risks to acceptable levels will enable authorities to identify suitable control measures and monitoring strategies. We suggest broadening the application of these models to other contaminants. PMID:27589798

  1. Acute development of collateral circulation and therapeutic prospects in ischemic stroke.

    PubMed

    Iwasawa, Eri; Ichijo, Masahiko; Ishibashi, Satoru; Yokota, Takanori

    2016-03-01

    In acute ischemic stroke, collateral circulation plays an important role in maintaining blood flow to the tissue that is at risk of progressing into ischemia, and in increasing the successful recanalization rate without hemorrhagic transformation. We have reported that well-developed collateral circulation is associated with smaller infarct volume and better long-term neurological outcome, and it disappears promptly once the effective recanalization is achieved. Contrary to the belief that collateral vessels develop over time in chronic stenotic condition, there exists a phenomenon that collateral circulation develops immediately in acute stenosis or occlusion of the arteries and it seems to be triggered by fluid shear stress, which occurs between the territories of stenotic/occluded arteries and those fed by surrounding intact arteries. We believe that this acute development of collateral circulation is a target of novel therapeutics in ischemic stroke and refer our recent attempt in enhancing collateral circulation by modulating sphingosine-1-phosphate receptor 1, which is a known shear-stress mechanosensing protein.

  2. [Development of acute myeloid leukemia from donor cells after allogeneic peripheral blood stem cell transplantation in a female patient with acute monoblastic leukemia].

    PubMed

    2011-01-01

    Development of leukemia from donor cells is a rare complication of allogeneic blood stem cells (BSC). The paper describes a case of evolving acute myeloid leukemia of a graft in a patient with resistant acute monoblastic leukemia after related allogeneic peripheral BSC transplantation. The rarity of this complication, difficulties in providing evidence for the donor origin of a leukemic clone demonstrate a need for all-round careful dynamic assessment of the hematopoietic system after allogeneic transplantation, by applying the current cytogenetic (fluorescence in situ hybridization) and molecular (hypervariable genomic region amplification test using the polymerase chain reaction, hypervariable number of tandem repeats (VNTR), and short number of tandem repeats (STR)) techniques, which permits errors to be avoided in the assessment of a clinical situation and in the diagnosis of leukemia from donor cells. There is no developed policy for treatment of acute graft-versus-leukemia.

  3. Medullary Thymic Epithelial Cells and Central Tolerance in Autoimmune Hepatitis Development: Novel Perspective from a New Mouse Model

    PubMed Central

    Alexandropoulos, Konstantina; Bonito, Anthony J.; Weinstein, Erica G.; Herbin, Olivier

    2015-01-01

    Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease. PMID:25603179

  4. Short-term selection for acute ethanol tolerance and sensitization from an F2 population derived from the high and low alcohol-sensitive selectively bred rat lines.

    PubMed

    Radcliffe, Richard A; Bludeau, Pequita; Deng, Xin-Sheng; Erwin, V Gene; Deitrich, Richard A

    2007-12-01

    Previous studies have identified quantitative trait loci (QTL) in the inbred high and low alcohol-sensitive rat (IHAS1 and ILAS1) strains. The original development of the strains involved selection for ethanol sensitivity based on duration of the loss of the righting reflex (LORR) after a standard dose of ethanol. This paper confirms some of these QTL using a short-term selection procedure based on the difference between the blood ethanol level at LORR and regain of the righting response. An F(2) population of rats was developed by a reciprocal cross of IHAS1 and ILAS1 rats. Selection for five generations was carried out using delta-blood ethanol concentration (dBEC) as the selection trait, where dBEC=BECLR (BEC at loss of righting reflex)-BECRR (BEC at regain of righting reflex). The lines were labeled tolerant (TOL) or sensitive (SENS). Approximately one-third of the offspring for each generation in each line were genotyped using DNA markers that had been previously found to be linked to QTL on chromosomes 1, 2, 5, 12, and 13. By the fifth generation of selection, the lines showed a very large difference in dBEC, BECRR, and duration of LORR; BECLR showed little segregation during the selection, and latency to lose the righting reflex showed none. IHAS allele frequency increased in the SENS line for markers on chromosomes 1, 5, 12, and 13 while ILAS allele frequency increased in the TOL line. These results were in good agreement with the two previous QTL studies. On chromosome 2, the selection resulted in an accumulation of ILAS alleles in both lines. This study provides independent confirmation of the location of QTL on chromosomes 1, 5, 12, and 13 for ethanol sensitivity. It also suggests that genetic differences in duration of LORR are mediated primarily by the dBEC phenotype.

  5. Development of EST-SSR markers related to salt tolerance and their application in genetic diversity and evolution analysis in Gossypium.

    PubMed

    Wang, B H; Zhu, P; Yuan, Y L; Wang, C B; Yu, C M; Zhang, H H; Zhu, X Y; Wang, W; Yao, C B; Zhuang, Z M; Li, P

    2014-05-13

    Salt stress is becoming one of the major problems in global agriculture with the onset of global warming, an increasing scarcity of fresh water, and improper land irrigation and fertilization practices, which leads to reduction of crop output and even causes crop death. To speed up the exploitation of saline land, it is a good choice to grow plants with a high level of salt tolerance and economic benefits. As the leading fiber crop grown commercially worldwide, cotton is placed in the moderately salt-tolerant group of plant species, and there is promising potential to improve salt tolerance in cultivated cotton. To facilitate the mapping of salt-tolerant quantitative trait loci in cotton so as to serve the aims of salt-tolerant molecular breeding in cotton, it is necessary to develop salt-tolerant molecular markers. The objective of this research was to develop simple sequence repeat (SSR) markers based on cotton salt-tolerant expressed sequence tags. To test the efficacy of these SSR markers, their polymorphism and cross-species transferability were evaluated, and their value was further investigated on the basis of genetic diversity and evolution analysis.

  6. Dieselzymes: development of a stable and methanol tolerant lipase for biodiesel production by directed evolution

    PubMed Central

    2013-01-01

    Background Biodiesels are methyl esters of fatty acids that are usually produced by base catalyzed transesterification of triacylglyerol with methanol. Some lipase enzymes are effective catalysts for biodiesel synthesis and have many potential advantages over traditional base or acid catalyzed transesterification. Natural lipases are often rapidly inactivated by the high methanol concentrations used for biodiesel synthesis, however, limiting their practical use. The lipase from Proteus mirabilis is a particularly promising catalyst for biodiesel synthesis as it produces high yields of methyl esters even in the presence of large amounts of water and expresses very well in Escherichia coli. However, since the Proteus mirabilis lipase is only moderately stable and methanol tolerant, these properties need to be improved before the enzyme can be used industrially. Results We employed directed evolution, resulting in a Proteus mirabilis lipase variant with 13 mutations, which we call Dieselzyme 4. Dieselzyme 4 has greatly improved thermal stability, with a 30-fold increase in the half-inactivation time at 50°C relative to the wild-type enzyme. The evolved enzyme also has dramatically increased methanol tolerance, showing a 50-fold longer half-inactivation time in 50% aqueous methanol. The immobilized Dieselzyme 4 enzyme retains the ability to synthesize biodiesel and has improved longevity over wild-type or the industrially used Brukholderia cepacia lipase during many cycles of biodiesel synthesis. A crystal structure of Dieselzyme 4 reveals additional hydrogen bonds and salt bridges in Dieselzyme 4 compared to the wild-type enzyme, suggesting that polar interactions may become particularly stabilizing in the reduced dielectric environment of the oil and methanol mixture used for biodiesel synthesis. Conclusions Directed evolution was used to produce a stable lipase, Dieselzyme 4, which could be immobilized and re-used for biodiesel synthesis. Dieselzyme 4 outperforms

  7. Development of a positive psychology intervention for patients with acute cardiovascular disease.

    PubMed

    Huffman, Jeff C; Mastromauro, Carol A; Boehm, Julia K; Seabrook, Rita; Fricchione, Gregory L; Denninger, John W; Lyubomirsky, Sonja

    2011-09-29

    The management of depression and other negative psychological states in cardiac patients has been a focus of multiple treatment trials, though such trials have not led to substantial improvements in cardiac outcomes. In contrast, there has been minimal focus on interventions to increase positive psychological states in cardiac patients, despite the fact that optimism and other positive states have been associated with superior cardiovascular outcomes. Our objective was to develop an 8-week, phone-based positive psychology intervention for patients hospitalized with acute cardiac disease (acute coronary syndrome or decompensated heart failure). Such an intervention would consist of positive psychology exercises adapted for this specific population, and it would need to be feasible for practitioners and patients in real-world settings. By adapting exercises that were previously validated in healthy individuals, we were able to generate a positive psychology telemedicine intervention for cardiac patients that focused on optimism, kindness, and gratitude. In addition, we successfully created a companion treatment manual for subjects to enhance the educational aspects of the intervention and facilitate completion of exercises. Finally, we successfully performed a small pilot trial of this intervention, and found that the positive psychology intervention appeared to be feasible and well-accepted in a cohort of patients with acute cardiac illness. Future studies should further develop this promising intervention and examine its impact on psychological and medical outcomes in this vulnerable population of cardiac patients.

  8. Brain cholinergic involvement in the diurnal variations of the rapid development of tolerance to the hypothermic effect of ethanol

    SciTech Connect

    Wang, Q.H.; Soliman, K.F.A. )

    1992-02-26

    Male Sprague-Dawley rats maintained under controlled environmental conditions were used. Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were determined in the hypothalamus, pons, medulla oblongata, thalamus, midbrain, cerebral cortex, cerebellum and hippocampus of control rats and rats treated with ethanol either after a single dose at 10:00 and 22:00, or after a second dose administered 24hrs later at the same time schedules. Results of this experiment indicate that repeated administration with ethanol was associated with rapid development of tolerance to the hypothermic action of ethanol. A single injection of ethanol at 10:00 resulted in significant increase in ChAT activity of pons and cerebellum and decline of ChAT activity of midbrain. There were no significant changes in AChE activity at all of these different brain regions. A single injection of ethanol at 22:00 resulted in significant decrease in ChAT activity of the hypothalamus, pons, midbrain, hippocampus. At the same time, there was a significant decline of AChE activity of the pons, medulla and midbrain. These findings indicate that changes in the responsiveness of the brain cholinergic enzymes may explain the increase in hypothermia and the rapid development of tolerance.

  9. Gonadal hormones do not alter the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol in adult rats.

    PubMed

    Wakley, Alexa A; Wiley, Jenny L; Craft, Rebecca M

    2015-06-01

    The purpose of this study was to determine whether sex differences in the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) are due to activational effects of gonadal hormones. Rats were sham-gonadectomized (sham-GDX) or gonadectomized (GDX). GDX females received no hormone replacement (GDX+0), estradiol (GDX+E2), progesterone (GDX+P4), or both (GDX+E2/P4). GDX male rats received no hormone (GDX+0) or testosterone (GDX+T). Two weeks later, antinociceptive potency of THC was determined (pre-chronic test) on the warm water tail withdrawal and paw pressure assays. Vehicle or a sex-specific THC dose (females, 5.7mg/kg, males, 9.9mg/kg) was administered twice-daily for 9days, then the THC dose-effect curves were re-determined (post-chronic test). On the pre-chronic test (both assays), THC was more potent in sham-GDX females than males, and gonadectomy did not alter this sex difference. In GDX females, P4 significantly decreased THC's antinociceptive potency, whereas E2 had no effect. In GDX males, T did not alter THC's antinociceptive potency. After chronic THC treatment, THC's antinociceptive potency was decreased more in sham-GDX females than males, on the tail withdrawal test; this sex difference in tolerance was not altered in GDX or hormone-treated groups. These results suggest that greater antinociceptive tolerance in females, which occurred despite females receiving 40% less THC than males, is not due to activational effects of gonadal hormones.

  10. Tolerance to allopregnanolone with focus on the GABA-A receptor

    PubMed Central

    Turkmen, Sahruh; Backstrom, Torbjorn; Wahlstrom, Goran; Andreen, Lotta; Johansson, Inga-Maj

    2011-01-01

    Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ-amino butyric acid –A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors. PMID:20883478

  11. Developing sporophytes transition from an inducible to a constitutive ecological strategy of desiccation tolerance in the moss Aloina ambigua: effects of desiccation on fitness

    PubMed Central

    Stark, Lloyd R.; Brinda, John C.

    2015-01-01

    Background and Aims Two ecological strategies of desiccation tolerance exist in plants, constitutive and inducible. Because of difficulties in culturing sporophytes, very little is known about desiccation tolerance in this generation and how desiccation affects sexual fitness. Methods Cultured sporophytes and vegetative shoots from a single genotype of the moss Aloina ambigua raised in the laboratory were tested for their strategy of desiccation tolerance by desiccating the shoot–sporophyte complex and vegetative shoots at different intensities, and comparing outcomes with those of undried shoot–sporophyte complexes and vegetative shoots. By using a dehardened clonal line, the effects of field, age and genetic variance among plants were removed. Key Results The gametophyte and embryonic sporophyte were found to employ a predominantly inducible strategy of desiccation tolerance, while the post-embryonic sporophyte was found to employ a moderately constitutive strategy of desiccation tolerance. Further, desiccation reduced sporophyte fitness, as measured by sporophyte mass, seta length and capsule size. However, the effects of desiccation on sporophyte fitness were reduced if the stress occurred during embryonic development as opposed to postembryonic desiccation. Conclusions The effects of desiccation on dehardened sporophytes of a bryophyte are shown for the first time. The transition from one desiccation tolerance strategy to the other in a single structure or generation is shown for only the second time in plants and for the first time in bryophytes. Finding degrees of inducible strategies of desiccation tolerance in different life phases prompts the formulation of a continuum hypothesis of ecological desiccation tolerance in mosses, where desiccation tolerance is not an either/or phenomenon, but varies in degree along a gradient of ecological inducibility. PMID:25578378

  12. Change in desiccation tolerance of maize embryos during development and germination at different water potential PEG-6000 in relation to oxidative process.

    PubMed

    Huang, Hui; Song, Songquan

    2013-07-01

    Desiccation tolerance is one of the most important traits determining seed survival during storage and under stress conditions. However, the mechanism of seed desiccation tolerance is still unclear in detail. In the present study, we used a combined model system, desiccation-tolerant and -sensitive maize embryos with identical genetic background, to investigate the changes in desiccation tolerance, malonyldialdehyde (MDA) level, hydrogen peroxide (H₂O₂) content and antioxidant enzyme activity during seed development and germination in 0, -0.6 and -1.2 MPa polyethylene glycol (PEG)-6000 solutions. Our results indicated that maize embryos gradually acquired and lost desiccation tolerance during development and germination, respectively. The acquirement and loss of desiccation tolerance of embryos during development and germination were related to the ability of antioxidant enzymes including superoxide dismutase (SOD, EC 1.15.1.1), ascorbate peroxidase (APX, EC 1.11.1.11), catalase (CAT, EC 1.11.1.6), glutathione reductase (GR, EC 1.6.4.2) and dehydroascorbate reductase (DHAR, EC 1.8.5.1) to scavenge reactive oxygen species (ROS) and to control MDA content. Compared with treatment in water, PEG-6000 treatment could markedly delay the loss of desiccation tolerance of germinating embryos by delaying water uptake and time course of germination, increasing GR activity and decreasing MDA content. Our data showed the combination of antioxidant enzyme activity and MDA content is a good parameter for assessing the desiccation tolerance of maize embryos. In addition, H₂O₂ accumulated in mature embryos and PEG-treated embryos after drying, which was at least partially related to a longer embryo/seedling length in rehydration and the physiological mechanisms of priming.

  13. Drought-tolerant rice germplasm developed from an Oryza officinalis transformation-competent artificial chromosome clone.

    PubMed

    Liu, R; Zhang, H H; Chen, Z X; Shahid, M Q; Fu, X L; Liu, X D

    2015-10-29

    Oryza officinalis has proven to be a natural gene reservoir for the improvement of domesticated rice as it carries many desirable traits; however, the transfer of elite genes to cultivated rice by conventional hybridization has been a challenge for rice breeders. In this study, the conserved sequence of plant stress-related NAC transcription factors was selected as a probe to screen the O. officinalis genomic transformation-competent artificial chromosome library by Southern blot; 11 positive transformation-competent artificial chromosome clones were subsequently detected. By Agrobacterium-mediated transformation, an indica rice variety, Huajingxian 74 (HJX74), was transformed with a TAC clone harboring a NAC gene-positive genomic fragment from O. officinalis. Molecular analysis revealed that the O. officinalis genomic fragment was integrated into the genome of HJX74. The transgenic lines exhibited high tolerance to drought stress. Our results demonstrate that the introduction of stress-related transformation-competent artificial chromosome clones, coupled with a transgenic validation approach, is an effective method of transferring agronomically important genes from O. officinalis to cultivated rice.

  14. Successful Starshade petal deployment tolerance verification in support of NASA's technology development for exoplanet missions

    NASA Astrophysics Data System (ADS)

    Webb, D.; Kasdin, N. J.; Lisman, D.; Shaklan, S.; Thomson, M.; Cady, E.; Marks, G. W.; Lo, A.

    2014-07-01

    A Starshade is a sunflower-shaped satellite with a large inner disk structure surrounded by petals. A Starshade flies in formation with a space-borne telescope, creating a deep shadow around the telescope over a broad spectral band to permit nearby exoplanets to be viewed. Removing extraneous starlight before it enters the observatory optics greatly loosens the tolerances on the telescope and instrument that comprise the optical system, but the nature of the Starshade dictates a large deployable structure capable of deploying to a very precise shape. These shape requirements break down into key mechanical requirements which include the rigid-body position and orientation of each of the petals that ring the periphery of the Starshade. To verify our capability to meet these requirements, we modified an existing flight-like Astromesh reflector, provided by Northrup Grumman, as the base ring to which the petals attach. The integrated system, including 4 of the 30 flight-like subscale petals, truss, connecting spokes and central hub, was deployed tens of times in a flight-like manner using a gravity compensation system. After each deployment, discrete points in prescribed locations covering the petals and truss were measured using a highly-accurate laser tracker system. These measurements were then compared against the mechanical requirements, and the as-measured data shows deployment accuracy well within our milestone requirements and resulting in a contrast ratio consistent with exoplanet detection and characterization.

  15. Successful Starshade Petal Deployment Tolerance Verification in Support of NASA's Technology Development for Exoplanet Missions

    NASA Technical Reports Server (NTRS)

    Webb, D.; Kasdin, N. J.; Lisman, D.; Shaklan, S.; Thomson, M.; Cady, E.; Marks, G. W.; Lo, A.

    2014-01-01

    A Starshade is a sunflower-shaped satellite with a large inner disk structure surrounded by petals that flies in formation with a space-borne telescope, creating a deep shadow around the telescope over a broad spectral band to permit nearby exoplanets to be viewed. Removing extraneous starlight before it enters the observatory optics greatly loosens the tolerances on the telescope and instrument that comprise the optical system, but the nature of the Starshade dictates a large deployable structure capable of deploying to a very precise shape. These shape requirements break down into key mechanical requirements, which include the rigid-body position and orientation of each of the petals that ring the periphery of the Starshade. To verify our capability to meet these requirements, we modified an existing flight-like Astromesh reflector, provided by Northrup Grumman, as the base ring to which the petals attach. The integrated system, including 4 of the 30 flight-like subscale petals, truss, connecting spokes and central hub, was deployed tens of times in a flight-like manner using a gravity compensation system. After each deployment, discrete points in prescribed locations covering the petals and truss were measured using a highly-accurate laser tracker system. These measurements were then compared against the mechanical requirements, and the as-measured data shows deployment accuracy well within our milestone requirements and resulting in a contrast ratio consistent with exoplanet detection and characterization.

  16. Overexpression of the Brassica napus BnLAS gene in Arabidopsis affects plant development and increases drought tolerance.

    PubMed

    Yang, Minggui; Yang, Qingyong; Fu, Tingdong; Zhou, Yongming

    2011-03-01

    The GRAS proteins are a family of transcription regulators found in plants and play diverse roles in plant growth and development. To study the biological roles of GRAS family genes in Brassica napus, an Arabidopsis LAS homologous gene, BnLAS and its two homologs were cloned from B. napus and its two progenitor species, Brassica rapa and Brassica oleracea. Relatively high levels of BnLAS were observed in roots, shoot tips, lateral meristems and flower organs based on the analysis of the transcripts by quantitative RT-PCR and promoter-reporter assays. Constitutive overexpression of BnLAS in Arabidopsis resulted in inhibition of growth, and delays in leaf senescence and flowering time. A large portion of transgenic lines had darker leaf color and higher chlorophyll content than in wild type plants. Interestingly, water lose rates in transgenic leaves were reduced, and transgenic plants exhibited enhanced drought tolerance and increased recovery after exposed to dehydration treatment. The stomatal density on leaves of the transgenic plants increased significantly due to the smaller cell size. However, the stomatal aperture on the leaves of the transgenic plants reduced significantly compared with wild type plants. More epidermal wax deposition on transgenic leaves was observed. Furthermore, several genes involved in wax synthesis and regulation, including CER1, CER2, KCS1 and KCS2, were upregulated in the transgenic plants. Our results indicate a potential to utilize BnLAS in the improvement of drought tolerance in plants.

  17. Development of Innovative Accident Tolerant High Thermal Conductivity UO2-Diamond Composite Fuel Pellets

    SciTech Connect

    Tulenko, James; Subhash, Ghatu

    2016-01-01

    The University of Florida (UF) evaluated a composite fuel consisting of UO2 powder mixed with diamond micro particles as a candidate as an accident-tolerant fuel (ATF). The research group had previous extensive experience researching with diamond micro particles as an addition to reactor coolant for improved plant thermal performance. The purpose of this research work was to utilize diamond micro particles to develop UO2-Diamond composite fuel pellets with significantly enhanced thermal properties, beyond that already being measured in the previous UF research projects of UO2 – SiC and UO2 – Carbon Nanotube fuel pins. UF is proving with the current research results that the addition of diamond micro particles to UO2 may greatly enhanced the thermal conductivity of the UO2 pellets producing an accident-tolerant fuel. The Beginning of life benefits have been proven and fuel samples are being irradiated in the ATR reactor to confirm that the thermal conductivity improvements are still present under irradiation.

  18. The Wheat GT Factor TaGT2L1D Negatively Regulates Drought Tolerance and Plant Development

    PubMed Central

    Zheng, Xin; Liu, Haipei; Ji, Hongtao; Wang, Youning; Dong, Baodi; Qiao, Yunzhou; Liu, Mengyu; Li, Xia

    2016-01-01

    GT factors are trihelix transcription factors that specifically regulate plant development and stress responses. Recently, several GT factors have been characterized in different plant species; however, little is known about the role of GT factors in wheat. Here, we show that TaGT2L1A, TaGT2L1B, and TaGT2L1D are highly homologous in hexaploid wheat, and are localized to wheat chromosomes 2A, 2B, and 2D, respectively. These TaGT2L1 genes encode proteins containing two SANT domains and one central helix. All three homologs were ubiquitously expressed during wheat development and were responsive to osmotic stress. Functional analyses demonstrated that TaGT2L1D acts as a transcriptional repressor; it was able to suppress the expression of AtSDD1 in Arabidopsis by binding directly to the GT3 box in its promoter that negatively regulates drought tolerance. TaGT2L1D overexpression markedly increased the number of stomata and reduced drought tolerance in gtl1-3 plants. Notably, ectopic expression of TaGT2L1D also affected floral organ development and overall plant growth. These results demonstrate that TaGT2L1 is an ortholog of AtGTL1, and that it plays an evolutionarily conserved role in drought resistance by fine tuning stomatal density in wheat. Our data also highlight the role of TaGT2L1 in plant growth and development. PMID:27245096

  19. Development of a Multicomponent Prediction Model for Acute Esophagitis in Lung Cancer Patients Receiving Chemoradiotherapy

    SciTech Connect

    De Ruyck, Kim; Sabbe, Nick; Oberije, Cary; Vandecasteele, Katrien; Thas, Olivier; De Ruysscher, Dirk; Lambin, Phillipe; Van Meerbeeck, Jan; De Neve, Wilfried; Thierens, Hubert

    2011-10-01

    Purpose: To construct a model for the prediction of acute esophagitis in lung cancer patients receiving chemoradiotherapy by combining clinical data, treatment parameters, and genotyping profile. Patients and Methods: Data were available for 273 lung cancer patients treated with curative chemoradiotherapy. Clinical data included gender, age, World Health Organization performance score, nicotine use, diabetes, chronic disease, tumor type, tumor stage, lymph node stage, tumor location, and medical center. Treatment parameters included chemotherapy, surgery, radiotherapy technique, tumor dose, mean fractionation size, mean and maximal esophageal dose, and overall treatment time. A total of 332 genetic polymorphisms were considered in 112 candidate genes. The predicting model was achieved by lasso logistic regression for predictor selection, followed by classic logistic regression for unbiased estimation of the coefficients. Performance of the model was expressed as the area under the curve of the receiver operating characteristic and as the false-negative rate in the optimal point on the receiver operating characteristic curve. Results: A total of 110 patients (40%) developed acute esophagitis Grade {>=}2 (Common Terminology Criteria for Adverse Events v3.0). The final model contained chemotherapy treatment, lymph node stage, mean esophageal dose, gender, overall treatment time, radiotherapy technique, rs2302535 (EGFR), rs16930129 (ENG), rs1131877 (TRAF3), and rs2230528 (ITGB2). The area under the curve was 0.87, and the false-negative rate was 16%. Conclusion: Prediction of acute esophagitis can be improved by combining clinical, treatment, and genetic factors. A multicomponent prediction model for acute esophagitis with a sensitivity of 84% was constructed with two clinical parameters, four treatment parameters, and four genetic polymorphisms.

  20. Effects of continuously administered murine interleukin-1 alpha: tolerance development and granuloma formation.

    PubMed Central

    Otterness, I G; Golden, H W; Brissette, W H; Seymour, P A; Daumy, G O

    1989-01-01

    Continuous infusion of murine recombinant interleukin-1 alpha (rIL-1 alpha) into rats by using intraperitoneally implanted osmotic pumps led to marked decreases in body weight, liver enzymes (serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, and sorbitol dehydrogenase), appetite, and mobility and increases in drinking, blood urea nitrogen, and total peripheral blood leukocytes within 3 days. Granuloma formation was found in the local area of rIL-1 alpha release. As early as day 3, a focal infiltrate of polymorphonuclear leukocytes, mononuclear leukocytes, and plasma cells filled the area; by day 6, extensive fibrosis was found. A loss of rIL-1 alpha-induced changes, with the exception of granuloma formation, occurred by day 10. A marked decrease in the response to rIL-1 alpha was also observed when animals were challenged by implantation of new pumps containing rIL-1 alpha, with monitoring of body weight, or by subcutaneous injection of rIL-1 alpha, with monitoring of serum colony-stimulating factor production. We propose that, even in the continuous presence of interleukin-1, replacement of the acute responses to interleukin-1 by restoration of more normal physiology may be advantageous upon acquisition of specific immunity. Images PMID:2788137

  1. Recent developments in the detection and management of acute kidney injury

    PubMed Central

    McCaffrey, James; Dhakal, Ajaya Kumar; Milford, David V; Webb, Nicholas J A; Lennon, Rachel

    2017-01-01

    Acute kidney injury (AKI) is a common condition in children admitted to hospital and existing serum and urine biomarkers are insensitive. There have been significant developments in stratifying the risk of AKI in children and also in the identification of new AKI biomarkers. Risk stratification coupled with a panel of AKI biomarkers will improve future detection of AKI, however, paediatric validation studies in mixed patient cohorts are required. The principles of effective management rely on treating the underlying cause and preventing secondary AKI by the appropriate use of fluids and medication. Further therapeutic innovation will depend on improving our understanding of the basic mechanisms underlying AKI in children. PMID:27496911

  2. Recent developments in the detection and management of acute kidney injury.

    PubMed

    McCaffrey, James; Dhakal, Ajaya Kumar; Milford, David V; Webb, Nicholas J A; Lennon, Rachel

    2017-01-01

    Acute kidney injury (AKI) is a common condition in children admitted to hospital and existing serum and urine biomarkers are insensitive. There have been significant developments in stratifying the risk of AKI in children and also in the identification of new AKI biomarkers. Risk stratification coupled with a panel of AKI biomarkers will improve future detection of AKI, however, paediatric validation studies in mixed patient cohorts are required. The principles of effective management rely on treating the underlying cause and preventing secondary AKI by the appropriate use of fluids and medication. Further therapeutic innovation will depend on improving our understanding of the basic mechanisms underlying AKI in children.

  3. MicroRNAs are involved in cadmium tolerance in Daphnia pulex.

    PubMed

    Chen, Shuai; Nichols, Krista M; Poynton, Helen C; Sepúlveda, Maria S

    2016-06-01

    Daphnia can develop tolerance to cadmium (Cd) after multi-generational exposures. Until now, Cd tolerance in this crustacean was thought to be mainly due to its sequestration via induction of metallothioneins (MTs). Our research supports other studies showing microRNAs (miRNAs) also play a role in this enhanced tolerance. We induced Cd tolerance in Daphnia pulex after exposing them for 25 generations and examined the maintenance of enhanced Cd tolerance under a Cd-free environment for an additional three generations. Acute Cd tolerance as well as long-term effects on population dynamics were measured in selected generations via 48h LC50 tests and 21 d reproductive tests, respectively. Cd tolerance was associated with differential expression of 10 miRNAs (miR-2, miR-33, miR-92, miR-96, miR-153, miR-252, miR-279, miR-283, miR-305 and miR-615). Pathway analysis revealed these miRNAs might increase Cd tolerance by suppressing cellular growth and proliferation by GTPase and cuticle protein pathways, which switch cellular energy allocation to detoxification processes. Moreover, we found increased Cd tolerance is related with induction of MT3 and MT4 and a subsequent downregulation of MT1 and MT3 expression when animals are moved to a Cd-free environment. This is the first study linking aquatic invertebrate miRNAs with induced tolerance to environmental stressors.

  4. Development of microsatellite markers for buffalograss (Buchloë dactyloides; Poaceae), a drought-tolerant turfgrass alternative1

    PubMed Central

    Hadle, Jacob J.; Konrade, Lauren A.; Beasley, Rochelle R.; Lance, Stacey L.; Jones, Kenneth L.; Beck, James B.

    2016-01-01

    Premise of the study: Buchloë dactyloides (Poaceae) is an important component of Great Plains prairies and a popular drought-tolerant turfgrass alternative in North America. This species comprises an autopolyploid series, and microsatellite primers were developed to understand the distribution of genetic variation among cytotypes and across its large geographic range. Methods and Results: Fifteen microsatellite loci were designed and successfully amplified in six B. dactyloides populations. Within-population genetic diversity was comparatively high, consistent with B. dactyloides’ life history. Allelic variation at 13 loci was consistent with the cytotype established in chromosome-counted samples. Conclusions: This variable, interpretable set of loci allows for the determination of multilocus genotype in B. dactyloides individuals of varying cytotype. Data such as these from a range-wide sample set can provide important insights for germplasm conservation and crop improvement in this ecologically and economically important species. PMID:27610277

  5. ACUTE AND REPEATED INHALATION OF TOLUENE BY RATS PERFORMING A SIGNAL DETECTION TASK LEADS TO BEHAVIORAL TOLERANCE ON SOME PERFORMANCE MEASURES.

    EPA Science Inventory

    Previous work showed that trichloroethylene (TCE) impairs accuracy and latency in a signal detection task (SDT) in rats, and that these effects abate during repeated exposures if rats inhale TCE during SDT testing. The present experiment compared the effects of acute and repeated...

  6. Extrapolating the Acute Behavioral Effects of Toluene from 1-Hour to 24-Hour Exposures in Rats: Roles of Dose Metric, and Metabolic and Behavioral Tolerance.

    EPA Science Inventory

    Recent research on the acute effects of volatile organic compounds (VQCs) suggests that extrapolation from short (~ 1 h) to long durations (up to 4 h) may be improved by using estimates of brain toluene concentration (Br[Tol]) instead of cumulative inhaled dose (C x t) as a metri...

  7. Exercise and cognition in multiple sclerosis: The importance of acute exercise for developing better interventions.

    PubMed

    Sandroff, Brian M

    2015-12-01

    Cognitive dysfunction is highly prevalent, disabling, and poorly-managed in persons with multiple sclerosis (MS). Exercise training represents a promising approach for managing this clinical symptom of the disease. However, results from early randomized controlled trials of exercise on cognition in MS are equivocal, perhaps due to methodological concerns. This underscores the importance of considering the well-established literature in the general population that documents robust, beneficial effects of exercise training on cognition across the lifespan. The development of such successful interventions is based on examinations of fitness, physical activity, and acute exercise effects on cognition. Applying such an evidence-based approach in MS serves as a way of better informing exercise training interventions for improving cognition in this population. To that end, this paper provides a focused, updated review on the evidence describing exercise effects on cognition in MS, and develops a rationale and framework for examining acute exercise on cognitive outcomes in this population. This will provide keen insight for better developing exercise interventions for managing cognitive impairment in MS.

  8. Development of ODS FeCrAl alloys for accident-tolerant fuel cladding

    SciTech Connect

    Dryepondt, Sebastien N.; Hoelzer, David T.; Pint, Bruce A.; Unocic, Kinga A.

    2015-09-18

    FeCrAl alloys are prime candidates for accident-tolerant fuel cladding due to their excellent oxidation resistance up to 1400 C and good mechanical properties at intermediate temperature. Former commercial oxide dispersion strengthened (ODS) FeCrAl alloys such as PM2000 exhibit significantly better tensile strength than wrought FeCrAl alloys, which would alloy for the fabrication of a very thin (~250 m) ODS FeCrAl cladding and limit the neutronic penalty from the replacement of Zr-based alloys by Fe-based alloys. Several Fe-12-Cr-5Al ODS alloys where therefore fabricated by ball milling FeCrAl powders with Y2O3 and additional oxides such as TiO2 or ZrO2. The new Fe-12Cr-5Al ODS alloys showed excellent tensile strength up to 800 C but limited ductility. Good oxidation resistance in steam at 1200 and 1400 C was observed except for one ODS FeCrAl alloy containing Ti. Rolling trials were conducted at 300, 600 C and 800 C to simulate the fabrication of thin tube cladding and a plate thickness of ~0.6mm was reached before the formation of multiple edge cracks. Hardness measurements at different stages of the rolling process, before and after annealing for 1h at 1000 C, showed that a thinner plate thickness could likely be achieved by using a multi-step approach combining warm rolling and high temperature annealing. Finally, new Fe-10-12Cr-5.5-6Al-Z gas atomized powders have been purchased to fabricate the second generation of low-Cr ODS FeCrAl alloys. The main goals are to assess the effect of O, C, N and Zr contents on the ODS FeCrAl microstructure and mechanical properties, and to optimize the fabrication process to improve the ductility of the 2nd gen ODS FeCrAl while maintaining good mechanical strength and oxidation resistance.

  9. Ontogeny of salinity tolerance and hyper-osmoregulation by embryos of the intertidal crabs Hemigrapsus edwardsii and Hemigrapsus crenulatus (Decapoda, Grapsidae): survival of acute hyposaline exposure.

    PubMed

    Taylor, H H; Seneviratna, Deepani

    2005-04-01

    The adults of Hemigrapsus edwardsii and Hemigrapsus crenulatus are euryhaline crabs and strong hyper-osmoregulators. Their embryos are carried externally attached to the abdominal pleopods of female crabs, where they are exposed to temporal and spatial changes in salinity associated with their intertidal and estuarine habitats. Although embryos lack the branchial and excretory organs responsible for adult osmoregulation, post-gastrula embryos were highly tolerant of exposure to hypo-osmotic sea water. Detached eggs (embryos+envelopes), of both species, at all developmental stages between gastrulation and hatching, exhibited 80-100% survival for periods up to 96 h in sea water (osmolality, 1050 mmol kg(-1)) and in dilutions to 50%, 10%, and 1%. Cleavage stages were less tolerant of dilution; H. edwardsii, <50% survived 24 h in 10% sea water; H. crenulatus <50% survived 6 h in 10% sea water. Post-gastrulation stages strongly hyper-osmoregulated but cleavage stages were hyper-osmoconformers (maintaining internal osmolality approximately 150 mmol kg(-1) above external). Osmoregulatory capacity was reduced just prior hatching, particularly in H. crenulatus, although salinity tolerance remained high. Gastrulation therefore marks a critical stage in the ontogeny of osmoregulation and salinity tolerance. Total Na+/K(+)-ATPase activity increased greatly during embryogenesis of H. crenulatus (undetectable in blastulae; gastrulae 0.31+/-0.05 pmol P(i) embryo(-1) min(-1); pre-hatching 16.4+/-1.0 pmol P(i) embryo(-1) min(-1)). Na+/K(+)-ATPase activity increased in embryos exposed to dilute sea water for 24 h implicating regulation of this transporter in a short-term acclimation response.

  10. Changes in development and ultrastructure of Aspergillus niger mycelium, strain with increased tolerance to toxic substances from beet molasses.

    PubMed

    Zakowska, Z; Gabara, B

    1991-01-01

    Effects of a defoamer and toxic molasses compounds on development and ultrastructure of A. niger mycelium, strain Z, characterized by high tolerance to these substances and producing citric acid in surface fermentation on proper molasses media with 70% yield were presented. Spumol BJ in concentration of 5 microliters/100 cm3 as well as toxic molasses compounds stimulated the process of swelling and germinating of conidia. Moreover, giant conidia, unable to germinate, appeared. Developing mycelium with dispersed hyphae became mucilaginous after 17-20 h culture, which indicated the process of sinking but after 24 h some part of the mycelium developed normally. Electron microscopic observations of mycelium developing in the presence of the toxic substances showed along with electron-transparent cytoplasm in a consequence of decrease in ribosome number, changes in ultrastructure of mitochondria. It may be assumed that one of the reasons of the above described abnormalities in development and ultrastructure of mycelium was a disturbance of respiration processes. The appearance of deposits of electron-dense material in mitochondria suggested the existence of a defence mechanism, eliminating toxic substances.

  11. MicroRNAs Are Involved in the Development of Morphine-Induced Analgesic Tolerance and Regulate Functionally Relevant Changes in Serpini1

    PubMed Central

    Tapocik, Jenica D.; Ceniccola, Kristin; Mayo, Cheryl L.; Schwandt, Melanie L.; Solomon, Matthew; Wang, Bi-Dar; Luu, Truong V.; Olender, Jacqueline; Harrigan, Thomas; Maynard, Thomas M.; Elmer, Greg I.; Lee, Norman H.

    2016-01-01

    Long-term opioid treatment results in reduced therapeutic efficacy and in turn leads to an increase in the dose required to produce equivalent pain relief and alleviate break-through or insurmountable pain. Altered gene expression is a likely means for inducing long-term neuroadaptations responsible for tolerance. Studies conducted by our laboratory (Tapocik et al., 2009) revealed a network of gene expression changes occurring in canonical pathways involved in neuroplasticity, and uncovered miRNA processing as a potential mechanism. In particular, the mRNA coding the protein responsible for processing miRNAs, Dicer1, was positively correlated with the development of analgesic tolerance. The purpose of the present study was to test the hypothesis that miRNAs play a significant role in the development of analgesic tolerance as measured by thermal nociception. Dicer1 knockdown, miRNA profiling, bioinformatics, and confirmation of high value targets were used to test the proposition. Regionally targeted Dicer1 knockdown (via shRNA) had the anticipated consequence of eliminating the development of tolerance in C57BL/6J (B6) mice, thus supporting the involvement of miRNAs in the development of tolerance. MiRNA expression profiling identified a core set of chronic morphine-regulated miRNAs (miR's 27a, 9, 483, 505, 146b, 202). Bioinformatics approaches were implemented to identify and prioritize their predicted target mRNAs. We focused our attention on miR27a and its predicted target serpin peptidase inhibitor clade I (Serpini1) mRNA, a transcript known to be intricately involved in dendritic spine density regulation in a manner consistent with chronic morphine's consequences and previously found to be correlated with the development of analgesic tolerance. In vitro reporter assay confirmed the targeting of the Serpini1 3′-untranslated region by miR27a. Interestingly miR27a was found to positively regulate Serpini1 mRNA and protein levels in multiple neuronal cell lines

  12. Regulation of B-cell development and tolerance by different members of the miR-17∼92 family microRNAs

    PubMed Central

    Lai, Maoyi; Gonzalez-Martin, Alicia; Cooper, Anthony B.; Oda, Hiroyo; Jin, Hyun Yong; Shepherd, Jovan; He, Linling; Zhu, Jiang; Nemazee, David; Xiao, Changchun

    2016-01-01

    The molecular mechanisms that regulate B-cell development and tolerance remain incompletely understood. In this study, we identify a critical role for the miR-17∼92 microRNA cluster in regulating B-cell central tolerance and demonstrate that these miRNAs control early B-cell development in a cell-intrinsic manner. While the cluster member miR-19 suppresses the expression of Pten and plays a key role in regulating B-cell tolerance, miR-17 controls early B-cell development through other molecular pathways. These findings demonstrate differential control of two closely linked B-cell developmental stages by different members of a single microRNA cluster through distinct molecular pathways. PMID:27481093

  13. New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance.

    PubMed

    Daiber, A; Wenzel, P; Oelze, M; Münzel, T

    2008-01-01

    Organic nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with organic nitrates, however, results in a rapid development of nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for organic nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various organic nitrates. Finally, we would like to draw the reader's attention to the protective properties of the organic nitrate pentaerithrityl tetranitrate (PETN), which, in contrast to all other organic nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.

  14. Managing patients with acute liver failure: developing a tool for practitioners.

    PubMed

    O'Neal, Helen; Olds, Jane; Webster, Nicola

    2006-01-01

    Patients with acute liver failure (ALF) are treated on the general intensive care unit (ICU) within this regional centre for hepatology and liver transplantation. This group of patients are at high risk of developing cerebral oedema, but because of the associated coagulopathy, intracranial pressure is not measured invasively. The safe management of these patients is vital to their outcome, and yet, there is no national or local guidance on the best practice for this group of patients. An absence of guidelines, or evidence base specific to caring for hepatology patients, was highlighted as we reviewed local clinical practices and those at other liver specialty centres, the British Liver Trust and published literature. We identified a need to develop evidence-based guidance for staff caring for patients with ALF within ICUs. A systematic approach enabled us to identify best practice to support the development of a structured evidence-based approach to care.

  15. Influence of adenosine receptors on the development of caerulein-induced acute pancreatitis.

    PubMed

    Szczerbiński, Mariusz; Celiński, Krzysztof; Słomka, Maria; Kasztelan-Szczerbińska, Beata; Cichoz-Lach, Halina

    2002-01-01

    Acute pancreatitis leads to hypoxia caused by vasoconstriction and to activation of lysosomal and digestive enzymes resulting in pancreas autodigestion and damage. This causes activation of leucocytes and increased expression of adhesive molecules enabling margination and adhesion of activated leucocytes to the endothelium. Activated leucocytes are the source of proinflammatory cytokins and oxygen-free radicals which intensify the inflammatory response. The reports indicating that adenosine may prevent activation of the above-mentioned processes in ischaemia prompted us to undertake this study. The study was performed in two stages. The first stage was to evaluate the effects of agonists and antagonists of adenosine receptors on normal pancreas while the second one was to determine the influence of these substances on the development of caerulein-induced acute pancreatitis. During the first stage, the animals were injected intraperitoneally with the substances examined: the A1 receptor antagonist--DPCPX, the A2 receptor agonist--CGS 21680, the A2 receptor antagonist--ZM 241385 and the A3 receptor agonist--IB-MECA and then received intravenous saline. The control animals were subjected only to the 12 h intravenous infusion of 0.15 M NaCl. During the second stage, after the intraperitoneal administration of adenosine receptor agonists and antagonists (as in the first stage), acute pancreatitis was induced with the 12 h intravenous infusion of 5 micrograms/kg/h caerulein. Identical acute pancreatitis was induced in the control animals, however no other substances were administered. The pancreatic tissue samples were collected directly after intravenous infusion. The severity of inflammatory processes in the pancreas was evaluated on the basis of the plasma amylase activity, pancreatic weight and enhancement of histopathological changes observed in this organ. In the animals infused with saline alone, no effects of the substances examined on the pancreatic weight

  16. Recent Developments and Challenges Implementing New and Improved Stress Intensity Factor (K) Solutions in NASGRO for Damage Tolerance Analyses

    NASA Technical Reports Server (NTRS)

    Cardinal, Joseph W.; McClung, R. Craig; Lee, Yi-Der; Guo, Yajun; Beek, Joachim M.

    2014-01-01

    Fatigue crack growth analysis software has been available to damage tolerance analysts for many years in either commercial products or via proprietary in-house codes. The NASGRO software has been publicly available since the mid-80s (known as NASA/FLAGRO up to 1999) and since 2000 has been sustained and further developed by a collaborative effort between Southwest Research Institute® (SwRI®), the NASA Johnson Space Center (JSC), and the members of the NASGRO Industrial Consortium. Since the stress intensity factor (K) is the foundation of fracture mechanics and damage tolerance analysis of aircraft structures, a significant focus of development efforts in the past fifteen years has been geared towards enhancing legacy K solutions and developing new and efficient numerical K solutions that can handle the complicated stress gradients computed by today’s analysts using detailed finite element models of fatigue critical locations. This paper provides an overview of K solutions that have been recently implemented or improved for the analysis of geometries such as two unequal through cracks at a hole and two unequal corner cracks at a hole, as well as state-of-the-art weight function models capable of computing K in the presence of univariant and/or bivariant stress gradients and complicated residual stress distributions. Some historical background is provided to review how common K solutions have evolved over the years, including selective examples from the literature and from new research. Challenges and progress in rectifying discrepancies between older legacy solutions and newer models are reviewed as well as approaches and challenges for verification and validation of K solutions. Finally, a summary of current challenges and future research and development needs is presented. A key theme throughout the presentation of this paper will be how members of the aerospace industry have collaborated with software developers to develop a practical analysis tool that is

  17. Overexpression of SlUPA-like induces cell enlargement, aberrant development and low stress tolerance through phytohormonal pathway in tomato

    PubMed Central

    Cui, Baolu; Hu, Zongli; Hu, Jingtao; Zhang, Yanjie; Yin, Wencheng; Zhu, Zhiguo; Feng, Ye; Chen, Guoping

    2016-01-01

    upa20 induces cell enlargement and hypertrophy development. In our research, overexpression of SlUPA-like, orthologous to upa20, severely affected the growth of vegetative and reproductive tissues. Wilted leaves curled upwardly and sterile flowers were found in transgenic lines. Through anatomical analysis, palisade and spongy tissues showed fluffy and hypertrophic development in transgenic plants. Gene expression analysis showed that GA responsive, biosynthetic and signal transduction genes (e.g. GAST1, SlGA20OXs, SlGA3OXs, SlGID1s, and SlPREs) were significantly upregulated, indicating that GA response is stimulated by overproduction of SlUPA-like. Furthermore, SlUPA-like was strongly induced by exogenous JA and wounding. Decreased expression of PI-I and induced expression of SlJAZs (including SlJAZ2, SlJAZ10 and SlJAZ11) were observed in transgenic plants, suggesting that JA response is repressed. In addition, SlUPA-like overexpressed plant exhibited more opened stoma and higher water loss than the control when treated with dehydration stress, which was related to decreased ABA biosynthesis, signal transduction and response. Particularly, abnormal developments of transgenic plants promote the plant susceptibility to Xanthomonas campestris pv. campestris. Therefore, it is deduced from these results that SlUPA-like plays vital role in regulation of plant development and stress tolerance through GA, JA and ABA pathways. PMID:27025226

  18. Overexpression of SlUPA-like induces cell enlargement, aberrant development and low stress tolerance through phytohormonal pathway in tomato.

    PubMed

    Cui, Baolu; Hu, Zongli; Hu, Jingtao; Zhang, Yanjie; Yin, Wencheng; Zhu, Zhiguo; Feng, Ye; Chen, Guoping

    2016-03-30

    upa20 induces cell enlargement and hypertrophy development. In our research, overexpression of SlUPA-like, orthologous to upa20, severely affected the growth of vegetative and reproductive tissues. Wilted leaves curled upwardly and sterile flowers were found in transgenic lines. Through anatomical analysis, palisade and spongy tissues showed fluffy and hypertrophic development in transgenic plants. Gene expression analysis showed that GA responsive, biosynthetic and signal transduction genes (e.g. GAST1, SlGA20OXs, SlGA3OXs, SlGID1s, and SlPREs) were significantly upregulated, indicating that GA response is stimulated by overproduction of SlUPA-like. Furthermore, SlUPA-like was strongly induced by exogenous JA and wounding. Decreased expression of PI-I and induced expression of SlJAZs (including SlJAZ2, SlJAZ10 and SlJAZ11) were observed in transgenic plants, suggesting that JA response is repressed. In addition, SlUPA-like overexpressed plant exhibited more opened stoma and higher water loss than the control when treated with dehydration stress, which was related to decreased ABA biosynthesis, signal transduction and response. Particularly, abnormal developments of transgenic plants promote the plant susceptibility to Xanthomonas campestris pv. campestris. Therefore, it is deduced from these results that SlUPA-like plays vital role in regulation of plant development and stress tolerance through GA, JA and ABA pathways.

  19. The development of an outcomes management system for acute medical rehabilitation.

    PubMed

    Cohen, B A; Grigonis, A M; Topper, M E; Morrison, M H

    1997-01-01

    In 1993, Continental Medical Systems, Inc. (CMS), a provider of comprehensive medical rehabilitation, developed the Total Outcomes and Prediction Program (TOPP) to measure and evaluate key medical rehabilitation outcomes, quality indicators, and patient satisfaction at its 37 acute rehabilitation hospitals. The broad purposes of TOPP are to manage patient treatment, improve the cost-effectiveness of care, and provide outcomes reporting for managed care and other interested parties. The challenge was to develop a system which could measure, evaluate, and report medical rehabilitation patient outcomes in a way that could be easily understood by multiple audiences, including payers, accrediting organizations, physicians, patients and families, case managers, and CMS clinical staff. Using data from the Uniform Data System for Medical Rehabilitation database, CMS created descriptive outcomes reports for each hospital and for the corporation overall, including performance statistics, outcomes report cards, and quality report cards. These initial reports, as well as updates, quarterly reports, and special ad hoc requests, provide CMS corporate and hospital staff with statistically valid and reliable information to manage the outcomes of medical rehabilitation treatment. TOPP has assisted CMS with meeting accreditation standards for outcomes management and measurement and has been used in managed care contract negotiations. Future TOPP efforts will integrate resource use data, medical acuity and outcomes from acute, subacute, and outpatient rehabilitation levels into CMS' outcomes reporting system.

  20. Impairment of T cell development and acute inflammatory response in HIV-1 Tat transgenic mice

    PubMed Central

    Fiume, Giuseppe; Scialdone, Annarita; Albano, Francesco; Rossi, Annalisa; Maria Tuccillo, Franca; Rea, Domenica; Palmieri, Camillo; Caiazzo, Elisabetta; Cicala, Carla; Bellevicine, Claudio; Falcone, Cristina; Vecchio, Eleonora; Pisano, Antonio; Ceglia, Simona; Mimmi, Selena; Iaccino, Enrico; Laurentiis, Annamaria de; Pontoriero, Marilena; Agosti, Valter; Troncone, Giancarlo; Mignogna, Chiara; Palma, Giuseppe; Arra, Claudio; Mallardo, Massimo; Maria Buonaguro, Franco; Scala, Giuseppe; Quinto, Ileana

    2015-01-01

    Immune activation and chronic inflammation are hallmark features of HIV infection causing T-cell depletion and cellular immune dysfunction in AIDS. Here, we addressed the issue whether HIV-1 Tat could affect T cell development and acute inflammatory response by generating a transgenic mouse expressing Tat in lymphoid tissue. Tat-Tg mice showed thymus atrophy and the maturation block from DN4 to DP thymic subpopulations, resulting in CD4+ and CD8+ T cells depletion in peripheral blood. In Tat-positive thymus, we observed the increased p65/NF-κB activity and deregulated expression of cytokines/chemokines and microRNA-181a-1, which are involved in T-lymphopoiesis. Upon LPS intraperitoneal injection, Tat-Tg mice developed an abnormal acute inflammatory response, which was characterized by enhanced lethality and production of inflammatory cytokines. Based on these findings, Tat-Tg mouse could represent an animal model for testing adjunctive therapies of HIV-1-associated inflammation and immune deregulation. PMID:26343909

  1. Recent advances in the dissection of drought-stress regulatory networks and strategies for development of drought-tolerant transgenic rice plants.

    PubMed

    Todaka, Daisuke; Shinozaki, Kazuo; Yamaguchi-Shinozaki, Kazuko

    2015-01-01

    Advances have been made in the development of drought-tolerant transgenic plants, including cereals. Rice, one of the most important cereals, is considered to be a critical target for improving drought tolerance, as present-day rice cultivation requires large quantities of water and as drought-tolerant rice plants should be able to grow in small amounts of water. Numerous transgenic rice plants showing enhanced drought tolerance have been developed to date. Such genetically engineered plants have generally been developed using genes encoding proteins that control drought regulatory networks. These proteins include transcription factors, protein kinases, receptor-like kinases, enzymes related to osmoprotectant or plant hormone synthesis, and other regulatory or functional proteins. Of the drought-tolerant transgenic rice plants described in this review, approximately one-third show decreased plant height under non-stressed conditions or in response to abscisic acid treatment. In cereal crops, plant height is a very important agronomic trait directly affecting yield, although the improvement of lodging resistance should also be taken into consideration. Understanding the regulatory mechanisms of plant growth reduction under drought stress conditions holds promise for developing transgenic plants that produce high yields under drought stress conditions. Plant growth rates are reduced more rapidly than photosynthetic activity under drought conditions, implying that plants actively reduce growth in response to drought stress. In this review, we summarize studies on molecular regulatory networks involved in response to drought stress. In a separate section, we highlight progress in the development of transgenic drought-tolerant rice plants, with special attention paid to field trial investigations.

  2. Recent advances in the dissection of drought-stress regulatory networks and strategies for development of drought-tolerant transgenic rice plants

    PubMed Central

    Todaka, Daisuke; Shinozaki, Kazuo; Yamaguchi-Shinozaki, Kazuko

    2015-01-01

    Advances have been made in the development of drought-tolerant transgenic plants, including cereals. Rice, one of the most important cereals, is considered to be a critical target for improving drought tolerance, as present-day rice cultivation requires large quantities of water and as drought-tolerant rice plants should be able to grow in small amounts of water. Numerous transgenic rice plants showing enhanced drought tolerance have been developed to date. Such genetically engineered plants have generally been developed using genes encoding proteins that control drought regulatory networks. These proteins include transcription factors, protein kinases, receptor-like kinases, enzymes related to osmoprotectant or plant hormone synthesis, and other regulatory or functional proteins. Of the drought-tolerant transgenic rice plants described in this review, approximately one-third show decreased plant height under non-stressed conditions or in response to abscisic acid treatment. In cereal crops, plant height is a very important agronomic trait directly affecting yield, although the improvement of lodging resistance should also be taken into consideration. Understanding the regulatory mechanisms of plant growth reduction under drought stress conditions holds promise for developing transgenic plants that produce high yields under drought stress conditions. Plant growth rates are reduced more rapidly than photosynthetic activity under drought conditions, implying that plants actively reduce growth in response to drought stress. In this review, we summarize studies on molecular regulatory networks involved in response to drought stress. In a separate section, we highlight progress in the development of transgenic drought-tolerant rice plants, with special attention paid to field trial investigations. PMID:25741357

  3. Thalidomide attenuates the development and expression of antinociceptive tolerance to μ-opioid agonist morphine through l-arginine-iNOS and nitric oxide pathway.

    PubMed

    Khan, Muhammad Imran; Ostadhadi, Sattar; Mumtaz, Faiza; Momeny, Majid; Moghaddaskho, Farima; Hassanipour, Mahsa; Ejtemaei-Mehr, Shahram; Dehpour, Ahmad Reza

    2017-01-01

    Morphine is a μ-opioid analgesic drug which is used in the treatment and management of chronic pain. However, due to development of antinociceptive tolerance its clinical use is limited. Thalidomide is an old glutamic acid derivative which recently reemerged because of its potential to counteract a number of disorders including neurodegenerative disorders. The potential underlying mechanisms and effects of thalidomide on morphine-induced antinociceptive tolerance is still elusive. Hence, the present study was designed to explore the effect of thalidomide on the development and expression of morphine antinociceptive tolerance targeting l-arginine-nitric oxide (NO) pathway in mice and T98G human glioblastoma cell line. When thalidomide was administered in a dose of 17.5mg/kg before each dose of morphine chronically for 5days it prevented the development of antinociceptive tolerance. Also, a single dose of thalidomide 20mg/kg attenuated the expression phase of antinociceptive tolerance. The protective effect of thalidomide was augmented in development phase when co-administration with NOS inhibitors like L-NAME (non- selective NOS inhibitor; 2mg/kg) or aminoguanidine (selective inducible NOS inhibitor; 50mg/kg). Also, the reversal effect of thalidomide in expression phase was potentiated when concomitantly administrated with L-NAME (5mg/kg) or aminoguanidine (100mg/kg). Co-administration of ODQ (a guanylyl cyclase inhibitor) 10mg/kg in developmental phase or 20mg/kg in expression phase also progressively increased the pain threshold. In addition, thalidomide (20μM) also significantly inhibited the overexpression of iNOS gene induced by morphine (2.5μM) in T98G cell line. Hence, our findings suggest that thalidomide has protective effect both in the development and expression phases of morphine antinociceptive tolerance. It is also evident that this effect of thalidomide is induced by the inhibition of NOS enzyme predominantly iNOS.

  4. Pillar III--optimisation of anaemia tolerance.

    PubMed

    Meier, Jens; Gombotz, Hans

    2013-03-01

    In the case of acute bleeding, the use of the anaemia tolerance of a patient enables the physician to either avoid blood transfusions or delay them after bleeding has ceased. This concept is the cornerstone of the third pillar of modern patient blood management programmes. Its efficacy depends on the degree of utilisation of anaemia tolerance, which is not constant but depends on the compensatory capacity of the individual patient in a given situation. Fortunately, the specifications of anaemia tolerance can be influenced by the anaesthesiologist. This article presents the concept of anaemia tolerance and highlights the options for how anaemia tolerance can be optimised in the pre-, intra-, and postoperative periods.

  5. Development of Graphical User Interface for ARRBOD (Acute Radiation Risk and BRYNTRN Organ Dose Projection)

    NASA Technical Reports Server (NTRS)

    Kim, Myung-Hee; Hu, Shaowen; Nounu, Hatem N.; Cucinotta, Francis A.

    2010-01-01

    The space radiation environment, particularly solar particle events (SPEs), poses the risk of acute radiation sickness (ARS) to humans; and organ doses from SPE exposure may reach critical levels during extra vehicular activities (EVAs) or within lightly shielded spacecraft. NASA has developed an organ dose projection model using the BRYNTRN with SUMDOSE computer codes, and a probabilistic model of Acute Radiation Risk (ARR). The codes BRYNTRN and SUMDOSE, written in FORTRAN, are a Baryon transport code and an output data processing code, respectively. The ARR code is written in C. The risk projection models of organ doses and ARR take the output from BRYNTRN as an input to their calculations. BRYNTRN code operation requires extensive input preparation. With a graphical user interface (GUI) to handle input and output for BRYNTRN, the response models can be connected easily and correctly to BRYNTRN in friendly way. A GUI for the Acute Radiation Risk and BRYNTRN Organ Dose (ARRBOD) projection code provides seamless integration of input and output manipulations, which are required for operations of the ARRBOD modules: BRYNTRN, SUMDOSE, and the ARR probabilistic response model. The ARRBOD GUI is intended for mission planners, radiation shield designers, space operations in the mission operations directorate (MOD), and space biophysics researchers. The ARRBOD GUI will serve as a proof-of-concept example for future integration of other human space applications risk projection models. The current version of the ARRBOD GUI is a new self-contained product and will have follow-on versions, as options are added: 1) human geometries of MAX/FAX in addition to CAM/CAF; 2) shielding distributions for spacecraft, Mars surface and atmosphere; 3) various space environmental and biophysical models; and 4) other response models to be connected to the BRYNTRN. The major components of the overall system, the subsystem interconnections, and external interfaces are described in this

  6. Genome-wide association study of heat tolerance of developing leaves during vegetative growth stages in a sorghum association panel

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Heat stress reduces grain yield and quality worldwide. Enhancing heat tolerance of crops is one of the essential strategies required for sustaining agricultural production, especially as frequent temperature extremes escalates due to climate change. Although heat tolerance mechanisms have been stud...

  7. Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder

    PubMed Central

    Wang, Zuowei; Kemp, David E.; Chan, Philip K.; Fang, Yiru; Ganocy, Stephen J.; Calabrese, Joseph R.; Gao, Keming

    2012-01-01

    Quetiapine extended-release (quetiapine-XR) has been studied in patients with schizophrenia, bipolar mania, bipolar depression, major depressive disorder (MDD), and generalized anxiety disorder (GAD). The purpose of this study was to compare the tolerability and sensitivity of quetiapine-XR among these psychiatric conditions. The discontinuation due to adverse events (DAEs) and reported somnolence in randomized, double-blind, placebo-controlled studies of quetiapine-XR in these psychiatric conditions were examined. The absolute risk reduction or increase and the number needed to treat to benefit (NNTB) or harm (NNTH) for DAEs and reported somnolence of quetiapine-XR ≥300 mg/d relative to placebo were estimated. Data from one study in schizophrenia (n=465), one in mania (n=316), one in bipolar depression (n=280), two in refractory MDD (n=624), two in MDD (n=669) and three in GAD (n=1109) were available. The risk for DAEs of quetiapine-XR relative to placebo was significantly increased in bipolar depression (NNTH=9), refractory MDD (NNTH=8), MDD (NNTH=9), and GAD (NNTH=5), but not in schizophrenia and mania. The risk for reported somnolence of quetiapine-XR relative to placebo was significantly increased in schizophrenia (600 mg/d NNTH=15 and 800 mg/d NNTH=11), mania (NNTH=8), bipolar depression (NNTH=4), refractory MDD (NNTH=5), MDD (NNTH=5) and GAD (NNTH=5). These results suggest that patients with GAD had the poorest tolerability during treatment with quetiapine-XR, but they had a similar sensitivity as those with bipolar depression and MDD. Patients with schizophrenia or mania had a higher tolerability and a lower sensitivity than those with bipolar depression, MDD, or GAD. PMID:20875219

  8. Development, molecular composition and freeze tolerance of bovine embryos cultured in TCM-199 supplemented with hyaluronan.

    PubMed

    Palasz, A T; Breña, P Beltrán; Martinez, Marcelo F; Perez-Garnelo, S S; Ramirez, M A; Gutiérrez-Adán, A; De la Fuente, J

    2008-02-01

    Hyaluronan (HA) is glycosaminoglycan that is present from the start of embryonic development and its role and concentration increases with embryo development. The objective of this study was to evaluate if the presence of HA in TCM-199 culture medium had an effect on the development and quality of bovine embryos. There was no effect of HA on the total number of zygotes developing to blastocysts on day 7, however more expanded and hatched blastocyst stages were observed on days 8 and 9 in the group supplemented with HA (p<0.05). Following freeze/thawing, significantly more (p<0.05) embryos cultured in medium supplemented with HA hatched than those cultured in TCM-199 alone or those with BSA. Medium supplemented with HA and BSA significantly increased the level of expression of glucose metabolism Glut-1 gene and embryo compaction Cx43 gene (p<0.05), and had no effect on Glut-5 and IGF-II expression. In addition, HA presence in culture decreased the level of expression of apoptosis Bax and oxidative stress SOX genes (p<0.05). There was significant difference in total number of nuclei between TCM-199 medium only and the remaining media containing BSA or HA plus BSA, between which there was no difference. In summary, our results indicate that the addition of high molecular weight HA to TCM-199 medium that contains BSA on day 4 of culture improved embryo development to hatching and hatched blastocysts and the quality of produced embryos, which were superior to embryos cultured without HA addition.

  9. Obstructive Sleep Apnea, Obesity, and the Development of Acute Respiratory Distress Syndrome

    PubMed Central

    Karnatovskaia, Lioudmila V.; Lee, Augustine S.; Bender, S. Patrick; Talmor, Daniel; Festic, Emir

    2014-01-01

    Background: Obstructive sleep apnea (OSA) may increase the risk of respiratory complications and acute respiratory distress syndrome (ARDS) among surgical patients. OSA is more prevalent among obese individuals; obesity can predispose to ARDS. Hypothesis: It is unclear whether OSA independently contributes towards the risk of ARDS among hospitalized patients. Methods: This is a pre-planned retrospective subgroup analysis of the prospectively identified cohort of 5,584 patients across 22 hospitals with at least one risk factor for ARDS at the time of hospitalization from a trial by the US Critical Illness and Injury Trials Group designed to validate the Lung Injury Prediction Score. A total of 252 patients (4.5%) had a diagnosis of OSA at the time of hospitalization; of those, 66% were obese. Following multivariate adjustment in the logistic regression model, there was no significant relationship between OSA and development of ARDS (OR = 0.65, 95%CI = 0.32-1.22). However, body mass index (BMI) was associated with subsequent ARDS development (OR = 1.02, 95%CI = 1.00-1.04, p = 0.03). Neither OSA nor BMI affected mechanical ventilation requirement or mortality. Conclusions: Prior diagnosis of OSA did not independently affect development of ARDS among patients with at least one predisposing condition, nor the need for mechanical ventilation or hospital mortality. Obesity appeared to independently increase the risk of ARDS. Citation: Karnatovskaia LV, Lee AS, Bender SP, Talmor D, Festic E. Obstructive sleep apnea, obesity, and the development of acute respiratory distress syndrome. J Clin Sleep Med 2014;10(6):657-662. PMID:24932146

  10. Acute kidney injury in elderly intensive care patients from a developing country: clinical features and outcome

    PubMed Central

    Yokota, Laís Gabriela; Sampaio, Beatriz Motta; Rocha, Erica; Balbi, André Luís; Ponce, Daniela

    2017-01-01

    Aim The elderly are at high risk of acute kidney injury (AKI) because of structural and functional degeneration over time and with the aging of the population, the demand for intensive care unit (ICU) admission for older patients has risen recently. However, data from developing countries are scarce. This study aimed to describe the incidence of AKI in elderly patients admitted to ICU from a developing country, to determine the most frequent etiologies for renal impairment and identify its risk factors and outcome. Methods All patients admitted to the ICU at a Brazilian teaching hospital for 12 consecutive months were followed prospectively from the time of admission until ICU discharge. Elderly was defined as aged >60 years and AKI was defined according to the Kidney Disease Improving Global Outcomes 2012 criteria. Multivariable logistic regression was used to adjust confounding and selection bias. Results Two hundred elderly patients were included in the study. AKI incidence was 27% and the main etiology was sepsis (48.1%). At logistic regression, baseline creatinine (odds ratio [OR]=5.17, p<0.0001), Acute Physiology and Chronic Health Evaluation (APACHE) II (OR=1.20, p<0.0001), sepsis (OR=2.96, p<0.0001), and longer ICU stay (OR=1.68, p<0.0001) were associated with AKI in elderly patients. Baseline creatinine (OR=1.97, p=0.018), APACHE II (OR=1.29, p<0.0001), sepsis (OR=1.87, p<0.0001), and AKI severity (OR=2.57, p=0.027) were identified as predictors of death. Conclusion AKI was frequent in elderly patients admitted to ICU from a developing country, and it was identified as a risk factor for death. Sepsis was an important risk factor for both AKI and mortality, similar to developed countries and in younger populations. PMID:28210101

  11. In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia.

    PubMed

    Francis, Stephen Starko; Wallace, Amelia D; Wendt, George A; Li, Linlin; Liu, Fenyong; Riley, Lee W; Kogan, Scott; Walsh, Kyle M; de Smith, Adam J; Dahl, Gary V; Ma, Xiaomei; Delwart, Eric; Metayer, Catherine; Wiemels, Joseph L

    2017-03-23

    It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.

  12. Hemorrhage and resuscitation induce alterations in cytokine expression and the development of acute lung injury.

    PubMed

    Shenkar, R; Coulson, W F; Abraham, E

    1994-03-01

    Acute pulmonary injury occurs frequently following hemorrhage and injury. In order to better examine the sequence of events leading to lung injury in this setting, we investigated lung histology as well as in vivo mRNA levels for cytokines with proinflammatory and immunoregulatory properties (IL-1 beta, IL-6, IL-10, TNF-alpha, TGF-beta, IFN-gamma) over the 3 days following hemorrhage and resuscitation. Significant increases in mRNA levels for IL-1 beta, IL-6, IL-10, and IFN-gamma, but not TNF-alpha, were present among intraparenchymal pulmonary mononuclear cells obtained 1 and 3 days after hemorrhage. Among alveolar macrophages, TNF-alpha and IL-1 beta mRNA levels were increased 3 days after hemorrhage. Few changes in cytokine mRNA levels, with the exception of TNF-alpha at 3 days after hemorrhage, were present among peripheral blood mononuclear cells. Histologic examination of lungs from hemorrhaged animals showed no alterations 1 day after hemorrhage, but neutrophil and mononuclear cell infiltrates, edema, intra-alveolar hemorrhage, and fibrin generation were present 3 days after hemorrhage. These results suggest that hemorrhage-induced enhancement of proinflammatory cytokine gene transcription may be an important mechanism contributing to the frequent development of acute lung injury following blood loss and injury.

  13. Investigation, Development, and Evaluation of Performance Proving for Fault-tolerant Computers

    NASA Technical Reports Server (NTRS)

    Levitt, K. N.; Schwartz, R.; Hare, D.; Moore, J. S.; Melliar-Smith, P. M.; Shostak, R. E.; Boyer, R. S.; Green, M. W.; Elliott, W. D.

    1983-01-01

    A number of methodologies for verifying systems and computer based tools that assist users in verifying their systems were developed. These tools were applied to verify in part the SIFT ultrareliable aircraft computer. Topics covered included: STP theorem prover; design verification of SIFT; high level language code verification; assembly language level verification; numerical algorithm verification; verification of flight control programs; and verification of hardware logic.

  14. Indoor air pollution in developing countries and acute lower respiratory infections in children

    PubMed Central

    Smith, K.; Samet, J.; Romieu, I.; Bruce, N.

    2000-01-01

    BACKGROUND—A critical review was conducted of the quantitative literature linking indoor air pollution from household use of biomass fuels with acute respiratory infections in young children, which is focused on, but not confined to, acute lower respiratory infection and pneumonia in children under two years in less developed countries. Biomass in the form of wood, crop residues, and animal dung is used in more than two fifths of the world's households as the principal fuel.
METHODS—Medline and other electronic databases were used, but it was also necessary to secure literature from colleagues in less developed countries where not all publications are yet internationally indexed.
RESULTS—The studies of indoor air pollution from household biomass fuels are reasonably consistent and, as a group, show a strong significant increase in risk for exposed young children compared with those living in households using cleaner fuels or being otherwise less exposed. Not all studies were able to adjust for confounders, but most of those that did so found that strong and significant risks remained.
CONCLUSIONS—It seems that the relative risks are likely to be significant for the exposures considered here. Since acute lower respiratory infection is the chief cause of death in children in less developed countries, and exacts a larger burden of disease than any other disease category for the world population, even small additional risks due to such a ubiquitous exposure as air pollution have important public health implications. In the case of indoor air pollution in households using biomass fuels, the risks also seem to be fairly strong, presumably because of the high daily concentrations of pollutants found in such settings and the large amount of time young children spend with their mothers doing household cooking. Given the large vulnerable populations at risk, there is an urgent need to conduct randomised trials to increase confidence in the cause

  15. [Development and clinical testing of the Russian version of the Acute Cystitis Symptom Score - ACSS].

    PubMed

    Alidjanov, J F; Abdufattaev, U A; Makhmudov, D Kh; Mirkhamidov, D Kh; Khadzhikhanov, F A; Azgamov, A V; Pilatz, A; Naber, K G; Wagenlehner, F M; Akilov, F A

    2014-01-01

    The Acute Cystitis Symptom Score - ACSS was originally developed in the Uzbek language and has demonstrated high reliability and validity. The study was aimed to develop a Russian version of the ACSS questionnaire and evaluate its psychometric properties. Translation and adaptation of the ACSS questionnaire containing 18 questions, 6 of them - for the typical symptoms of acute cystitis (AC), 4 - for the differential diagnosis; 3 - for the quality of life, and 5 - for the conditions that may affect the choice of treatment, were performed according to the recommendations developed by the Mapi Research Institute. Study involved 83 Russian-speaking women (mean age, 35.6 ±13.7 years); 38 (45.8%) patients were in the main group (patients with AC), and 45 (54.2%) - in the control group (without AC). Medical examination and appropriate treatment of the respondents were conducted in accordance with approved standards. After completing the course of therapy, 19 (50%) patients of the main group came for the control examination. There was statistically significant difference in the scores obtained in the two groups. Score profiles positively correlated with the results of laboratory tests (rho = 0.26-0.48). Cronbach's alpha for the Russian version of the questionnaire was 0.86 (95% CI, 0.81-0.91), area under the curve in the ROC analysis was 0.96. The results of testing the Russian version correspond to those of the original version. The Russian version of the ACSS questionnaire has high. reliability and validity, and can be recommended for clinical research and diagnosis of primary AC, and dynamic monitoring of the effectiveness of the treatment of the Russian-speaking population of patients.

  16. Ectopic expression of a cyanobacterial flavodoxin in creeping bentgrass impacts plant development and confers broad abiotic stress tolerance.

    PubMed

    Li, Zhigang; Yuan, Shuangrong; Jia, Haiyan; Gao, Fangyuan; Zhou, Man; Yuan, Ning; Wu, Peipei; Hu, Qian; Sun, Dongfa; Luo, Hong

    2016-09-16

    Flavodoxin (Fld) plays a pivotal role in photosynthetic microorganisms as an alternative electron carrier flavoprotein under adverse environmental conditions. Cyanobacterial Fld has been demonstrated to be able to substitute ferredoxin of higher plants in most electron transfer processes under stressful conditions. We have explored the potential of Fld for use in improving plant stress response in creeping bentgrass (Agrostis stolonifera L.). Overexpression of Fld altered plant growth and development. Most significantly, transgenic plants exhibited drastically enhanced performance under oxidative, drought and heat stress as well as nitrogen (N) starvation, which was associated with higher water retention and cell membrane integrity than wild-type controls, modified expression of heat-shock protein genes, production of more reduced thioredoxin, elevated N accumulation and total chlorophyll content as well as up-regulated expression of nitrite reductase and N transporter genes. Further analysis revealed that the expression of other stress-related genes was also impacted in Fld-expressing transgenics. Our data establish a key role of Fld in modulating plant growth and development and plant response to multiple sources of adverse environmental conditions in crop species. This demonstrates the feasibility of manipulating Fld in crop species for genetic engineering of plant stress tolerance.

  17. GOLDEN 2-LIKE transcription factors for chloroplast development affect ozone tolerance through the regulation of stomatal movement

    PubMed Central

    Nagatoshi, Yukari; Mitsuda, Nobutaka; Hayashi, Maki; Inoue, Shin-ichiro; Okuma, Eiji; Kubo, Akihiro; Murata, Yoshiyuki; Seo, Mitsunori; Saji, Hikaru; Kinoshita, Toshinori; Ohme-Takagi, Masaru

    2016-01-01

    Stomatal movements regulate gas exchange, thus directly affecting the efficiency of photosynthesis and the sensitivity of plants to air pollutants such as ozone. The GARP family transcription factors GOLDEN 2-LIKE1 (GLK1) and GLK2 have known functions in chloroplast development. Here, we show that Arabidopsis thaliana (A. thaliana) plants expressing the chimeric repressors for GLK1 and -2 (GLK1/2-SRDX) exhibited a closed-stomata phenotype and strong tolerance to ozone. By contrast, plants that overexpress GLK1/2 exhibited an open-stomata phenotype and higher sensitivity to ozone. The plants expressing GLK1-SRDX had reduced expression of the genes for inwardly rectifying K+ (K+in) channels and reduced K+in channel activity. Abscisic acid treatment did not affect the stomatal phenotype of 35S:GLK1/2-SRDX plants or the transcriptional activity for K+in channel gene, indicating that GLK1/2 act independently of abscisic acid signaling. Our results indicate that GLK1/2 positively regulate the expression of genes for K+in channels and promote stomatal opening. Because the chimeric GLK1-SRDX repressor driven by a guard cell-specific promoter induced a closed-stomata phenotype without affecting chloroplast development in mesophyll cells, modulating GLK1/2 activity may provide an effective tool to control stomatal movements and thus to confer resistance to air pollutants. PMID:27035938

  18. GOLDEN 2-LIKE transcription factors for chloroplast development affect ozone tolerance through the regulation of stomatal movement.

    PubMed

    Nagatoshi, Yukari; Mitsuda, Nobutaka; Hayashi, Maki; Inoue, Shin-Ichiro; Okuma, Eiji; Kubo, Akihiro; Murata, Yoshiyuki; Seo, Mitsunori; Saji, Hikaru; Kinoshita, Toshinori; Ohme-Takagi, Masaru

    2016-04-12

    Stomatal movements regulate gas exchange, thus directly affecting the efficiency of photosynthesis and the sensitivity of plants to air pollutants such as ozone. The GARP family transcription factors GOLDEN 2-LIKE1 (GLK1) and GLK2 have known functions in chloroplast development. Here, we show that Arabidopsis thaliana (A. thaliana) plants expressing the chimeric repressors for GLK1 and -2 (GLK1/2-SRDX) exhibited a closed-stomata phenotype and strong tolerance to ozone. By contrast, plants that overexpress GLK1/2 exhibited an open-stomata phenotype and higher sensitivity to ozone. The plants expressing GLK1-SRDX had reduced expression of the genes for inwardly rectifying K(+) (K(+) in) channels and reduced K(+) in channel activity. Abscisic acid treatment did not affect the stomatal phenotype of 35S:GLK1/2-SRDX plants or the transcriptional activity for K(+) in channel gene, indicating that GLK1/2 act independently of abscisic acid signaling. Our results indicate that GLK1/2 positively regulate the expression of genes for K(+) in channels and promote stomatal opening. Because the chimeric GLK1-SRDX repressor driven by a guard cell-specific promoter induced a closed-stomata phenotype without affecting chloroplast development in mesophyll cells, modulating GLK1/2 activity may provide an effective tool to control stomatal movements and thus to confer resistance to air pollutants.

  19. Development of operational immunologic tolerance with neonatal gene transfer in nonhuman primates: preliminary studies.

    PubMed

    Tai, D S; Hu, C; Lee, C C I; Martinez, M; Cantero, G; Kim, E H; Tarantal, A F; Lipshutz, G S

    2015-11-01

    Achieving persistent expression is a prerequisite for effective genetic therapies for inherited disorders. These proof-of-concept studies focused on adeno-associated virus (AAV) administration to newborn monkeys. Serotype rh10 AAV expressing ovalbumin and green fluorescent protein (GFP) was administered intravenously at birth and compared with vehicle controls. At 4 months postnatal age, a second injection was administered intramuscularly, followed by vaccination at 1 year of age with ovalbumin and GFP. Ovalbumin was highest 2 weeks post administration in the treated monkey, which declined but remained detectable thereafter; controls demonstrated no expression. Long-term AAV genome copies were present in myocytes. At 4 weeks, neutralizing antibodies to rh10 were present in the experimental animal only. With AAV9 administration at 4 months, controls showed transient ovalbumin expression that disappeared with the development of strong anti-ovalbumin and anti-GFP antibodies. In contrast, increased and maintained ovalbumin expression was noted in the monkey administered AAV at birth, without antibody development. After vaccination, the experimental monkey maintained levels of ovalbumin without antibodies, whereas controls demonstrated high levels of antibodies. These preliminary studies suggest that newborn AAV administration expressing secreted and intracellular xenogenic proteins may result in persistent expression in muscle, and subsequent vector administration can result in augmented expression without humoral immune responses.

  20. Dung Beetles Eat Acorns to Increase Their Ovarian Development and Thermal Tolerance

    PubMed Central

    Verdú, José R.; Casas, José L.; Lobo, Jorge M.; Numa, Catherine

    2010-01-01

    Animals eat different foods in proportions that yield a more favorable balance of nutrients. Despite known examples of these behaviors across different taxa, their ecological and physiological benefits remain unclear. We identified a surprising dietary shift that confers ecophysiological advantages in a dung beetle species. Thorectes lusitanicus, a Mediterranean ecosystem species adapted to eat semi-dry and dry dung (dung-fiber consumers) is also actively attracted to oak acorns, consuming and burying them. Acorn consumption appears to confer potential advantages over beetles that do not eat acorns: acorn-fed beetles showed important improvements in the fat body mass, hemolymph composition, and ovary development. During the reproductive period (October-December) beetles incorporating acorns into their diets should have greatly improved resistance to low-temperature conditions and improved ovarian development. In addition to enhancing the understanding of the relevance of dietary plasticity to the evolutionary biology of dung beetles, these results open the way to a more general understanding of the ecophysiological implications of differential dietary selection on the ecology and biogeography of these insects. PMID:20404931

  1. Dung beetles eat acorns to increase their ovarian development and thermal tolerance.

    PubMed

    Verdú, José R; Casas, José L; Lobo, Jorge M; Numa, Catherine

    2010-04-09

    Animals eat different foods in proportions that yield a more favorable balance of nutrients. Despite known examples of these behaviors across different taxa, their ecological and physiological benefits remain unclear. We identified a surprising dietary shift that confers ecophysiological advantages in a dung beetle species. Thorectes lusitanicus, a Mediterranean ecosystem species adapted to eat semi-dry and dry dung (dung-fiber consumers) is also actively attracted to oak acorns, consuming and burying them. Acorn consumption appears to confer potential advantages over beetles that do not eat acorns: acorn-fed beetles showed important improvements in the fat body mass, hemolymph composition, and ovary development. During the reproductive period (October-December) beetles incorporating acorns into their diets should have greatly improved resistance to low-temperature conditions and improved ovarian development. In addition to enhancing the understanding of the relevance of dietary plasticity to the evolutionary biology of dung beetles, these results open the way to a more general understanding of the ecophysiological implications of differential dietary selection on the ecology and biogeography of these insects.

  2. Development of butanol-tolerant Bacillus subtilis strain GRSW2-B1 as a potential bioproduction host

    PubMed Central

    2011-01-01

    As alternative microbial hosts for butanol production with organic-solvent tolerant trait are in high demands, a butanol-tolerant bacterium, Bacillus subtilis GRSW2-B1, was thus isolated. Its tolerance covered a range of organic solvents at high concentration (5%v/v), with remarkable tolerance in particular to butanol and alcohol groups. It was susceptible for butanol acclimatization, which resulted in significant tolerance improvement. It has versatility for application in a variety of fermentation process because it has superior tolerance when cells were exposed to butanol either as high-density, late-exponential grown cells (up to 5%v/v) or under growing conditions (up to 2.25%v/v). Genetic transformation procedure was optimized, yielding the highest efficiency at 5.17 × 103 colony forming unit (μg DNA)-1. Gene expression could be effectively driven by several promoters with different levels, where as the highest expression was observed with a xylose promoter. The constructed vector was stably maintained in the transformants, in the presence or absence of butanol stress. Adverse effect of efflux-mediated tetracycline resistance determinant (TetL) to bacterial organic-solvent tolerance property was unexpectedly observed and thus discussed. Overall results indicate that B. subtilis GRSW2-B1 has potential to be engineered and further established as a genetic host for bioproduction of butanol. PMID:21906347

  3. Cold tolerance of third-instar Drosophila suzukii larvae.

    PubMed

    Jakobs, Ruth; Ahmadi, Banafsheh; Houben, Sarah; Gariepy, Tara D; Sinclair, Brent J

    2017-01-01

    Drosophila suzukii is an emerging global pest of soft fruit; although it likely overwinters as an adult, larval cold tolerance is important both for determining performance during spring and autumn, and for the development of temperature-based control methods aimed at larvae. We examined the low temperature biology of third instar feeding and wandering larvae in and out of food. We induced phenotypic plasticity of thermal biology by rearing under short days and fluctuating temperatures (5.5-19°C). Rearing under fluctuating temperatures led to much slower development (42.1days egg-adult) compared to control conditions (constant 21.5°C; 15.7days), and yielded larger adults of both sexes. D. suzukii larvae were chill-susceptible, being killed by low temperatures not associated with freezing, and freezing survival was not improved when ice formation was inoculated externally via food or silver iodide. Feeding larvae were more cold tolerant than wandering larvae, especially after rearing under fluctuating temperatures, and rearing under fluctuating temperatures improved survival of prolonged cold (0°C) to beyond 72h in both larval stages. There was no evidence that acute cold tolerance could be improved by rapid cold-hardening. We conclude that D. suzukii has the capacity to develop at low temperatures under fluctuating temperatures, but that they have limited cold tolerance. However, phenotypic plasticity of prolonged cold tolerance must be taken into account when developing low temperature treatments for sanitation of this species.

  4. Heterosexual and Homosexual Partners Practising Unprotected Sex May Develop Allogeneic Immunity and to a Lesser Extent Tolerance

    PubMed Central

    Kingsley, Cherry; Peters, Barry; Babaahmady, Kaboutar; Pomeroy, Laura; Rahman, Durdana; Vaughan, Robert; Lehner, Thomas

    2009-01-01

    Background Epidemiological studies suggest that allogeneic immunity may inhibit HIV-1 transmission from mother to baby and is less frequent in multiparous than uniparous women. Alloimmune responses may also be elicited during unprotected heterosexual intercourse, which is associated ex vivo with resistance to HIV infection. Methodology/Principal Findings The investigation was carried out in well-defined heterosexual and homosexual monogamous partners, practising unprotected sex and a heterosexual cohort practising protected sex. Allogeneic CD4+ and CD8+ T cell proliferative responses were elicited by stimulating PBMC with the partners' irradiated monocytes and compared with 3rd party unrelated monocytes, using the CFSE method. Significant increase in allogeneic proliferative responses was found in the CD4+ and CD8+ T cells to the partners' irradiated monocytes, as compared with 3rd party unrelated monocytes (p≤0.001). However, a significant decrease in proliferative responses, especially of CD8+ T cells to the partners' compared with 3rd party monocytes was consistent with tolerization, in both the heterosexual and homosexual partners (p<0.01). Examination of CD4+CD25+FoxP3+ regulatory T cells by flow cytometry revealed a significantly greater proportion of these cells in the homosexual than heterosexual partners practising unprotected sex (p<0.05). Ex vivo studies of infectivity of PBMC with HIV-1 showed significantly greater inhibition of infectivity of PBMC from heterosexual subjects practising unprotected compared with those practising protected sex (p = 0.02). Conclusions/Significance Both heterosexual and homosexual monogamous partners practising unprotected sex develop allogeneic CD4+ and CD8+ T cell proliferative responses to the partners' unmatched cells and a minority may be tolerized. However, a greater proportion of homosexual rather than heterosexual partners developed CD4+CD25FoxP3+ regulatory T cells. These results, in addition to finding

  5. Recent development in the design, testing and impact-damage tolerance of stiffened composite panels

    NASA Technical Reports Server (NTRS)

    Williams, J. G.; Anderson, M. S.; Rhodes, M. D.; Starnes, J. H., Jr.; Stroud, W. J.

    1979-01-01

    Structural technology of laminated filamentary-composite stiffened-panel structures under combined inplane and lateral loadings is discussed. Attention is focused on: (1) methods for analyzing the behavior of these structures under load and for determining appropriate structural proportions for weight-efficient configurations; and (2) effects of impact damage and geometric imperfections on structural performance. Recent improvements in buckling analysis involving combined inplane compression and shear loadings and transverse shear deformations are presented. A computer code is described for proportioning or sizing laminate layers and cross-sectional dimensions, and the code is used to develop structural efficiency data for a variety of configurations, loading conditions, and constraint conditions. Experimental data on buckling of panels under inplane compression is presented. Mechanisms of impact damage initiation and propagation are described.

  6. Self-reported fast eating is a potent predictor of development of impaired glucose tolerance in Japanese men and women: Tsukuba Medical Center Study.

    PubMed

    Totsuka, Kumiko; Maeno, Takami; Saito, Kazumi; Kodama, Satoru; Asumi, Mihoko; Yachi, Yoko; Hiranuma, Yuri; Shimano, Hitoshi; Yamada, Nobuhiro; Ono, Yukio; Naito, Takashi; Sone, Hirohito

    2011-12-01

    We recorded self-reported eating patterns in 172 Japanese men and women who were subsequently followed for 3 years for the occurrence of impaired glucose tolerance (IGT). Incidence of IGT was significantly higher in those who reported eating fast. Self-reported eating fast is a potent risk factor for development of IGT.

  7. Development of drought and/or heat tolerant crop varieties, an adaptation approach to mitigate impact of climate change on agriculture

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As global climate change becomes inevitable, the sustainability of agricultural production in US and worldwide faces serious threat from extreme weather conditions, such as drought and high temperature (heat wave). Development of drought and/or heat tolerant crop varieties is one of the most effecti...

  8. Development of a more fish tolerant turbine runner advanced hydropower turbine project. Final report

    SciTech Connect

    Cook, T.C.; Hecker, G.E.; Faulkner, H.B.; Jansen, W.

    1997-01-01

    The Hidrostal pump is a single bladed combined screw/centrifugal pump which has been proven to transport fish with minimal injury. The focus of the ARL/NREC research project was to develop a new runner geometry which is effective in downstream fish passage and hydroelectric power generation. A flow of 1,000 cfs and a head in the range of 75 ft to 100 ft were selected for conceptual design of the new runner. Criteria relative to hydraulic characteristics which are favorable for fish passage were prepared based on a reassessment of the available information. Important criteria used to develop the new runner design included low pressure change rates, minimum absolute pressures, and minimum shear. Other criteria which are reflected in the runner design are a minimum number of blades (only two), minimum total length of leading edges, and large flow passages. Flow characteristics of the new runner were analyzed using two- dimensional and three-dimensional Computational Fluid Dynamic (CFD) models. The basic runner geometry was initially selected using the two-dimensional model. The three-dimensional model was used to investigate the flow characteristics in detail through the entire runner and to refine the design by eliminating potential problem areas at the leading and trailing edges. Results of the analyses indicated that the runner has characteristics which should provide safe fish passage with an overall power efficiency of approximately 90%. The size of the new runner, which is larger than conventional turbine runners with the same design flow and head, will provide engineering, fabrication, and installation.challenges related to the turbine components and the civil works. A small reduction in the overall efficiency would reduce the size of the runner considerably, would simplify the turbine manufacturing operations, and would allow installation of the new turbine at more hydroelectric sites.

  9. Diagnostic Stability of Acute and Transient Psychotic Disorders in Developing Country Settings: An Overview

    PubMed Central

    Mehta, Shubham

    2015-01-01

    Acute and transient psychotic disorders (ATPD), introduced in the International Classification of Diseases (ICD-10) diagnostic system in 1992, are not receiving much attention in developing countries. Therefore, the main objective of this article is to review the literature related to the diagnostic stability of ATPD in developing countries. A PubMed search was conducted to review the studies concerned with this issue in the context of developing countries, as diagnostic stability is more of a direct test of validity of psychiatric diagnoses. Four publications were found. According to the literature search, the stability percentage of the ICD-10 ATPD diagnosis is 63-100%. The diagnostic shift is more commonly either towards bipolar disorder or schizophrenia, if any. Shorter duration of illness (<1 month) and abrupt onset (<48 hours) predict a stable diagnosis of ATPD. Based on available evidence, the diagnosis of ATPD appears to be relatively stable in developing countries. However, it is difficult to make a definitive conclusion, as there is a substantial lack of literature in developing country settings. PMID:26266021

  10. Speed of leukemia development and genetic diversity in xenograft models of T cell acute lymphoblastic leukemia

    PubMed Central

    Poglio, Sandrine; Lewandowski, Daniel; Calvo, Julien; Caye, Aurélie; Gros, Audrey; Laharanne, Elodie; Leblanc, Thierry; Landman-Parker, Judith; Baruchel, André; Soulier, Jean; Ballerini, Paola; Clappier, Emmanuelle; Pflumio, Françoise

    2016-01-01

    T cell acute lymphoblastic leukemia (T-ALL) develops through accumulation of multiple genomic alterations within T-cell progenitors resulting in clonal heterogeneity among leukemic cells. Human T-ALL xeno-transplantation in immunodeficient mice is a gold standard approach to study leukemia biology and we recently uncovered that the leukemia development is more or less rapid depending on T-ALL sample. The resulting human leukemia may arise through genetic selection and we previously showed that human T-ALL development in immune-deficient mice is significantly enhanced upon CD7+/CD34+ leukemic cell transplantations. Here we investigated the genetic characteristics of CD7+/CD34+ and CD7+/CD34− cells from newly diagnosed human T-ALL and correlated it to the speed of leukemia development. We observed that CD7+/CD34+ or CD7+/CD34− T-ALL cells that promote leukemia within a short-time period are genetically similar, as well as xenograft-derived leukemia resulting from both cell fractions. In the case of delayed T-ALL growth CD7+/CD34+ or CD7+/CD34− cells were either genetically diverse, the resulting xenograft leukemia arising from different but branched subclones present in the original sample, or similar, indicating decreased fitness to mouse micro-environment. Altogether, our work provides new information relating the speed of leukemia development in xenografts to the genetic diversity of T-ALL cell compartments. PMID:27191650

  11. Regulation of µ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

    PubMed Central

    Williams, John T.; Ingram, Susan L.; Henderson, Graeme; Chavkin, Charles; von Zastrow, Mark; Schulz, Stefan; Koch, Thomas; Evans, Christopher J.

    2013-01-01

    Morphine and related µ-opioid receptor (MOR) agonists remain among the most effective drugs known for acute relief of severe pain. A major problem in treating painful conditions is that tolerance limits the long-term utility of opioid agonists. Considerable effort has been expended on developing an understanding of the molecular and cellular processes that underlie acute MOR signaling, short-term receptor regulation, and the progression of events that lead to tolerance for different MOR agonists. Although great progress has been made in the past decade, many points of contention and controversy cloud the realization of this progress. This review attempts to clarify some confusion by clearly defining terms, such as desensitization and tolerance, and addressing optimal pharmacological analyses for discerning relative importance of these cellular mechanisms. Cellular and molecular mechanisms regulating MOR function by phosphorylation relative to receptor desensitization and endocytosis are comprehensively reviewed, with an emphasis on agonist-biased regulation and areas where knowledge is lacking or controversial. The implications of these mechanisms for understanding the substantial contribution of MOR signaling to opioid tolerance are then considered in detail. While some functional MOR regulatory mechanisms contributing to tolerance are clearly understood, there are large gaps in understanding the molecular processes responsible for loss of MOR function after chronic exposure to opioids. Further elucidation of the cellular mechanisms that are regulated by opioids will be necessary for the successful development of MOR-based approaches to new pain therapeutics that limit the development of tolerance. PMID:23321159

  12. Review of technology development and clinical trials of transcranial laser therapy for acute ischemic stroke treatment

    NASA Astrophysics Data System (ADS)

    Catanzaro, Brian E.; Streeter, Jackson; de Taboada, Luis

    2010-02-01

    Stroke is the one of the leading causes of mortality in the United States, claiming 600,000 lives each year. Evidence suggests that near infrared (NIR) illumination has a beneficial effect on a variety of cells when these cells are exposed to adverse conditions. Among these conditions is the hypoxic state produced by acute ischemic stroke (AIS). To demonstrate the impact NIR Transcranial Laser Therapy (TLT) has on AIS in humans, a series of double blind, placebo controlled clinical trials were designed using the NeuroThera(R) System (NTS). The NTS was designed and developed to treat subjects non-invasively using 808 nm NIR illumination. TLT, as it applies to stroke therapy, and the NTS will be described. The results of the two clinical trials: NeuroThera(R) Safety and Efficacy Trial 1 (NEST-1) and NeuroThera(R) Safety and Efficacy Trial 2 (NEST-2) will be reviewed and discussed.

  13. Heat tolerance during embryonic development has not diverged among populations of a widespread species (Sceloporus undulatus)

    PubMed Central

    Angilletta, Michael J.; Zelic, Maximilian H.; Adrian, Gregory J.; Hurliman, Alex M.; Smith, Colton D.

    2013-01-01

    The frequency and magnitude of heat waves have increased in recent decades, imposing additional stresses on organisms in extreme environments. Most reptilian embryos are regularly exposed to thermal stress because they develop in shallow, warm soils for weeks to months. We studied cardiac performance during warming to infer lethal temperatures for embryonic lizards in the Sceloporus undulatus complex. Embryos from four populations throughout the geographical range (New Jersey, South Carolina, Colorado, and Arizona) were warmed at a rate observed in natural nests. Embryos from all populations exhibited a similar pattern of thermal sensitivity, as follows: heart rate rose between 34 and 41°C, remained stable between 41 and 44°C, and dropped sharply between 44 and 47°C. No embryos recovered from cardiac arrest, indicating that the upper lethal temperature was ≤47°C. Despite the putative selective pressures, the thermal limit to cardiac performance seems to have been conserved during the evolution of this species. PMID:27293602

  14. A cross-over study of the acute effects of espresso coffee on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus.

    PubMed

    Krebs, Jeremy D; Parry-Strong, Amber; Weatherall, Mark; Carroll, Richard W; Downie, Michelle

    2012-09-01

    The objective was to determine the effect of a single dose of espresso caffeinated coffee, decaffeinated coffee, or water on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus. Eighteen participants who were habitual coffee drinkers, were studied using a random-order cross-over design. After a fasting blood sample participants consumed either a double-shot black espresso coffee, decaffeinated coffee, or hot water. The main outcomes were area under the curve (AUC) glucose and insulin, and insulin sensitivity (Matsuda index) during a 75 g oral glucose tolerance test (OGTT) performed one hour later. Other outcomes were change in glucose and insulin and also the insulinogenic index (IGI) and disposition index (DI). AUC glucose was marginally different between beverages (P=.06) being greater following caffeinated coffee than water, mean difference 104 mmol/L/180 min (95% CI 0.1 to 198.1, P=.031), or decaffeinated coffee, mean difference 92.1 mmol/L/180 min (95% CI -1.9 to 186.1, P=.055). There was no difference in AUC insulin (P=.87) or insulin sensitivity (P=.47), nor in change in glucose or insulin over the hour following beverage consumption. There was a marginal difference in IGI between beverages (P=.097) with coffee having a lower incremental increase in insulin/glucose than water (P=.037) though no difference between coffee and decaffeinated coffee (P=.54) and no difference in DI (P=.23). Black espresso coffee in people with type 2 diabetes mellitus results in a marginally greater excursion of glucose during a following OGTT compared with water or decaffeinated coffee. This effect does not appear to be mediated by changes in insulin sensitivity.

  15. Development of a non-infectious rat model of acute exacerbation of idiopathic pulmonary fibrosis

    PubMed Central

    Chen, Shan-Shan; Yin, Zhao-Fang; Chen, Tao; Qiu, Hui; Wei, Ya-Ru; Du, Shan-Shan; Jin, Yue-Ping; Zhao, Meng-Meng; Wu, Qin

    2017-01-01

    Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with severe pulmonary fibrosis. The main cause of IPF-associated death is acute exacerbation of IPF (AE-IPF). This study aims to develop a rat model of AE-IPF by two intratracheal perfusions with bleomycin (BLM). Methods Ninety male Sprague Dawley (SD) rats were randomized into three groups: an AE-IPF model group (BLM + BLM group), an IPF model group (BLM group), and a normal control group. Rats in the BLM + BLM group underwent a second perfusion with BLM on day 28 after the first perfusion with BLM. Rats in the other two groups received saline as the second perfusion. Six rats in each group were sacrificed on day 31, day 35, and day 42 after the first perfusion, respectively. Additional 18 rats in each group were observed for survival. Results Rats in the BLM + BLM group had significantly worse pulmonary alveolar inflammation and fibrosis than rats in the BLM group. Rats in the BLM + BLM group also developed large amounts of hyaline membrane, showed high levels of albumin (ALB) and various inflammatory factors in the bronchoalveolar lavage fluid (BALF), and had markedly increased lung water content. Furthermore, rat survival was reduced in the BLM + BLM group. The pathophysiological characteristics of rats in the BLM + BLM group resemble those of patients with AE-IPF. Conclusions A second perfusion with BLM appears to induce acute exacerbation of pulmonary fibrosis and may be used to model AE-IPF in rats. PMID:28203411

  16. Development and evaluation of a fault-tolerant multiprocessor (FTMP) computer. Volume 1: FTMP principles of operation

    NASA Technical Reports Server (NTRS)

    Smith, T. B., Jr.; Lala, J. H.

    1983-01-01

    The basic organization of the fault tolerant multiprocessor, (FTMP) is that of a general purpose homogeneous multiprocessor. Three processors operate on a shared system (memory and I/O) bus. Replication and tight synchronization of all elements and hardware voting is employed to detect and correct any single fault. Reconfiguration is then employed to repair a fault. Multiple faults may be tolerated as a sequence of single faults with repair between fault occurrences.

  17. Fault Tolerance and Scaling in e-Science Cloud Applications: Observations from the Continuing Development of MODISAzure

    SciTech Connect

    Li, Jie; Humphrey, Marty; Cheah, You-Wei; Ryu, Youngryel; Agarwal, Deb; Jackson, Keith; van Ingen, Catharine

    2010-04-01

    It can be natural to believe that many of the traditional issues of scale have been eliminated or at least greatly reduced via cloud computing. That is, if one can create a seemingly wellfunctioning cloud application that operates correctly on small or moderate-sized problems, then the very nature of cloud programming abstractions means that the same application will run as well on potentially significantly larger problems. In this paper, we present our experiences taking MODISAzure, our satellite data processing system built on the Windows Azure cloud computing platform, from the proof-of-concept stage to a point of being able to run on significantly larger problem sizes (e.g., from national-scale data sizes to global-scale data sizes). To our knowledge, this is the longest-running eScience application on the nascent Windows Azure platform. We found that while many infrastructure-level issues were thankfully masked from us by the cloud infrastructure, it was valuable to design additional redundancy and fault-tolerance capabilities such as transparent idempotent task retry and logging to support debugging of user code encountering unanticipated data issues. Further, we found that using a commercial cloud means anticipating inconsistent performance and black-box behavior of virtualized compute instances, as well as leveraging changing platform capabilities over time. We believe that the experiences presented in this paper can help future eScience cloud application developers on Windows Azure and other commercial cloud providers.

  18. Association of oliguria with the development of acute kidney injury in the critically ill.

    PubMed

    Vaara, Suvi T; Parviainen, Ilkka; Pettilä, Ville; Nisula, Sara; Inkinen, Outi; Uusaro, Ari

    2016-01-01

    Urine output (UO) criterion may increase the sensitivity of the definition of acute kidney injury (AKI). We determined whether the empirically derived definition for oliguria(<0.5 ml/kg/h) is independently associated with adverse outcome. Data analysis included hourly recorded UO from the prospective, multicenter FINNAKI study conducted in 16 Finnish intensive care units. Confounder-adjusted association of oliguria of different severity and duration primarily with the development of AKI defined by creatinine criterion (Cr-AKI) or renal replacement therapy(RRT) was assessed. Secondarily, we determined the association of oliguria with 90-day mortality. Of the 1966 patients analyzed for the development of AKI, 454 (23.1%) reached this endpoint. Within this AKI cohort, 312 (68.7%)developed Cr-AKI, 21 (4.6%) commenced RRT without Cr-AKI, and 121 (26.7%) commenced RRT with Cr-AKI. Episodes of severe oliguria (<0.1 ml/kg/h) for more than 3 h were independently associated with the development of Cr-AKI or RRT. The shortest periods of consecutive oliguria independently associated with an increased risk for 90-day mortality were 6–12 h of oliguria from 0.3 to <0.5 ml/kg/h, over 6 h of oliguria from 0.1 to <0.3 ml/kg/h, and severe oliguria lasting over 3 h.Thus, our findings underlie the importance of hourly UO measurements.

  19. Critical processes and parameters in the development of accident tolerant fuels drop-in capsule irradiation tests

    SciTech Connect

    Barrett, K. E.; Ellis, K. D.; Glass, C. R.; Roth, G. A.; Teague, M. P.; Johns, J.

    2015-12-01

    The goal of the Accident Tolerant Fuel (ATF) program is to develop the next generation of Light Water Reactor (LWR) fuels with improved performance, reliability, and safety characteristics during normal operations and accident conditions and with reduced waste generation. An irradiation test series has been defined to assess the performance of proposed ATF concepts under normal LWR operating conditions. The Phase I ATF irradiation test series is planned to be performed as a series of drop-in capsule tests to be irradiated in the Advanced Test Reactor (ATR) operated by the Idaho National Laboratory (INL). Design, analysis, and fabrication processes for ATR drop-in capsule experiment preparation are presented in this paper to demonstrate the importance of special design considerations, parameter sensitivity analysis, and precise fabrication and inspection techniques for figure innovative materials used in ATF experiment assemblies. A Taylor Series Method sensitivity analysis approach was used to identify the most critical variables in cladding and rodlet stress, temperature, and pressure calculations for design analyses. The results showed that internal rodlet pressure calculations are most sensitive to the fission gas release rate uncertainty while temperature calculations are most sensitive to cladding I.D. and O.D. dimensional uncertainty. The analysis showed that stress calculations are most sensitive to rodlet internal pressure uncertainties, however the results also indicated that the inside radius, outside radius, and internal pressure were all magnified as they propagate through the stress equation. This study demonstrates the importance for ATF concept development teams to provide the fabricators as much information as possible about the material properties and behavior observed in prototype testing, mock-up fabrication and assembly, and chemical and mechanical testing of the materials that may have been performed in the concept development phase. Special

  20. Critical processes and parameters in the development of accident tolerant fuels drop-in capsule irradiation tests

    DOE PAGES

    Barrett, K. E.; Ellis, K. D.; Glass, C. R.; ...

    2015-12-01

    The goal of the Accident Tolerant Fuel (ATF) program is to develop the next generation of Light Water Reactor (LWR) fuels with improved performance, reliability, and safety characteristics during normal operations and accident conditions and with reduced waste generation. An irradiation test series has been defined to assess the performance of proposed ATF concepts under normal LWR operating conditions. The Phase I ATF irradiation test series is planned to be performed as a series of drop-in capsule tests to be irradiated in the Advanced Test Reactor (ATR) operated by the Idaho National Laboratory (INL). Design, analysis, and fabrication processes formore » ATR drop-in capsule experiment preparation are presented in this paper to demonstrate the importance of special design considerations, parameter sensitivity analysis, and precise fabrication and inspection techniques for figure innovative materials used in ATF experiment assemblies. A Taylor Series Method sensitivity analysis approach was used to identify the most critical variables in cladding and rodlet stress, temperature, and pressure calculations for design analyses. The results showed that internal rodlet pressure calculations are most sensitive to the fission gas release rate uncertainty while temperature calculations are most sensitive to cladding I.D. and O.D. dimensional uncertainty. The analysis showed that stress calculations are most sensitive to rodlet internal pressure uncertainties, however the results also indicated that the inside radius, outside radius, and internal pressure were all magnified as they propagate through the stress equation. This study demonstrates the importance for ATF concept development teams to provide the fabricators as much information as possible about the material properties and behavior observed in prototype testing, mock-up fabrication and assembly, and chemical and mechanical testing of the materials that may have been performed in the concept development phase

  1. Lysosomal membrane stability, phagocytosis and tolerance to emersion in the mussel Perna viridis (Bivalvia: Mytilidae) following exposure to acute, sublethal, copper.

    PubMed

    Nicholson, S

    2003-08-01

    The mytilid mussel Perna viridis is distributed throughout the Indo-Pacific region and is potentially a suitable candidate for biological effects (biomarker) monitoring in the subtropics. A suite of cytological and physiological responses to acute (48-72 h) copper exposures of 50-200 microgl(-1) were assessed in order to determine the suitability of P. viridis for marine pollution monitoring. Copper elicited significant destabilisation of the haemocyte lysosomal membranes and also impaired phagocytosis. Survival during emersion following exposure to copper was not related to the experimental copper exposures suggesting that higher metal concentrations may be required to interfere with anaerobic enzymes responsible for suppression of metabolism. Based on this preliminary study, cytological biomarkers evaluated in the haemocytes extracted from P. viridis should prove an effective non-destructive means of assessing metal pollution throughout the mussels subtropical range.

  2. Non-Chimeric HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic Biomarkers

    PubMed Central

    Leventhal, J.R.; Mathew, J.M.; Salomon, D.R.; Kurian, S.M.; Friedewald, J.J.; Gallon, L.; Konieczna, I.; Tambur, A.R.; charette, j.; Levitsky, J.; Jie, C.; Kanwar, Y. S.; Abecassis, M. M.; Miller, J.

    2015-01-01

    We previously described early results of a non-chimeric operational tolerance protocol in HLA identical living donor renal transplants and now update these results. Recipients given alemtuzumab, tacrolimus/MPA with early sirolimus conversion were multiply infused with donor hematopoietic CD34+ stem cells. Immunosuppression was withdrawn by 24 months. Twelve months later operational tolerance was confirmed by rejection-free transplant biopsies. Five of the first 8 enrollees were initially tolerant one year off immunosuppression. Biopsies of 3 others after total withdrawal showed Banff 1A acute cellular rejection without renal dysfunction. With longer follow-up including 5 year post-transplant biopsies 4 of the 5 tolerant recipients remain without rejection while one developed Banff 1A without renal dysfunction. We now add 7 new subjects (2 operationally tolerant), and demonstrate time-dependent increases of circulating CD4+CD25+++CD127−FOXP3+ Tregs vs. losses of Tregs in non-tolerant subjects (p< 0.001). Gene expression signatures, developed using global RNA expression profiling of sequential whole blood and protocol biopsy samples, were highly associative with operational tolerance as early as 1 year post-transplant. The blood signature was validated by an external ITN data set. Our approach to non-chimeric operational HLA identical tolerance reveals association with Treg immunophenotypes and serial gene expression profiles. PMID:26227106

  3. Nonchimeric HLA-Identical Renal Transplant Tolerance: Regulatory Immunophenotypic/Genomic Biomarkers.

    PubMed

    Leventhal, J R; Mathew, J M; Salomon, D R; Kurian, S M; Friedewald, J J; Gallon, L; Konieczna, I; Tambur, A R; Charette, J; Levitsky, J; Jie, C; Kanwar, Y S; Abecassis, M M; Miller, J

    2016-01-01

    We previously described early results of a nonchimeric operational tolerance protocol in human leukocyte antigen (HLA)-identical living donor renal transplants and now update these results. Recipients given alemtuzumab, tacrolimus/MPA with early sirolimus conversion were multiply infused with donor hematopoietic CD34(+) stem cells. Immunosuppression was withdrawn by 24 months. Twelve months later, operational tolerance was confirmed by rejection-free transplant biopsies. Five of the first eight enrollees were initially tolerant 1 year off immunosuppression. Biopsies of three others after total withdrawal showed Banff 1A acute cellular rejection without renal dysfunction. With longer follow-up including 5-year posttransplant biopsies, four of the five tolerant recipients remain without rejection while one developed Banff 1A without renal dysfunction. We now add seven new subjects (two operationally tolerant), and demonstrate time-dependent increases of circulating CD4(+) CD25(+++) CD127(-) FOXP3(+) Tregs versus losses of Tregs in nontolerant subjects (p < 0.001). Gene expression signatures, developed using global RNA expression profiling of sequential whole blood and protocol biopsy samples, were highly associative with operational tolerance as early as 1 year posttransplant. The blood signature was validated by an external Immune Tolerance Network data set. Our approach to nonchimeric operational HLA-identical tolerance reveals association with Treg immunophenotypes and serial gene expression profiles.

  4. Development and application of an enzyme immunoassay for coronavirus OC43 antibody in acute respiratory illness.

    PubMed Central

    Gill, E P; Dominguez, E A; Greenberg, S B; Atmar, R L; Hogue, B G; Baxter, B D; Couch, R B

    1994-01-01

    Study of coronavirus OC43 infections has been limited because of the lack of sensitive cell culture systems and serologic assays. To improve this circumstance, we developed an indirect enzyme immunoassay (EIA) to detect serum antibody to OC43. Antigen (100 ng) prepared by polyethylene glycol precipitation provided optimal results without a postcoat procedure. Evaluation of intraplate variation indicated that a > or = 2.5-fold increase in serum titer was significant. Sixteen of 18 (89%) paired serum samples with previously identified, reproducible increases in the level of hemagglutination inhibition (HAI) antibody to OC43 also showed significant increases as detected by EIA. Specificity for the EIA was established with paired sera obtained from persons given influenza immunizations or experiencing a respiratory infection. No rise in antibody titers occurred among 33 persons with documented coronavirus 229E infection. EIA was then performed on each of 419 paired serum samples from ambulatory chronic obstructive pulmonary disease patients and healthy older adults, from asthmatic adults presenting for emergency room treatment, and from persons hospitalized with acute respiratory symptoms. Twenty-three antibody rises to OC43 were detected; only nine of these were detected by the HAI test, and the HAI test did not detect any increases in antibody titers that were not detected by EIA. Nineteen of 25 coronavirus OC43 infections for which a month of infection could be assigned occurred between November and February. Overall, 4.4% of acute respiratory illnesses in the studied populations were associated with a coronavirus OC43 infection. PMID:7814468

  5. Cost-effectiveness of zinc as adjunct therapy for acute childhood diarrhoea in developing countries.

    PubMed Central

    Robberstad, Bjarne; Strand, Tor; Black, Robert E.; Sommerfelt, Halvor

    2004-01-01

    OBJECTIVE: To analyse the incremental costs, effects and cost-effectiveness of zinc used as adjunct therapy to standard treatment of acute childhood diarrhoea, including dysentery, and to reassess the cost-effectiveness of standard case management with oral rehydration salt (ORS). METHODS: A decision tree was used to model expected clinical outcomes and expected costs under four alternative treatment strategies. The best available epidemiological, clinical and economic evidence was used in the calculations, and the United Republic of Tanzania was the reference setting. Probabilistic cost-effectiveness analysis was performed using a Monte-Carlo simulation technique and the potential impacts of uncertainty in single parameters were explored in one-way sensitivity analyses. FINDINGS: ORS was found to be less cost-effective than previously thought. The use of zinc as adjunct therapy significantly improved the cost-effectiveness of standard management of diarrhoea for dysenteric as well as non-dysenteric illness. The results were particularly sensitive to mortality rates in non-dysenteric diarrhoea, but the alternative interventions can be defined as highly cost-effective even in pessimistic scenarios. CONCLUSION: There is sufficient evidence to recommend the inclusion of zinc into standard case management of both dysenteric and non-dysenteric acute diarrhoea.A direct transfer of our findings from the United Republic of Tanzania to other settings is not justified, but there are no indications of large geographical differences in the efficacy of zinc. It is therefore plausible that our findings are also applicable to other developing countries. PMID:15500284

  6. Development and Validation of Intracranial Thrombus Segmentation on CT Angiography in Patients with Acute Ischemic Stroke

    PubMed Central

    Santos, Emilie M. M.; Marquering, Henk A.; Berkhemer, Olvert A.; van Zwam, Wim H.; van der Lugt, Aad; Majoie, Charles B.; Niessen, Wiro J.

    2014-01-01

    Background and Purpose Thrombus characterization is increasingly considered important in predicting treatment success for patients with acute ischemic stroke. The lack of intensity contrast between thrombus and surrounding tissue in CT images makes manual delineation a difficult and time consuming task. Our aim was to develop an automated method for thrombus measurement on CT angiography and validate it against manual delineation. Materials and Methods Automated thrombus segmentation was achieved using image intensity and a vascular shape prior derived from the segmentation of the contralateral artery. In 53 patients with acute ischemic stroke due to proximal intracranial arterial occlusion, automated length and volume measurements were performed. Accuracy was assessed by comparison with inter-observer variation of manual delineations using intraclass correlation coefficients and Bland–Altman analyses. Results The automated method successfully segmented the thrombus for all 53 patients. The intraclass correlation of automated and manual length and volume measurements were 0.89 and 0.84. Bland-Altman analyses yielded a bias (limits of agreement) of −0.4 (−8.8, 7.7) mm and 8 (−126, 141) mm3 for length and volume, respectively. This was comparable to the best interobserver agreement, with an intraclass correlation coefficients of 0.90 and 0.85 and a bias (limits of agreement) of −0.1 (−11.2, 10.9) mm and −17 (−216, 185) mm3. Conclusions The method facilitates automated thrombus segmentation for accurate length and volume measurements, is relatively fast and requires minimal user input, while being insensitive to high hematocrit levels and vascular calcifications. Furthermore, it has the potential to assess thrombus characteristics of low-density thrombi. PMID:25032691

  7. Predictors of hypoxaemia in hospital admissions with acute lower respiratory tract infection in a developing country

    PubMed Central

    Weber, M.; Usen, S.; Palmer, A.; Jaffar, S.; Mulholland, E

    1997-01-01

    Accepted 5 November 1996
 Since oxygen has to be given to most children in developing countries on the basis of clinical signs without performing blood gas analyses, possible clinical predictors of hypoxaemia were studied. Sixty nine children between the ages of 2 months and 5 years admitted to hospital with acute lower respiratory tract infection and an oxygen saturation (SaO2) < 90% were compared with 67 children matched for age and diagnosis from the same referral hospital with an SaO2 of 90% or above (control group 1), and 44unreferred children admitted to a secondary care hospital with acute lower respiratory infection (control group 2). Using multiple logistic regression analysis, sleepiness, arousal, quality of cry, cyanosis, head nodding, decreased air entry, nasal flaring, and upper arm circumference were found to be independent predictors of hypoxaemia on comparison of the cases with control group 1.Using a simple model of cyanosis or head nodding or not crying, the sensitivity to predict hypoxaemia was 59%, and the specificity 94% and 93% compared to control groups 1 and 2, respectively; 80% of the children with an SaO2 < 80% were identified by the combination of these signs. Over half of the children with hypoxaemia could be identified with a combination of three signs: extreme respiratory distress, cyanosis, and severely compromised general status. Further prospective validation of this model with other datasets is warranted. No other signs improved the sensitivity without compromising specificity. If a higher sensitivity is required, pulse oximetry has to be used.

 PMID:9166021

  8. Developing a market orientation in the Health Service: a survey of acute NHS Trusts in Scotland.

    PubMed

    Laing, A W; Galbraith, A

    1996-01-01

    Argues that the introduction of the quasi market mechanism into the Health Service has required that managers within NHS trusts acquire new managerial skills relating to market operations and, more importantly, reorientate their organizations towards the marketplace. Examines the pattern of development which has occurred within acute trusts across Scotland in the past three years, and argues that managers in the majority of trusts have developed a remarkably robust and relevant conceptualization of the nature and application of marketing within the NHS, reflecting the difficulties managers have faced in selling the concept of marketing to a generally sceptical body of clinicians. Notes, in part owing to such professional scepticism, that the development of marketing as an implementable approach to operations has lagged significantly behind the managerial conceptualization, although this cannot be attributed solely to resistance from clinicians and other health care professionals. Rather, suggests that such limited progress in implementing a market orientation reflects a range of "structural" barriers, both within individual trusts and the specific market environment faced by trusts.

  9. Composites Damage Tolerance Workshop

    NASA Technical Reports Server (NTRS)

    Gregg, Wayne

    2006-01-01

    The Composite Damage Tolerance Workshop included participants from NASA, academia, and private industry. The objectives of the workshop were to begin dialogue in order to establish a working group within the Agency, create awareness of damage tolerance requirements for Constellation, and discuss potential composite hardware for the Crew Launch Vehicle (CLV) Upper Stage (US) and Crew Module. It was proposed that a composites damage tolerance working group be created that acts within the framework of the existing NASA Fracture Control Methodology Panel. The working group charter would be to identify damage tolerance gaps and obstacles for implementation of composite structures into manned space flight systems and to develop strategies and recommendations to overcome these obstacles.

  10. Development of Graves’ disease after long-standing hypothyroidism on treatment, with acute toxicity to thionamides and lithium

    PubMed Central

    Gupta, Yashdeep; Singh, Sandeep; Ammini, Ariachery C

    2012-01-01

    Thyroid hyperfunction in a patient with long-standing hypothyroidism is uncommon. Here, we describe and discuss the unusual scenario of development of severe skin rash to carbimazole, with subsequent acute toxicity to lithium in clinically indicated doses, in a patient who manifested hyperthyroidism after being on treatment for hypothyroidism for 7 years. PMID:22854236

  11. The support for smoke free policy and how it is influenced by tolerance to smoking - experience of a developing country.

    PubMed

    Rashid, Abdul; Manan, Azizah Ab; Yahya, Noorlia; Ibrahim, Lailanor

    2014-01-01

    This cross sectional survey was conducted to determine the support in making Penang UNESCO World Heritage Site (GTWHS) smoke free and to determine the influence of tolerance towards smoking on this support. This is the first phase in making Penang, Malaysia a smoke free state. A multistage sampling process was done to select a sample of respondents to represent the population of GTWHS. Attitude towards smoking was assessed using tolerance as a proxy. A total of 3,268 members of the community participated in the survey. A big majority (n = 2969; 90.9%) of the respondents supported the initiative. Support was lowest among the owners and residents/tenants, higher age groups, the Chinese, men, respondents who had poor knowledge of the places gazetted as smoke free, and respondents with poor knowledge of the health effects on smokers and on passive smokers. The odds (both adjusted and unadjusted) of not supporting the initiative was high among those tolerant to smoking in public areas. Tolerance towards smoking was associated with 80.3% risk of non-support in the respondents who were tolerant to smoking and a 57.2% risk in the population. Health promotion and education concerning the harm of tobacco smoke in Malaysia, which has mainly targeted smokers, must change. Health education concerning the risks of second hand smoke must also be given to non-smokers and efforts should be made to denormalize smoking.

  12. Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation

    PubMed Central

    Bohne, Felix; Martínez-Llordella, Marc; Lozano, Juan-José; Miquel, Rosa; Benítez, Carlos; Londoño, María-Carlota; Manzia, Tommaso-María; Angelico, Roberta; Swinkels, Dorine W.; Tjalsma, Harold; López, Marta; Abraldes, Juan G.; Bonaccorsi-Riani, Eliano; Jaeckel, Elmar; Taubert, Richard; Pirenne, Jacques; Rimola, Antoni; Tisone, Giuseppe; Sánchez-Fueyo, Alberto

    2011-01-01

    Following organ transplantation, lifelong immunosuppressive therapy is required to prevent the host immune system from destroying the allograft. This can cause severe side effects and increased recipient morbidity and mortality. Complete cessation of immunosuppressive drugs has been successfully accomplished in selected transplant recipients, providing proof of principle that operational allograft tolerance is attainable in clinical transplantation. The intra-graft molecular pathways associated with successful drug withdrawal, however, are not well defined. In this study, we analyzed sequential blood and liver tissue samples collected from liver transplant recipients enrolled in a prospective multicenter immunosuppressive drug withdrawal clinical trial. Before initiation of drug withdrawal, operationally tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis. Furthermore, as compared with non-tolerant recipients, operationally tolerant patients exhibited higher serum levels of hepcidin and ferritin and increased hepatocyte iron deposition. Finally, liver tissue gene expression measurements accurately predicted the outcome of immunosuppressive withdrawal in an independent set of patients. These results point to a critical role for iron metabolism in the regulation of intra-graft alloimmune responses in humans and provide a set of biomarkers to conduct drug-weaning trials in liver transplantation. PMID:22156196

  13. Physiological variables associated with the development of acute mountain sickness at the South Pole

    PubMed Central

    Harrison, Michael F; Anderson, Paul J; Miller, Andrew D; O'Malley, Kathy A; Richert, Maile L; Johnson, Jacob B; Johnson, Bruce D

    2013-01-01

    Exposure to altitudes >2500 m can result in acute mountain sickness (AMS), a mild and usually self-limiting condition. Research has attempted to identify factors associated with developing AMS without controlling important factors related to the ascent or collecting a comprehensive set of variables. Objectives The Antarctic Study of Altitude Physiology (ASAP) investigated variables associated with the development of AMS in adults experiencing rapid passive transport to altitude by airplane. Design Our prospective observational trial collected data, including personal history, anthropometrics, vital signs, blood samples and pulmonary function, at sea level and at altitude. Statistical analysis utilised independent sample t tests to investigate between-group differences (p<0.05) and a forward, step-wise binary logisitic regression analysis was performed. Participants Of 248 eligible ASAP participants, those who did not use acetazolamide (N=98) were included in the present analysis. Primary outcome measures The diagnosis of AMS using the Lake Louise Symptom Score. Results Analysis of participants not using acetazolamide (n=90) found 30 participants developed AMS and 60 participants did not. Estimated plasma volume decreased significantly at altitude (p=0.025) in the AMS group as compared with the No AMS group while body weight did not change (p=0.125). Serum sodium (p=0.045) and low-density lipoprotein (LDL) (p=0.049) levels were higher in the No AMS group. A logistic regression analysis emphasised the contributions of LDL and eosinophil levels in the development of AMS. Conclusions These results suggest that the body water regulation and inflammation are key factors in AMS development when all other factors such as the level of physical exertion during ascent, the rate and magnitude of ascent and the use of acetazolamide are controlled. PMID:23869103

  14. Development of a novel model of hypertriglyceridemic acute pancreatitis in mice

    PubMed Central

    Pan, Yiyuan; Li, Yong; Gao, Lin; Tong, Zhihui; Ye, Bo; Liu, Shufeng; Li, Baiqiang; Chen, Yizhe; Yang, Qi; Meng, Lei; Wang, Yuhui; Liu, George; Lu, Guotao; Li, Weiqin; Li, Jieshou

    2017-01-01

    The morbidity rate of hypertriglyceridemic acute pancreatitis (HTG-AP) increased rapidly over the last decade. However an appropriate animal model was lacking to recapitulate this complicated human disease. We established a novel mice model of HTG-AP by poloxamer 407 (P-407) combined with caerulein (Cae). In our study, serum triglyceride levels of P-407 induced mice were elevated in a dose-dependent manner, and the pancreatic and pulmonary injuries were much severer in HTG mice than normal mice when injected with conventional dose Cae (50 ug/kg), what’s more, the severity of AP was positively correlative with duration and extent of HTG. In addition, we found that a low dose Cae (5 ug/kg) could induce pancreatic injury in HTG mice while there was no obvious pathological injury in normal mice. Finally, we observed that HTG leaded to the increased infiltrations of macrophages and neutrophils in mice pancreatic tissues. In conclusion, we have developed a novel animal model of HTG-AP that can mimic physiological, histological, clinical features of human HTG-AP and it could promote the development of therapeutic strategies and advance the mechanism research on HTG-AP. PMID:28079184

  15. Development of a new model for acute myocardial infarction in rabbits

    PubMed Central

    TAN, Mei-Yun; XIA, Bo; XIAO, Zhun; FAN, Zhong-Wei; ZHOU, Hong; GUO, Xing; HUANG, Yong-Can

    2017-01-01

    The rabbit left anterior descending coronary artery is not macroscopically apparent; this often leads to failure in creation of an acute myocardial infarction (AMI) model. In order to devise a simple method with good reproducibility and high success rate for use as a rabbit AMI model, a new surgical technique was developed, in which the obtuse marginal (OM) branch of the left circumflex coronary artery was coagulated with an electric knife using a left parasternal approach. Four weeks after OM branch coagulation, an electrocardiogram (ECG), blood biochemistry analysis, echocardiographic measurements and pathologic analysis were performed. The left parasternal approach provided the surgeon clear visualization of the targeted blood vessel to accurately identify the proper site to occlude. The successful development of AMI was confirmed by ST segment elevation on the ECG, by high levels of AMI-related markers in blood samples, by cardiac functional damage reflected on echocardiographic images and by changes in pathological sections. Furthermore, an acceptable success rate and low mortality were achieved. Hence, this surgical technique was suggested to be a highly reliable and reproducible method to induce AMI in rabbits for the assessment of new therapeutic interventions or regenerative approaches. PMID:28111375

  16. Development of a MALDI MS‐based platform for early detection of acute kidney injury

    PubMed Central

    Vanmassenhove, Jill; Glorieux, Griet; Metzger, Jochen; Dakna, Mohammed; Pejchinovski, Martin; Jankowski, Vera; Mansoorian, Bahareh; Husi, Holger; Mullen, William; Mischak, Harald; Vanholder, Raymond; Van Biesen, Wim

    2016-01-01

    1 Purpose Septic acute kidney injury (AKI) is associated with poor outcome. This can partly be attributed to delayed diagnosis and incomplete understanding of the underlying pathophysiology. Our aim was to develop an early predictive test for AKI based on the analysis of urinary peptide biomarkers by MALDI‐MS. 2 Experimental design Urine samples from 95 patients with sepsis were analyzed by MALDI‐MS. Marker search and multimarker model establishment were performed using the peptide profiles from 17 patients with existing or within the next 5 days developing AKI and 17 with no change in renal function. Replicates of urine sample pools from the AKI and non‐AKI patient groups and normal controls were also included to select the analytically most robust AKI markers. 3 Results Thirty‐nine urinary peptides were selected by cross‐validated variable selection to generate a support vector machine multidimensional AKI classifier. Prognostic performance of the AKI classifier on an independent validation set including the remaining 61 patients of the study population (17 controls and 44 cases) was good with an area under the receiver operating characteristics curve of 0.82 and a sensitivity and specificity of 86% and 76%, respectively. 4 Conclusion and clinical relevance A urinary peptide marker model detects onset of AKI with acceptable accuracy in septic patients. Such a platform can eventually be transferred to the clinic as fast MALDI‐MS test format. PMID:27119821

  17. Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia

    PubMed Central

    Will, Britta; Vogler, Thomas O.; Narayanagari, Swathi; Bartholdy, Boris; Todorova, Tihomira I.; da Silva Ferreira, Mariana; Chen, Jiahao; Yu, Yiting; Mayer, Jillian; Barreyro, Laura; Carvajal, Luis; Ben Neriah, Daniela; Roth, Michael; van Oers, Johanna; Schaetzlein, Sonja; McMahon, Christine; Edelmann, Winfried; Verma, Amit; Steidl, Ulrich

    2016-01-01

    Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reduction of PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging. Heterozygous deletion of an enhancer of PU.1, which resulted in 35% reduction of PU.1 expression, was sufficient to induce myeloid biased preleukemic stem cells and subsequent transformation to AML in a DNA mismatch repair-deficient background. AML progression was mediated by inhibition of expression of a PU.1 cooperating transcription factor, Irf8. Strikingly, we found significant molecular similarities with human myelodysplastic syndrome and AML. This study demonstrates that minimal reduction of a key lineage-specific transcription factor that commonly occurs in human disease is sufficient to initiate cancer development and provides mechanistic insight into the formation and progression of preleukemic stem cells in AML. PMID:26343801

  18. Inhibition of brain oxidative stress and inducible nitric oxide synthase expression by thymoquinone attenuates the development of morphine tolerance and dependence in mice.

    PubMed

    Abdel-Zaher, Ahmed O; Mostafa, Mostafa G; Farghly, Hanan M; Hamdy, Mostafa M; Omran, Ghada A; Al-Shaibani, Najlaà K M

    2013-02-28

    In this study, the effect of thymoquinone on morphine-induced tolerance and dependence in mice was investigated. Repeated administration of thymoquinone along with morphine attenuated the development of morphine tolerance, as measured by the hot plate test, and dependence, as assessed by naloxone-precipitated withdrawal manifestations. Concurrently, morphine-induced progressive increase in brain malondialdehyde (MDA) level and nitric oxide (NO) production as well as progressive decrease in brain intracellular reduced glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity were inhibited by co-administration of thymoquinone. Morphine-induced progressive increase in brain glutamate level was not inhibited by concomitant administration of thymoquinone. Similarly, co-administration of thymoquinone inhibited naloxone-induced increase in brain MDA level, NO overproduction and decrease in brain intracellular GSH level and GSH-Px activities but it did not inhibit naloxone-induced elevation of brain glutamate level in morphine-dependent mice. The inhibitory effect of thymoquinone on morphine-induced tolerance and dependence on naloxone-induced biochemical alterations in morphine-dependent mice was enhanced by concurrent i.p. administration of the NMDA receptor antagonist, dizocilpine, the antioxidant, N-acetylcysteine or the NO synthase inhibitor, L-N (G)-nitroarginine methyl ester. On the other hand, this inhibitory effect of thymoquinone was antagonized by concurrent i.p. administration of NO precursor, L-arginine. In addition, concomitant administration of thymoquinone inhibited morphine tolerance and dependence-induced increase in inducible but not in neuronal NO synthase mRNA expression in mice brain. These results demonstrate that inhibition of morphine-induced oxidative stress, increase in the expression of brain inducible NO synthase and NO overproduction by thymoquinone can attenuate the development of morphine tolerance and dependence.

  19. Development of new tolerant strains to hydrophilic and hydrophobic organic solvents by the yeast surface display methodology.

    PubMed

    Perpiñá, C; Vinaixa, J; Andreu, C; del Olmo, M

    2015-01-01

    Yeast surface display is a research methodology based on anchoring functional proteins and peptides onto the surface of the cells of this eukaryotic organism. Its development has resulted in the construction of a good number of new whole-cell biocatalysts with diverse applications in biotechnology, pharmacy, and medicine. In this work, we describe the design of new yeast strains in which several proteins and peptides have been introduced at the N-terminal position of protein agglutinin Aga2p. In all cases, proteins were correctly expressed and displayed on the cell surface according to the western blot, fluorescence microscopy, and fluorescence-activated cell sorting (FACS) analyses. The introduction of a glycosylable, Ser/Thr-rich protein (S1) resulted in improved resistance to ethanol, nonane, and dimethyl sulfoxide (DMSO) stress. The protein with a very high hydrophobic content (S2d) proved to confer tolerance to acetonitrile, ethanol, nonane, salt, and sodium dodecyl sulfate (SDS). The introduction of five leucine residues at the N-terminal position of S1 and S2 resulted in similar or increased resistance to the above-mentioned stress conditions. The adverse effects described in a previous work, when these residues were introduced into the N-terminus of Aga2p, with no other protein acting as a spacer, were not observed. Indeed, these strains grew better in the presence of hydrophilic solvents such as acetonitrile and ethanol. The new strains reported in this work have biotechnological potentiality given their behavior under adverse conditions of interest for biocatalytic and industrial processes.

  20. Role of uptake of (14C)valine into protein in the development of tolerance to diisopropylphosphorofluoridate (DFP) toxicity

    SciTech Connect

    Gupta, R.C.; Dettbarn, W.D.

    1986-07-01

    In a subchronic toxicity study male Sprague-Dawley rats were daily treated with diisopropylphosphorofluoridate (DFP) (0.5 mg/kg, sc) for 14 days. Maximum signs of anticholinesterase toxicity were observed during Days 4 and 5 comparable to those seen 10-15 min following a single sublethal dosage (1.5 mg DFP/kg, sc). Signs disappeared after Days 6-7 of exposure and rats became apparently normal during the remainder of the treatment period. Significant hypothermia was seen following the second to fifth doses with maximum effect after the fifth injection. Subsequent injections of DFP did not cause any reduction in temperature. Incorporation of (/sup 14/C)valine was measured 24 hr after the 5th and 14th injections of DFP, at a time when body temperature had recovered to control values. The rate of in vivo incorporation of (/sup 14/C)valine was measured 0.5, 1.0, and 2.0 hr after a subcutaneous injection of L-(1-/sup 14/C)valine at a dose of 5 microCi/mmol/100 g body wt. After five injections the rate of L-(1-/sup 14/C)valine uptake into the free amino acid pool and the incorporation into the protein bound pool was significantly (p less than 0.01) reduced in discrete brain regions, liver, kidney, and skeletal muscles. At the end of the 14-day treatment, protein synthesis in all the skeletal muscles tested had recovered completely (p greater than 0.01) to the values of nontreated control animals. In brain, liver, and kidney, however, no recovery was seen during this period. The recovery of protein synthesis in skeletal muscle may be one of the mechanisms that lead to tolerance development during prolonged administration of subacute concentrations of DFP.

  1. Development of ketoprofen loaded proliposomal powders for improved gastric absorption and gastric tolerance: in vitro and in situ evaluation.

    PubMed

    Gangishetty, Himabindu; Eedara, Basanth Babu; Bandari, Suresh

    2015-01-01

    The aim of the current investigation was to improve dissolution rate, gastric absorption and tolerance of a water insoluble non-steroidal anti-inflammatory drug ketoprofen by developing proliposomal powders. Ketoprofen proliposomal powders were prepared by solvent evaporation method with varying ratios of hydrogenated soyphosphatidyl choline (HSPC) and cholesterol. The prepared proliposomal powders were characterized for vesicle size, micromeritics, entrapment efficiency and in vitro dissolution behavior. Proliposomal powder (KPL3) composed of equimolar ratios of HSPC and cholesterol loaded on pearlitol SD 200 was selected as optimized formulation as it produced smaller liposomes (5.24 ± 1.35 μm) upon hydration with highest entrapment efficiency (53.16 ± 0.06%). All proliposomal powders showed improved dissolution characteristics than pure drug, however dissolution of drug from KPL3 was found to be highest (91.17 ± 6.3) and which is about 24 times higher than pure ketoprofen within 5 min. The transformation of crystalline ketoprofen to amorphous form was confirmed by solid state characterization. The absorption rate per hour for pure ketoprofen and proliposomal formulation (KPL3) was assessed in the stomach by conducting in situ gastric absorption studies in Wistar rats and was found to be 27 ± 1.22 and 36.98 ± 1.95%, respectively. In conclusion, enhanced dissolution and gastric absorption rate of ketoprofen from proliposomal powders suggest them as potential candidate for oral bioavailability improvement of ketoprofen.

  2. Effect of MEM vitamins and forskolin on embryo development and vitrification tolerance of in vitro-produced pig embryos.

    PubMed

    Cuello, C; Gomis, J; Almiñana, C; Maside, C; Sanchez-Osorio, J; Gil, M A; Sánchez, A; Parrilla, I; Vazquez, J M; Roca, J; Martinez, E A

    2013-01-30

    The aims of this study were (1) to determine the effect of in vitro maturation (IVM) medium supplementation with MEM vitamins on in vitro embryo development and sensitivity to vitrification of Day 6 blastocysts and (2) to evaluate whether the addition of forskolin to in vitro culture (IVC) medium enhances blastocyst survival following Super Open Pulled Straw (SOPS) vitrification. Cumulus-oocyte complexes (COCs; n=4000) were matured with 0.0% or 0.05% (v/v) MEM vitamins. After 44h of IVM, the oocytes were in vitro fertilized, and presumptive zygotes were cultured. At Day 5 of IVC, embryos from both experimental groups were cultured for 24h with 0 or 10μM forskolin, achieving a 2×2 factorial design. The blastocyst formation rate was assessed on Day 6, and subsets of samples from the four experimental groups were vitrified (n=469) or kept fresh (n=546). Fresh and vitrified-warmed blastocysts were cultured for 24h prior to embryo survival and total blastocyst cell number assessment. The MEM vitamins increased (P<0.001) the blastocyst formation rate at Day 6, but they did not affect embryo survival after vitrification. In contrast, the addition of forskolin to the culture medium enhanced (P<0.05) the blastocyst vitrification tolerance. The total blastocyst cell number was similar among the groups. In conclusion, supplementation with 0.05% MEM vitamins improved the blastocyst formation rate, and the addition of 10μM forskolin to the culture medium increased survival in Day 6 in vitro-produced blastocysts after SOPS vitrification.

  3. In vivo sodium salicylate causes tolerance to acute morphine exposure and alters the ability of high frequency stimulation to induce long-term potentiation in hippocampus area CA1.

    PubMed

    Hosseinmardi, Narges; Azimi, Lila; Fathollahi, Yaghoub; Javan, Mohammad; Naghdi, Naser

    2011-11-30

    Effects of morphine on synaptic transmission and plasticity in the hippocampus area CA1 following in vivo sodium salicylate and the potential molecular mechanism were investigated. Population spikes (PS) were recorded from stratum pylamidale of area CA1 following stimulation of Schaffer collaterals in slices taken from control and sodium salicylate injected rats. To induce long term potentiation (LTP), a 100Hz tetanic stimulation was used. Acute in vitro morphine increased baseline PS amplitude in control slices but not in slices taken from sodium salicylate treated rats. In vivo chronic salicylate did slightly decrease and/or destabilize LTP of CA1 synaptic transmission. We also found that mRNA of NR2A subunit of NMDA receptor was reduced in the hippocampus of sodium salicylate treated rats as compared to control ones. Following LTP induction, the mRNA of NR2A and PP1 (protein phosphatase 1) in slices taken from salicylate-treated rats were more than those of control ones. After long-term exposure to in vitro morphine, high frequency stimulation (HFS) decreased NR2A mRNA level significantly in sodium salicylate treated slices. It is concluded that in vivo sodium salicylate causes tolerance to excitatory effect of morphine and changes the ability of HFS to induce PS LTP in the hippocampus area CA1 in vitro. These changes in synaptic response may be due to alterations in NR2A and PP1 expression.

  4. Development of equipment parameter tolerances for the ultrasonic inspection of steel components: Application to components up to 3 inches thick. Volume 1

    SciTech Connect

    Green, E.R.; Doctor, S.R.; Hockey, R.L.; Diaz, A.A.

    1992-06-01

    This report documents work performed at Pacific Northwest Laboratory on the effect of frequency domain equipment interactions on the reliability of ultrasonic inservice inspection. The primary focus of this work is to provide information to the United States Nuclear Regulatory Commission on the acceptability of equipment parameter tolerances as given in the American Society of Mechanical Engineers (ASME) Boiler and Pressure Vessel Code Section 11 Appendix 8. Mathematical models were developed for the entire ultrasonic inspection system including sound propagation through the inspection sample. The models were used to determine worst-case inspection scenarios for thin sections (piping), and these worst-case inspection scenarios were then used in sensitivity studies to determine the suitability of equipment parameter tolerances. Ultrasonics literature was reviewed to find worst-case inspection scenarios outside the scope of the model used, but none that were significantly worse were found. Experiments were performed to confirm the important modeling results. Methods for reducing parameter sensitivity such as the use of a phase insensitive receive were also investigated. The model predicted that ASME Code tolerances for equipment bandwidth are acceptable, but tolerances for center frequency are too broad to provide reliable inspection of worst-case defects using narrow band systems. Experiments confirmed the basic trends predicted by the model, but the model seems to be conservative in that it shows greater sensitivity than is found empirically.

  5. Changing picture of renal cortical necrosis in acute kidney injury in developing country

    PubMed Central

    Prakash, Jai; Singh, Vijay Pratap

    2015-01-01

    Renal cortical necrosis (RCN) is characterized by patchy or diffuse ischemic destruction of all the elements of renal cortex resulting from significantly diminished renal arterial perfusion due to vascular spasm and microvascular injury. In addition, direct endothelial injury particularly in setting of sepsis, eclampsia, haemolytic uremic syndrome (HUS) and snake bite may lead to endovascular thrombosis with subsequent renal ischemia. Progression to end stage renal disease is a rule in diffuse cortical necrosis. It is a rare cause of acute kidney injury (AKI) in developed countries with frequency of 1.9%-2% of all patients with AKI. In contrast, RCN incidence is higher in developing countries ranging between 6%-7% of all causes of AKI. Obstetric complications (septic abortion, puerperal sepsis, abruptio placentae, postpartum haemorrhage and eclampsia) are the main (60%-70%) causes of RCN in developing countries. The remaining 30%-40% cases of RCN are caused by non-obstetrical causes, mostly due to sepsis and HUS. The incidence of RCN ranges from 10% to 30% of all cases of obstetric AKI compared with only 5% in non-gravid patients. In the developed countries, RCN accounts for 2% of all cases of AKI in adults and more than 20% of AKI during the third trimester of pregnancy. The reported incidence of RCN in obstetrical AKI varies between 18%-42.8% in different Indian studies. However, the overall incidence of RCN in pregnancy related AKI has decreased from 20%-30% to 5% in the past two decades in India. Currently RCN accounts for 3% of all causes of AKI. The incidence of RCN in obstetrical AKI was 1.44% in our recent study. HUS is most common cause of RCN in non-obstetrical group, while puerperal sepsis is leading cause of RCN in obstetric group. Because of the catastrophic sequelae of RCN, its prevention and aggressive management should always be important for the better renal outcome and prognosis of the patients. PMID:26558184

  6. Changing picture of renal cortical necrosis in acute kidney injury in developing country.

    PubMed

    Prakash, Jai; Singh, Vijay Pratap

    2015-11-06

    Renal cortical necrosis (RCN) is characterized by patchy or diffuse ischemic destruction of all the elements of renal cortex resulting from significantly diminished renal arterial perfusion due to vascular spasm and microvascular injury. In addition, direct endothelial injury particularly in setting of sepsis, eclampsia, haemolytic uremic syndrome (HUS) and snake bite may lead to endovascular thrombosis with subsequent renal ischemia. Progression to end stage renal disease is a rule in diffuse cortical necrosis. It is a rare cause of acute kidney injury (AKI) in developed countries with frequency of 1.9%-2% of all patients with AKI. In contrast, RCN incidence is higher in developing countries ranging between 6%-7% of all causes of AKI. Obstetric complications (septic abortion, puerperal sepsis, abruptio placentae, postpartum haemorrhage and eclampsia) are the main (60%-70%) causes of RCN in developing countries. The remaining 30%-40% cases of RCN are caused by non-obstetrical causes, mostly due to sepsis and HUS. The incidence of RCN ranges from 10% to 30% of all cases of obstetric AKI compared with only 5% in non-gravid patients. In the developed countries, RCN accounts for 2% of all cases of AKI in adults and more than 20% of AKI during the third trimester of pregnancy. The reported incidence of RCN in obstetrical AKI varies between 18%-42.8% in different Indian studies. However, the overall incidence of RCN in pregnancy related AKI has decreased from 20%-30% to 5% in the past two decades in India. Currently RCN accounts for 3% of all causes of AKI. The incidence of RCN in obstetrical AKI was 1.44% in our recent study. HUS is most common cause of RCN in non-obstetrical group, while puerperal sepsis is leading cause of RCN in obstetric group. Because of the catastrophic sequelae of RCN, its prevention and aggressive management should always be important for the better renal outcome and prognosis of the patients.

  7. Inhibition of the development of morphine tolerance by a potent dual mu-delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph.

    PubMed

    Jinsmaa, Yunden; Marczak, Ewa D; Balboni, Gianfranco; Salvadori, Severo; Lazarus, Lawrence H

    2008-10-01

    Three analogues of the dual mu-/delta-antagonist, H-Dmt-Tic-R-NH-CH2-Ph (R = 1, Lys-Z; 2, Lys-Ac; 3, Lys) were examined in vivo: 1 and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (delta-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOP, a mu antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance.

  8. Polymorphisms in key pulmonary inflammatory pathways and the development of acute respiratory distress syndrome

    PubMed Central

    Brown, Samuel M.; Grissom, Colin K.; Rondina, Matthew T.; Hoidal, John R.; Scholand, Mary Beth; Wolff, Roger K.; Morris, Alan H.; Paine, Robert

    2015-01-01

    Purpose/Aim Acute Respiratory Distress Syndrome (ARDS) is an important clinical and public health problem. Why some at-risk individuals develop ARDS and others do not is unclear but may be related to differences in inflammatory and cell signaling systems. The Receptor for Advanced Glycation Endproducts (RAGE) and Granulocyte-Monocyte Stimulating Factor (GM-CSF) pathways have recently been implicated in pulmonary pathophysiology; whether genetic variation within these pathways contributes to ARDS risk or outcome is unknown. Materials and Methods We studied 842 patients from three centers in Utah and 14 non-Utah ARDS Network centers. We studied patients at risk for ARDS and patients with ARDS to determine whether Single Nucleotide Polymorphisms (SNPs) in the RAGE and GM-CSF pathways were associated with development of ARDS. We studied 29 SNPs in 5 genes within the two pathways and controlled for age, sepsis as ARDS risk factor, and severity of illness, while targeting a false discovery rate of ≤5%. In a secondary analysis we evaluated associations with mortality. Results Of 842 patients, 690 had ARDS, and 152 were at-risk. Sepsis was the risk factor for ARDS in 250 (30%) patients. When controlling for age, APACHE III score, sepsis as risk factor, and multiple comparisons, no SNPs were significantly associated with ARDS. In a secondary analysis, only rs743564 in CSF2 approached significance with regard to mortality (OR 2.17, unadjusted p = 0.005, adjusted p = 0.15). Conclusions Candidate SNPs within 5 genes in the RAGE and GM-CSF pathways were not significantly associated with development of ARDS in this multi-centric cohort. PMID:25513711

  9. Limits of desiccation tolerance in developing embryos of Pritchardia remota (Arecaceae): the orthodox-recalcitrant seed paradigm

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Orthodox and recalcitrant seeds are distinguished by the ability of embryos to survive desiccation. Seeds of many palm species do not conform to the dichotomous classification and storage physiology is considered intermediate or ambiguous. We studied the acquisition of desiccation tolerance in embr...

  10. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia.

    PubMed

    Herranz, Daniel; Ambesi-Impiombato, Alberto; Palomero, Teresa; Schnell, Stephanie A; Belver, Laura; Wendorff, Agnieszka A; Xu, Luyao; Castillo-Martin, Mireia; Llobet-Navás, David; Cordon-Cardo, Carlos; Clappier, Emmanuelle; Soulier, Jean; Ferrando, Adolfo A

    2014-10-01

    Efforts to identify and annotate cancer driver genetic lesions have been focused primarily on the analysis of protein-coding genes; however, most genetic abnormalities found in human cancer are located in intergenic regions. Here we identify a new long range-acting MYC enhancer controlled by NOTCH1 that is targeted by recurrent chromosomal duplications in human T cell acute lymphoblastic leukemia (T-ALL). This highly conserved regulatory element, hereby named N-Me for NOTCH MYC enhancer, is located within a broad super-enhancer region +1.47 Mb from the MYC transcription initiating site, interacts with the MYC proximal promoter and induces orientation-independent MYC expression in reporter assays. Moreover, analysis of N-Me knockout mice demonstrates a selective and essential role of this regulatory element during thymocyte development and in NOTCH1-induced T-ALL. Together these results identify N-Me as a long-range oncogenic enhancer implicated directly in the pathogenesis of human leukemia and highlight the importance of the NOTCH1-MYC regulatory axis in T cell transformation and as a therapeutic target in T-ALL.

  11. MicroRNA-29b mediates altered innate immune development in acute leukemia

    PubMed Central

    Mundy-Bosse, Bethany L.; Scoville, Steven D.; Chen, Li; McConnell, Kathleen; Mao, Hsiaoyin C.; Ahmed, Elshafa H.; Zorko, Nicholas; Harvey, Sophia; Cole, Jordan; Zhang, Xiaoli; Costinean, Stefan; Croce, Carlo M.; Larkin, Karilyn; Byrd, John C.; Vasu, Sumithira; Blum, William; Yu, Jianhua; Freud, Aharon G.; Caligiuri, Michael A.

    2016-01-01

    Natural killer (NK) cells can have potent antileukemic activity following haplo-mismatched, T cell–depleted stem cell transplantations for the treatment of acute myeloid leukemia (AML), but they are not successful in eradicating de novo AML. Here, we have used a mouse model of de novo AML to elucidate the mechanisms by which AML evades NK cell surveillance. NK cells in leukemic mice displayed a marked reduction in the cytolytic granules perforin and granzyme B. Further, as AML progressed, we noted the selective loss of an immature subset of NK cells in leukemic mice and in AML patients. This absence was not due to elimination by cell death or selective reduction in proliferation, but rather to the result of a block in NK cell differentiation. Indeed, NK cells from leukemic mice and humans with AML showed lower levels of TBET and EOMES, transcription factors that are critical for terminal NK cell differentiation. Further, the microRNA miR-29b, a regulator of T-bet and EOMES, was elevated in leukemic NK cells. Finally, deletion of miR-29b in NK cells reversed the depletion of this NK cell subset in leukemic mice. These results indicate that leukemic evasion of NK cell surveillance occurs through miR-mediated dysregulation of lymphocyte development, representing an additional mechanism of immune escape in cancer. PMID:27775550

  12. The Interaction Effects of Meteorological Factors and Air Pollution on the Development of Acute Coronary Syndrome

    PubMed Central

    Huang, Ching-Hui; Lin, Heng-Cheng; Tsai, Chen-Dao; Huang, Hung-Kai; Lian, Ie-Bin; Chang, Chia-Chu

    2017-01-01

    This study investigated the interaction effects of meteorological factors and air pollutants on the onset of acute coronary syndrome (ACS). Data of ACS patients were obtained from the Taiwan ACS Full Spectrum Registry and comprised 3164 patients with a definite onset date during the period October 2008 and January 2010 at 39 hospitals. Meteorological conditions and air pollutant concentrations at the 39 locations during the 488-day period were obtained. Time-lag Poisson and logistic regression were used to explore their association with ACS incidence. One-day lag atmospheric pressure (AP), humidity, particulate matter (PM2.5, and PM10), and carbon monoxide (CO) all had significant interaction effects with temperature on ACS occurrence. Days on which high temperatures (>26 °C) and low AP (<1009 hPa) occurred the previous day were associated with a greater likelihood of increased incidence of developing ACS. Typhoon Morakot was an example of high temperature with extremely low AP associated with higher ACS incidence than the daily average. Combinations of high concentrations of PM or CO with low temperatures (<21 °C) and high humidity levels with low temperatures were also associated with increased incidence of ACS. Atmospheric pollution and weather factors have synergistic effects on the incidence of ACS. PMID:28276507

  13. Severe acute respiratory syndrome (SARS) S protein production in plants: Development of recombinant vaccine

    PubMed Central

    Pogrebnyak, Natalia; Golovkin, Maxim; Andrianov, Vyacheslav; Spitsin, Sergei; Smirnov, Yuriy; Egolf, Richard; Koprowski, Hilary

    2005-01-01

    In view of a recent spread of severe acute respiratory syndrome (SARS), there is a high demand for production of a vaccine to prevent this disease. Recent studies indicate that SARS-coronavirus (CoV) spike protein (S protein) and its truncated fragments are considered the best candidates for generation of the recombinant vaccine. Toward the development of a safe, effective, and inexpensive vaccine candidate, we have expressed the N-terminal fragment of SARS-CoV S protein (S1) in tomato and low-nicotine tobacco plants. Incorporation of the S1 fragment into plant genomes as well as its transcription was confirmed by PCR and RT-PCR analyses. High levels of expression of recombinant S1 protein were observed in several transgenic lines by Western blot analysis using specific antibodies. Plant-derived antigen was evaluated to induce the systemic and mucosal immune responses in mice. Mice showed significantly increased levels of SARS-CoV-specific IgA after oral ingestion of tomato fruits expressing S1 protein. Sera of mice parenterally primed with tobacco-derived S1 protein revealed the presence of SARS-CoV-specific IgG as detected by Western blot and ELISA analysis. PMID:15956182

  14. The Interaction Effects of Meteorological Factors and Air Pollution on the Development of Acute Coronary Syndrome

    NASA Astrophysics Data System (ADS)

    Huang, Ching-Hui; Lin, Heng-Cheng; Tsai, Chen-Dao; Huang, Hung-Kai; Lian, Ie-Bin; Chang, Chia-Chu

    2017-03-01

    This study investigated the interaction effects of meteorological factors and air pollutants on the onset of acute coronary syndrome (ACS). Data of ACS patients were obtained from the Taiwan ACS Full Spectrum Registry and comprised 3164 patients with a definite onset date during the period October 2008 and January 2010 at 39 hospitals. Meteorological conditions and air pollutant concentrations at the 39 locations during the 488-day period were obtained. Time-lag Poisson and logistic regression were used to explore their association with ACS incidence. One-day lag atmospheric pressure (AP), humidity, particulate matter (PM2.5, and PM10), and carbon monoxide (CO) all had significant interaction effects with temperature on ACS occurrence. Days on which high temperatures (>26 °C) and low AP (<1009 hPa) occurred the previous day were associated with a greater likelihood of increased incidence of developing ACS. Typhoon Morakot was an example of high temperature with extremely low AP associated with higher ACS incidence than the daily average. Combinations of high concentrations of PM or CO with low temperatures (<21 °C) and high humidity levels with low temperatures were also associated with increased incidence of ACS. Atmospheric pollution and weather factors have synergistic effects on the incidence of ACS.

  15. Distribution of common genetic subgroups in childhood acute lymphoblastic leukemia in four developing countries.

    PubMed

    Siddiqui, Rubina; Nancy, Nirmala; Naing, Win P; Ali, Sarah; Dar, Lalit; Khan, Baldip K; Padua, Rose A; Carr, Robert

    2010-07-15

    An international project was conducted to identify the common acute lymphoblastic leukemia (ALL)-specific fusion genes (ETV6-RUNX1,MLL-AF4,TCF3-PBX1, and BCR-ABL1) in developing countries to provide additional prognostic information at diagnosis. A total of 181 children with newly diagnosed ALL were tested by reverse transcriptase-polymerase chain reaction at laboratories in India, Pakistan, Myanmar, and Sudan, following a common protocol. To our knowledge, this report is novel in its report from these countries, except India. Across the four countries, the ETV6-RUNX1 (TEL-AML1) fusion gene was present in only 5% of cases. All the positive samples were from children aged 1 to 10 years, in whom the prevalence of this fusion gene, which is associated with good prognosis, was 7.4% (9 out of 121 samples), a much lower rate than reported from Western populations. In the 18 ALL cases tested in Sudan, a notable excess of MLL-AF4 (17%) and BCR-ABL1 (22%) fusion genes was found. This study highlights the need for wider international surveys of the molecular epidemiology of ALL.

  16. Inhibitory effects of alprazolam on the development of acute experimental autoimmune encephalomyelitis in stressed rats.

    PubMed

    Núñez-Iglesias, María J; Novío, Silvia; Almeida-Dias, Antonio; Freire-Garabal, Manuel

    2010-12-01

    The progression and development of multiple sclerosis (MS) has long been hypothesized to be associated with stress. Benzodiazepines have been observed to reduce negative consequences of stress on the immune system in experimental and clinical models, but there are no data on their effects on MS, or experimental autoimmune encephalomyelitis (EAE), a model for human MS. We designed experiments conducted to ascertain whether alprazolam could modify the clinical, histological and neuroendocrine manifestations of acute EAE in Lewis rats exposed to a chronic auditory stressor. EAE was induced by injection of an emulsion of MBP and complete Freund's adjuvant containing Mycobacterium tuberculosis H37Ra. Stress application and treatment with drugs (placebo or alprazolam) were initiated 5days before inoculation and continued daily for the duration of the experiment (days 14 or 34 postinoculation).Our results show significant increases in the severity of neurological signs, the histological lesions of the spinal cord (inflammation), and the corticosterone plasmatic levels in stressed rats compared to those non-stressed ones. Treatment with alprazolam reversed the adverse effects of stress. These findings could have clinical implications in patients suffering from MS treated with benzodiazepines, so besides the psychopharmacological properties of alprazolam against stress, it has beneficial consequences on EAE.

  17. MicroRNA-29b mediates altered innate immune development in acute leukemia.

    PubMed

    Mundy-Bosse, Bethany L; Scoville, Steven D; Chen, Li; McConnell, Kathleen; Mao, Hsiaoyin C; Ahmed, Elshafa H; Zorko, Nicholas; Harvey, Sophia; Cole, Jordan; Zhang, Xiaoli; Costinean, Stefan; Croce, Carlo M; Larkin, Karilyn; Byrd, John C; Vasu, Sumithira; Blum, William; Yu, Jianhua; Freud, Aharon G; Caligiuri, Michael A

    2016-12-01

    Natural killer (NK) cells can have potent antileukemic activity following haplo-mismatched, T cell-depleted stem cell transplantations for the treatment of acute myeloid leukemia (AML), but they are not successful in eradicating de novo AML. Here, we have used a mouse model of de novo AML to elucidate the mechanisms by which AML evades NK cell surveillance. NK cells in leukemic mice displayed a marked reduction in the cytolytic granules perforin and granzyme B. Further, as AML progressed, we noted the selective loss of an immature subset of NK cells in leukemic mice and in AML patients. This absence was not due to elimination by cell death or selective reduction in proliferation, but rather to the result of a block in NK cell differentiation. Indeed, NK cells from leukemic mice and humans with AML showed lower levels of TBET and EOMES, transcription factors that are critical for terminal NK cell differentiation. Further, the microRNA miR-29b, a regulator of T-bet and EOMES, was elevated in leukemic NK cells. Finally, deletion of miR-29b in NK cells reversed the depletion of this NK cell subset in leukemic mice. These results indicate that leukemic evasion of NK cell surveillance occurs through miR-mediated dysregulation of lymphocyte development, representing an additional mechanism of immune escape in cancer.

  18. Involvement of phosphoinositide 3-kinases in neutrophil activation and the development of acute lung injury.

    PubMed

    Yum, H K; Arcaroli, J; Kupfner, J; Shenkar, R; Penninger, J M; Sasaki, T; Yang, K Y; Park, J S; Abraham, E

    2001-12-01

    Activated neutrophils contribute to the development and severity of acute lung injury (ALI). Phosphoinositide 3-kinases (PI3-K) and the downstream serine/threonine kinase Akt/protein kinase B have a central role in modulating neutrophil function, including respiratory burst, chemotaxis, and apoptosis. In the present study, we found that exposure of neutrophils to endotoxin resulted in phosphorylation of Akt, activation of NF-kappaB, and expression of the proinflammatory cytokines IL-1beta and TNF-alpha through PI3-K-dependent pathways. In vivo, endotoxin administration to mice resulted in activation of PI3-K and Akt in neutrophils that accumulated in the lungs. The severity of endotoxemia-induced ALI was significantly diminished in mice lacking the p110gamma catalytic subunit of PI3-K. In PI3-Kgamma(-/-) mice, lung edema, neutrophil recruitment, nuclear translocation of NF-kappaB, and pulmonary levels of IL-1beta and TNF-alpha were significantly lower after endotoxemia as compared with PI3-Kgamma(+/+) controls. Among neutrophils that did accumulate in the lungs of the PI3-Kgamma(-/-) mice after endotoxin administration, activation of NF-kappaB and expression of proinflammatory cytokines was diminished compared with levels present in lung neutrophils from PI3-Kgamma(+/+) mice. These results show that PI3-K, and particularly PI3-Kgamma, occupies a central position in regulating endotoxin-induced neutrophil activation, including that involved in ALI.

  19. Difficulties, guidelines and review of developing an acute rejection model after rat intestinal transplantation.

    PubMed

    Andres, Ane Miren; Santamaria, Monica; Hernandez-Oliveros, Francisco; Guerra, Laura; Lopez, Sergio; Stringa, Pablo; Vallejo, Maria Teresa; Largo, Carlota; Encinas, Jose Luis; Garcia de Las Heras, Maria Soledad; Lopez-Santamaria, Manuel; Tovar, Juan Antonio

    2016-05-01

    Experimental small bowel transplantation (SBT) in rats has been proven to be a useful tool for the study of ischemia-reperfusion and immunological aspects related to solid organ transplantation. However, the model is not completely refined, specialized literature is scarce and complex technical details are typically omitted or confusing. Most studies related to acute rejection (AR) use the orthotopic standard, with small sample sizes due to its high mortality, whereas those studying chronic rejection (CR) use the heterotopic standard, which allows longer term survival but does not exactly reflect the human clinical scenario. Various animal strains have been used, and the type of rejection and the timing of its analysis differ among authors. The double purpose of this study was to develop an improved unusual AR model of SBT using the heterotopic technique, and to elaborate a guide useful to implement experimental models for studying AR. We analyzed the model's technical details and expected difficulties in overcoming the learning curve for such a complex microsurgical model, identifying the potential problem areas and providing a step-by-step protocol and reference guide for future surgeons interested in the topic. We also discuss the historic and more recent options in the literature.

  20. Acute dysprosium toxicity to Daphnia pulex and Hyalella azteca and development of the biotic ligand approach.

    PubMed

    Vukov, Oliver; Smith, D Scott; McGeer, James C

    2016-01-01

    The toxicological understanding of rare earth elements (REEs) in the aquatic environment is very limited but of increasing concern. The objective of this research is to compare the toxicological effect of the REE dysprosium to the freshwater invertebrates Daphnia pulex and Hyalella azteca and in the more sensitive organism, understand the toxicity modifying influence of Ca, Na, Mg, pH and dissolved organic matter (DOM). Standard methods (Environment Canada) were followed for testing and culture in media of intermediate hardness (60mg CaCO3 mg/L) at pH 7.8 with Ca at 0.5, Na 0.5, Mg 0.125 (mM) and 23°C. Acute toxicity tests were done with <24h old neonates for 48h in the case of D. pulex and with 2-9 days old offspring for 96h tests with Hyalella. The potential protective effect of cationic competition was tested with Ca (0.5-2.0mM), Na (0.5-2.0mM) and Mg (0.125-0.5mM). The effect of pH (6.5-8.0) and Suwannee River DOM complexation (at dissolved organic carbon (DOC) concentrations of 9 and 13mg C/L) were evaluated. Dissolved Dy concentrations were lower than total (unfiltered) indicating precipitation, particularly at higher concentrations. Acute toxicity of Dy to H. azteca and D. pulex revealed Hyalella to be 1.4 times more sensitive than Daphnia. Additions of Ca and Na but not Mg provided significant protection against Dy toxicity to Hyalella. Similarly, low pH was associated with reduction in toxicity. Exposures which were pH buffered with and without MOPS were significantly different and indicated that MOPS enhanced Dy toxicity. DOM also mitigated Dy toxicity. Biotic ligand based parameters (LogK values) were calculated based on free ion relationships as determined by geochemical equilibrium modeling software (WHAM ver. 7.02). The logK value for Dy(3+) toxicity to Hyalella was 7.75 while the protective influence of Ca and Na were 3.95 and 4.10, respectively. This study contributes data towards the development of site specific water quality guidelines and

  1. Pesticide Tolerances

    EPA Pesticide Factsheets

    EPA regulates pesticides used to protect crops and sets limits on the amount of pesticide remaining in or on foods in the U.S. The limits on pesticides on foods are called tolerances in the U.S. (maximum residue limits (MRLs) in many other countries).

  2. The Solanum lycopersicum Zinc Finger2 Cysteine-2/Histidine-2 Repressor-Like Transcription Factor Regulates Development and Tolerance to Salinity in Tomato and Arabidopsis1[W

    PubMed Central

    Hichri, Imène; Muhovski, Yordan; Žižková, Eva; Dobrev, Petre I.; Franco-Zorrilla, Jose Manuel; Solano, Roberto; Lopez-Vidriero, Irene; Motyka, Vaclav; Lutts, Stanley

    2014-01-01

    The zinc finger superfamily includes transcription factors that regulate multiple aspects of plant development and were recently shown to regulate abiotic stress tolerance. Cultivated tomato (Solanum lycopersicum Zinc Finger2 [SIZF2]) is a cysteine-2/histidine-2-type zinc finger transcription factor bearing an ERF-associated amphiphilic repression domain and binding to the ACGTCAGTG sequence containing two AGT core motifs. SlZF2 is ubiquitously expressed during plant development, and is rapidly induced by sodium chloride, drought, and potassium chloride treatments. Its ectopic expression in Arabidopsis (Arabidopsis thaliana) and tomato impaired development and influenced leaf and flower shape, while causing a general stress visible by anthocyanin and malonyldialdehyde accumulation. SlZF2 enhanced salt sensitivity in Arabidopsis, whereas SlZF2 delayed senescence and improved tomato salt tolerance, particularly by maintaining photosynthesis and increasing polyamine biosynthesis, in salt-treated hydroponic cultures (125 mm sodium chloride, 20 d). SlZF2 may be involved in abscisic acid (ABA) biosynthesis/signaling, because SlZF2 is rapidly induced by ABA treatment and 35S::SlZF2 tomatoes accumulate more ABA than wild-type plants. Transcriptome analysis of 35S::SlZF2 revealed that SlZF2 both increased and reduced expression of a comparable number of genes involved in various physiological processes such as photosynthesis, polyamine biosynthesis, and hormone (notably ABA) biosynthesis/signaling. Involvement of these different metabolic pathways in salt stress tolerance is discussed. PMID:24567191

  3. The homeodomain transcription factor TaHDZipI-2 from wheat regulates frost tolerance, flowering time and spike development in transgenic barley.

    PubMed

    Kovalchuk, Nataliya; Chew, William; Sornaraj, Pradeep; Borisjuk, Nikolai; Yang, Nannan; Singh, Rohan; Bazanova, Natalia; Shavrukov, Yuri; Guendel, Andre; Munz, Eberhard; Borisjuk, Ljudmilla; Langridge, Peter; Hrmova, Maria; Lopato, Sergiy

    2016-07-01

    Homeodomain leucine zipper class I (HD-Zip I) transcription factors (TFs) play key roles in the regulation of plant growth and development under stresses. Functions of the TaHDZipI-2 gene isolated from the endosperm of developing wheat grain were revealed. Molecular characterization of TaHDZipI-2 protein included studies of its dimerisation, protein-DNA interactions and gene activation properties using pull-down assays, in-yeast methods and transient expression assays in wheat cells. The analysis of TaHDZipI-2 gene functions was performed using transgenic barley plants. It included comparison of developmental phenotypes, yield components, grain quality, frost tolerance and the levels of expression of potential target genes in transgenic and control plants. Transgenic TaHDZipI-2 lines showed characteristic phenotypic features that included reduced growth rates, reduced biomass, early flowering, light-coloured leaves and narrowly elongated spikes. Transgenic lines produced 25-40% more seeds per spike than control plants, but with 50-60% smaller grain size. In vivo lipid imaging exposed changes in the distribution of lipids between the embryo and endosperm in transgenic seeds. Transgenic lines were significantly more tolerant to frost than control plants. Our data suggest the role of TaHDZipI-2 in controlling several key processes underlying frost tolerance, transition to flowering and spike development.

  4. The Solanum lycopersicum Zinc Finger2 cysteine-2/histidine-2 repressor-like transcription factor regulates development and tolerance to salinity in tomato and Arabidopsis.

    PubMed

    Hichri, Imène; Muhovski, Yordan; Žižkova, Eva; Dobrev, Petre I; Franco-Zorrilla, Jose Manuel; Solano, Roberto; Lopez-Vidriero, Irene; Motyka, Vaclav; Lutts, Stanley

    2014-04-01

    The zinc finger superfamily includes transcription factors that regulate multiple aspects of plant development and were recently shown to regulate abiotic stress tolerance. Cultivated tomato (Solanum lycopersicum Zinc Finger2 [SIZF2]) is a cysteine-2/histidine-2-type zinc finger transcription factor bearing an ERF-associated amphiphilic repression domain and binding to the ACGTCAGTG sequence containing two AGT core motifs. SlZF2 is ubiquitously expressed during plant development, and is rapidly induced by sodium chloride, drought, and potassium chloride treatments. Its ectopic expression in Arabidopsis (Arabidopsis thaliana) and tomato impaired development and influenced leaf and flower shape, while causing a general stress visible by anthocyanin and malonyldialdehyde accumulation. SlZF2 enhanced salt sensitivity in Arabidopsis, whereas SlZF2 delayed senescence and improved tomato salt tolerance, particularly by maintaining photosynthesis and increasing polyamine biosynthesis, in salt-treated hydroponic cultures (125 mm sodium chloride, 20 d). SlZF2 may be involved in abscisic acid (ABA) biosynthesis/signaling, because SlZF2 is rapidly induced by ABA treatment and 35S::SlZF2 tomatoes accumulate more ABA than wild-type plants. Transcriptome analysis of 35S::SlZF2 revealed that SlZF2 both increased and reduced expression of a comparable number of genes involved in various physiological processes such as photosynthesis, polyamine biosynthesis, and hormone (notably ABA) biosynthesis/signaling. Involvement of these different metabolic pathways in salt stress tolerance is discussed.

  5. Effect of acute stress on NTPDase and 5'-nucleotidase activities in brain synaptosomes in different stages of development.

    PubMed

    Horvat, Anica; Stanojević, Ivana; Drakulić, Dunja; Velicković, Natasa; Petrović, Snjezana; Milosević, Maja

    2010-04-01

    The aim of the present study was to examine the effect of acute restraint stress on rat brain synaptosomal plasma membrane (SPM) ecto-nucleotidase activities at specific stages of postnatal development (15-, 30-, 60- and 90-day-old rats) by measuring the rates of ATP, ADP and AMP hydrolysis 1, 24 and 72 h post-stress. At 1 h after stress NTPDase and ecto-5'-nucleotidase activities were decreased in rats aged up to 60 days old. In adult rats elevated enzyme activities were detected, which indicated the existence of different short-term stress responses during development. A similar pattern of ATP and ADP hydrolysis changes as well as the ATP/ADP ratio in all developmental stages indicated that NTPDase3 was acutely affected after stress. The long-term effect of acute stress on NTPDase activity differed during postnatal development. In juvenile animals (15 days old) NTPDase activity was not altered. However, in later developmental stages (30 and 60 days old rats) NTPDase activity decreased and persisted for 72 h post-stress. In adult rats only ATP hydrolysis was decreased after 24 h, indicating that ecto-ATPase was affected by stress. Ecto-5'-nucleotidase hydrolysing activity was decreased within 24 h in adult rats, while in 15- and 30-day old rats it decreased 72 h post-stress. At equivalent times in pubertal rats (60 days old) a slight activation of ecto-5'-nucleotidase was detected. Our results highlight the developmental-dependence of brain ecto-nucleotidase susceptibility to acute stress and the likely existence of different mechanisms involved in time-dependent ecto-nucleotidase activity modulation following stress exposure. Clearly there are differences in the response of the purinergic system to acute restraint stress between young and adult rats.

  6. Development of a general baseline toxicity QSAR model for the fish embryo acute toxicity test.

    PubMed

    Klüver, Nils; Vogs, Carolina; Altenburger, Rolf; Escher, Beate I; Scholz, Stefan

    2016-12-01

    Fish embryos have become a popular model in ecotoxicology and toxicology. The fish embryo acute toxicity test (FET) with the zebrafish embryo was recently adopted by the OECD as technical guideline TG 236 and a large database of concentrations causing 50% lethality (LC50) is available in the literature. Quantitative Structure-Activity Relationships (QSARs) of baseline toxicity (also called narcosis) are helpful to estimate the minimum toxicity of chemicals to be tested and to identify excess toxicity in existing data sets. Here, we analyzed an existing fish embryo toxicity database and established a QSAR for fish embryo LC50 using chemicals that were independently classified to act according to the non-specific mode of action of baseline toxicity. The octanol-water partition coefficient Kow is commonly applied to discriminate between non-polar and polar narcotics. Replacing the Kow by the liposome-water partition coefficient Klipw yielded a common QSAR for polar and non-polar baseline toxicants. This developed baseline toxicity QSAR was applied to compare the final mode of action (MOA) assignment of 132 chemicals. Further, we included the analysis of internal lethal concentration (ILC50) and chemical activity (La50) as complementary approaches to evaluate the robustness of the FET baseline toxicity. The analysis of the FET dataset revealed that specifically acting and reactive chemicals converged towards the baseline toxicity QSAR with increasing hydrophobicity. The developed FET baseline toxicity QSAR can be used to identify specifically acting or reactive compounds by determination of the toxic ratio and in combination with appropriate endpoints to infer the MOA for chemicals.

  7. Acute dietary zinc deficiency before conception compromises oocyte epigenetic programming and disrupts embryonic development

    PubMed Central

    Tian, X; Diaz, FJ

    2013-01-01

    Recent findings show that zinc is an important factor necessary for regulating the meiotic cell cycle and ovulation. However, the role of zinc in promoting oocyte quality and developmental potential is not known. Using an in vivo model of acute dietary zinc deficiency, we show that feeding a zinc deficient diet (ZDD) for 3–5 days before ovulation (preconception) dramatically disrupts oocyte chromatin methylation and preimplantation development. There was a dramatic decrease in histone H3K4 trimethylation and global DNA methylation in zinc deficient oocytes. Moreover, there was a 3–20 fold increase in transcript abundance of repetitive elements (Iap, Line1, Sineb1, Sineb2), but a decrease in Gdf9, Zp3 and Figla mRNA. Only 53% and 8% of mature eggs reached the 2-cell stage after IVF in animals receiving a 3 and 5 day ZDD, respectively, while a 5 day ZDD in vivo reduced the proportion of 2-cells to 49%. In vivo fertilized 2-cell embryos cultured in vitro formed fewer (38%) blastocysts compared to control embryos (74%). Likewise, fewer blastocyst and expanded blastocyst were collected from the reproductive tract of zinc deficient animals on day 3.5 of pregnancy. This could be due to a decrease in Igf2 and H19 mRNA in ZDD blastocyst. Supplementation with a methyl donor (SAM) during IVM restored histone H3K4me3 and doubled the IVF success rate from 17% to 43% in oocytes from zinc deficient animals. Thus, the terminal period of oocyte development is extremely sensitive to perturbation in dietary zinc availability. PMID:23348678

  8. A Cyclin Dependent Kinase Regulatory Subunit (CKS) Gene of Pigeonpea Imparts Abiotic Stress Tolerance and Regulates Plant Growth and Development in Arabidopsis.

    PubMed

    Tamirisa, Srinath; Vudem, Dashavantha R; Khareedu, Venkateswara R

    2017-01-01

    Frequent climatic changes in conjunction with other extreme environmental factors are known to affect growth, development and productivity of diverse crop plants. Pigeonpea, a major grain legume of the semiarid tropics, endowed with an excellent deep-root system, is known as one of the important drought tolerant crop plants. Cyclin dependent kinases (CDKs) are core cell cycle regulators and play important role in different aspects of plant growth and development. The cyclin-dependent kinase regulatory subunit gene (CKS) was isolated from the cDNA library of pigeonpea plants subjected to drought stress. Pigeonpea CKS (CcCKS) gene expression was detected in both the root and leaf tissues of pigeonpea and was upregulated by polyethylene glycol (PEG), mannitol, NaCl and abscisic acid (ABA) treatments. The overexpression of CcCKS gene in Arabidopsis significantly enhanced tolerance of transgenics to drought and salt stresses as evidenced by different physiological parameters. Under stress conditions, transgenics showed higher biomass, decreased rate of water loss, decreased MDA levels, higher free proline contents, and glutathione levels. Moreover, under stress conditions transgenics exhibited lower stomatal conductance, lower transpiration, and higher photosynthetic rates. However, under normal conditions, CcCKS-transgenics displayed decreased plant growth rate, increased cell size and decreased stomatal number compared to those of wild-type plants. Real-time polymerase chain reaction revealed that CcCKS could regulate the expression of both ABA-dependent and ABA-independent genes associated with abiotic stress tolerance as well as plant growth and development. As such, the CcCKS seems promising and might serve as a potential candidate gene for enhancing the abiotic stress tolerance of crop plants.

  9. A Cyclin Dependent Kinase Regulatory Subunit (CKS) Gene of Pigeonpea Imparts Abiotic Stress Tolerance and Regulates Plant Growth and Development in Arabidopsis

    PubMed Central

    Tamirisa, Srinath; Vudem, Dashavantha R.; Khareedu, Venkateswara R.

    2017-01-01

    Frequent climatic changes in conjunction with other extreme environmental factors are known to affect growth, development and productivity of diverse crop plants. Pigeonpea, a major grain legume of the semiarid tropics, endowed with an excellent deep-root system, is known as one of the important drought tolerant crop plants. Cyclin dependent kinases (CDKs) are core cell cycle regulators and play important role in different aspects of plant growth and development. The cyclin-dependent kinase regulatory subunit gene (CKS) was isolated from the cDNA library of pigeonpea plants subjected to drought stress. Pigeonpea CKS (CcCKS) gene expression was detected in both the root and leaf tissues of pigeonpea and was upregulated by polyethylene glycol (PEG), mannitol, NaCl and abscisic acid (ABA) treatments. The overexpression of CcCKS gene in Arabidopsis significantly enhanced tolerance of transgenics to drought and salt stresses as evidenced by different physiological parameters. Under stress conditions, transgenics showed higher biomass, decreased rate of water loss, decreased MDA levels, higher free proline contents, and glutathione levels. Moreover, under stress conditions transgenics exhibited lower stomatal conductance, lower transpiration, and higher photosynthetic rates. However, under normal conditions, CcCKS-transgenics displayed decreased plant growth rate, increased cell size and decreased stomatal number compared to those of wild-type plants. Real-time polymerase chain reaction revealed that CcCKS could regulate the expression of both ABA-dependent and ABA-independent genes associated with abiotic stress tolerance as well as plant growth and development. As such, the CcCKS seems promising and might serve as a potential candidate gene for enhancing the abiotic stress tolerance of crop plants. PMID:28239388

  10. Expression of wheat expansin driven by the RD29 promoter in tobacco confers water-stress tolerance without impacting growth and development.

    PubMed

    Li, Feng; Han, Yangyang; Feng, Yanan; Xing, Shichao; Zhao, Meirong; Chen, Yanhui; Wang, Wei

    2013-02-10

    Expansins are the key regulators of cell wall extension during plant growth. Previously, we produced transgenic tobacco plants with increased tolerance to water stress by overexpressing the wheat expansin gene TaEXPB23 driven by the constitutive 35S cauliflower mosaic virus (CaMV) promoter. However, the growth and development of 35S::TaEXPB23 transgenic tobacco plants were altered under normal growth conditions, with a faster growth rate at the seedling stage, earlier flowering and maturation, and a shorter plant height compared to WT. In the current study, we determined that cellular characteristics and carbohydrate metabolism were altered in 35S::TaEXPB23 transgenic tobacco plants. We also generated transgenic Arabidopsis plants using the same vector. The transgenic Arabidopsis plants had the same phenotype as the transgenic tobacco plants, which may have resulted from the altered expression of several flowering-related genes. We then produced TaEXPB23 transgenic tobacco plants using the stress-inducible RD29A promoter. The use of this promoter reduced the negative effects of TaEXPB23 on plant growth and development. The RD29A::TaEXPB23 transgenic tobacco plants had greater tolerance to water stress than WT, as determined by examining physiological and biochemical parameters. Therefore, the use of stress-inducible promoters, such as RD29A, may minimize the negative effects of constitutive transgene expression and improve the water-stress tolerance of plants.

  11. Association of Human Development Index with rates and outcomes of hematopoietic stem cell transplantation for patients with acute leukemia.

    PubMed

    Giebel, Sebastian; Labopin, Myriam; Ehninger, Gerhard; Beelen, Dietrich; Blaise, Didier; Ganser, Arnold; Bacigalupo, Andrea; Czerw, Tomasz; Holowiecki, Jerzy; Fagundes, Evandro M; Nowara, Elzbieta; Frassoni, Francesco; Rocha, Vanderson

    2010-07-08

    Human Development Index (HDI) is used by the United Nations Organization to measure socioeconomic achievements of countries. We evaluated the association of HDI with rates and outcomes of hematopoietic stem cell transplantation (HSCT) for patients with acute leukemia. For the analysis of HSCT rates, all adults with acute leukemia (n = 16 403) treated in 30 European countries, between 2001 and 2005, were included. Association of HDI with the outcome was analyzed for 2015 patients with acute myeloid leukemia treated with myeloablative allotransplantation. Countries were classified according to HDI quintiles. Highly significant correlation was found for HDI and the total number of HSCT per population (R = 0.78; P < .001), as well as separately for sibling HSCT (R = 0.84; P < .001), unrelated HSCT (R = 0.66; P < .001), and autologous HSCT (R = 0.43; P = .02). The probabilities of leukemia-free survival for 5 consecutive groups of countries with increasing HDI were: 56%, 59%, 63%, 58%, and 68% (P = .01). In a multivariate analysis, transplantations performed in countries belonging to the upper HDI category were associated with higher leukemia-free survival compared with the remaining ones (HR = 1.36, P = .008), which resulted mainly from reduced risk of relapse (HR = 0.72, P = .04). We conclude that, in Europe, the HDI is associated with both rates and results of HSCT for acute leukemia.

  12. Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention

    PubMed Central

    Han, Mingda

    2016-01-01

    Background Embryonic acute exposure to ethanol (EtOH), lithium, and homocysteine (HCy) induces cardiac defects at the time of exposure; folic acid (FA) supplementation protects normal cardiogenesis (Han et al., 2009, 2012; Serrano et al., 2010). Our hypothesis is that EtOH exposure and FA protection relate to lipid and FA metabolism during mouse cardiogenesis and placentation. Methods On the morning of conception, pregnant C57BL/6J mice were placed on either of two FA‐containing diets: a 3.3 mg health maintenance diet or a high FA diet of 10.5 mg/kg. Mice were injected a binge level of EtOH, HCy, or saline on embryonic day (E) 6.75, targeting gastrulation. On E15.5, cardiac and umbilical blood flow were examined by ultrasound. Embryonic cardiac tissues were processed for gene expression of lipid and FA metabolism; the placenta and heart tissues for neutral lipid droplets, or for medium chain acyl‐dehydrogenase (MCAD) protein. Results EtOH exposure altered lipid‐related gene expression on E7.5 in comparison to control or FA‐supplemented groups and remained altered on E15.5 similarly to changes with HCy, signifying FA deficiency. In comparison to control tissues, the lipid‐related acyl CoA dehydrogenase medium length chain gene and its protein MCAD were altered with EtOH exposure, as were neutral lipid droplet localization in the heart and placenta. Conclusion EtOH altered gene expression associated with lipid and folate metabolism, as well as neutral lipids, in the E15.5 abnormally functioning heart and placenta. In comparison to controls, the high FA diet protected the embryo and placenta from these effects allowing normal development. Birth Defects Research (Part A) 106:749–760, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc. PMID:27296863

  13. Damage Tolerance of Composites

    NASA Technical Reports Server (NTRS)

    Hodge, Andy

    2007-01-01

    Fracture control requirements have been developed to address damage tolerance of composites for manned space flight hardware. The requirements provide the framework for critical and noncritical hardware assessment and testing. The need for damage threat assessments, impact damage protection plans, and nondestructive evaluation are also addressed. Hardware intended to be damage tolerant have extensive coupon, sub-element, and full-scale testing requirements in-line with the Building Block Approach concept from the MIL-HDBK-17, Department of Defense Composite Materials Handbook.

  14. Sensitivity of Danio rerio (Teleostei, Cyprinidae) during two stages of development based on acute toxicity tests.

    PubMed

    Freiry, R; Stelzer, J A A; Maltchik, L; Arenzon, A

    2014-10-01

    The sensitivity of Danio rerio to three chemicals was compared at two growth stages [larval (10 ± 2 after hatching) and post-larval (60 ± 4 days after hatching)] based on acute toxicity tests. Thirty-nine 48 h acute toxicity tests were performed with the substances CuSO4, NaCl and KCl. The 48 h LC50 values at the two growth stages were compared by independent samples t-tests. The results showed a clear decrease in sensitivity when post-larval organisms were used. Since acute toxicity test methods for D. rerio that recommend using post-larval stage fish do not represent the most sensitive stage of the test organism, our study suggests a revision of the methods to use larval fish.

  15. Development of an emergency department response to acute stroke ("Code Stroke").

    PubMed

    Leira, Enrique C; Ahmed, Azeemuddin

    2009-01-01

    Minimizing delays is a crucial step in improving outcomes with acute stroke therapies whose efficacy is clearly time dependent. Logistic and human barriers to rapid stroke care can be overcome with a systematic "Code Stroke" approach provided by a structured multidisciplinary acute stroke response team. Such teams should include Emergency Medical Services providers, neurologists, neurosurgeons, diagnostic radiologists, nurses, radiology technicians, laboratory personnel, hospital administrators, and emergency medicine, intensive care, and neurointerventional physicians. An acute stroke team improves treatment practices and provides a gratifying experience for patients, families, and referring physicians. On the other hand, maintaining proficiency of the team's operation is time consuming and personally onerous for team responders. Successful maintenance requires strong departmental and institutional commitment.

  16. Development of an acute and chronic ecotoxicity assay using lux-marked Rhizobium leguminosarum biovar trifolii.

    PubMed

    Paton, G I; Palmer, G; Burton, M; Rattray, E A; McGrath, S P; Glover, L A; Killham, K

    1997-04-01

    A soil isolate of Rhizobium leguminosarum bv. trifolii was marked with a lux CDABE gene cassette to enable the expression of bioluminescence. The suitability of the bacterium as a soil pollution biosensor was assessed using acute and chronic assays. Bacterial bioluminescence responded sensitively to the metals studied. The order of sensitivity was found to be Cd > Ni = Zn > Cu for the acute test and Cd > Ni = Zn = Cu for the chronic test. The sensitive response of the biosensor highlighted its potential for use as an indicator of soil pollution.

  17. Acute phosphate nephropathy.

    PubMed

    Monfared, Ali; Habibzadeh, Seyed Mahmoud; Mesbah, Seyed Alireza

    2014-05-01

    We present acute phosphate nephropathy in a 28-year-old man, which was developed after a car accident due to rhabdomyolysis. Treatment of acute kidney injury was done with administration of sodium bicarbonate.

  18. Manipulation of the gut microbiota in C57BL/6 mice changes glucose tolerance without affecting weight development and gut mucosal immunity.

    PubMed

    Bech-Nielsen, Gunilla Veslemøy; Hansen, Camilla Hartmann Friis; Hufeldt, Majbritt Ravn; Nielsen, Dennis Sandris; Aasted, Bent; Vogensen, Finn Kvist; Midtvedt, Tore; Hansen, Axel Kornerup

    2012-06-01

    Inflammatory diseases such as type 2 diabetes (T2D) in humans and mice are under the influence of the composition of the gut microbiota (GM). It was previously demonstrated that treating Lep(ob) mice with antibiotics improved glucose tolerance. However, wild type C57BL/6J mice may also exhibit plasma glucose intolerance reminiscent of human T2D. We hypothesized that antibiotic treatment in C57BL/6 mice would have an impact on glucose tolerance without affecting weight and gut immunology. When compared to mice treated with erythromycin or the controls, treatment for five weeks with ampicillin improved glucose tolerance without significantly affecting the weight or the number of gut mucosal regulatory T cells, tolerogenic dendritic cells or T helper cells type 1. 16S rRNA gene based denaturing gradient gel electrophoresis profiles clearly clustered according to treatment and showed that antibiotic treatment reduced GM diversity. It is concluded that antibiotic treatment changes glucose metabolism as well as the composition of the GM in C57BL/6 mice, and that this does not seem to be correlated to weight development in the mice.

  19. Development of industrial yeast strain with improved acid- and thermo-tolerance through evolution under continuous fermentation conditions followed by haploidization and mating.

    PubMed

    Mitsumasu, Kanako; Liu, Ze-Shen; Tang, Yue-Qin; Akamatsu, Takashi; Taguchi, Hisataka; Kida, Kenji

    2014-12-01

    Continuous fermentation using the industrial Saccharomyces cerevisiae diploid strain WW was carried out under acidic or high-temperature conditions to achieve acid- or thermo-tolerant mutants. Mutants isolated at pH 2.5 and 41°C showed improved growth and fermentation ability under acidic and elevated temperature conditions. Haploid strains WW17A1 and WW17A4 obtained from the mutated diploid strain WW17A showed better growth and 4.5-6.5% higher ethanol yields at pH 2.7 than the original strains. Haploid strain WW12T4 obtained from mutated diploid strain WW12T showed 1.25-1.50 times and 2.8-4.7 times higher total cell number and cell viability, respectively, than the original strains at 42°C. Strain AT, which had significantly improved acid- and thermo-tolerance, was developed by mating strain WW17A1 with WW12T4. Batch fermentation at 41°C and pH 3.5 showed that the ethanol concentration and yield achieved during fermentation by strain AT were 55.4 g/L and 72.5%, respectively, which were 10 g/L and 13.4% higher than that of the original strain WW. The present study demonstrates that continuous cultivation followed by haploidization and mating is a powerful approach for enhancing the tolerance of industrial strains.

  20. Metal-tolerant PAH-degrading bacteria: development of suitable test medium and effect of cadmium and its availability on PAH biodegradation.

    PubMed

    Thavamani, Palanisami; Megharaj, Mallavarapu; Naidu, Ravi

    2015-06-01

    The use of metal-tolerant polyaromatic hydrocarbon (PAH)-degrading bacteria is viable for mitigating metal inhibition of organic compound biodegradation in the remediation of mixed contaminated sites. Many microbial growth media used for toxicity testing contain high concentrations of metal-binding components such as phosphates that can reduce solution-phase metal concentrations thereby underestimate the real toxicity. In this study, we isolated two PAHs-degrading bacterial consortia from long-term mixed contaminated soils. We have developed a new mineral medium by optimising the concentrations of medium components to allow the bacterial growth and at the same time maintain high bioavailable metal (Cd(2+) as a model metal) in the medium. This medium has more than 60 % Cd as Cd(2+) at pH 6.5 as measured by an ion selective electrode and visual MINTEQ model. The Cd-tolerant patterns of the consortia were tested and minimum inhibitory concentration (MIC) derived. The consortium-5 had the highest MIC of 5 mg l(-1) Cd followed by consortium-9. Both cultures were able to completely metabolise 200 mg l(-1) phenanthrene in less than 4 days in the presence of 5 mg l(-1) Cd. The isolated metal-tolerant PAH-degrading bacterial cultures have great potential for bioremediation of mixed contaminated soils.

  1. A novel bHLH transcription factor PebHLH35 from Populus euphratica confers drought tolerance through regulating stomatal development, photosynthesis and growth in Arabidopsis

    SciTech Connect

    Dong, Yan; Wang, Congpeng; Han, Xiao; Tang, Sha; Liu, Sha; Xia, Xinli; Yin, Weilun

    2014-07-18

    Highlights: • PebHLH35 is firstly cloned from Populus euphratica and characterized its functions. • PebHLH35 is important for earlier seedling establishment and vegetative growth. • PebHLH35 enhances tolerance to drought by regulating growth. • PebHLH35 enhances tolerance to drought by regulating stomatal development. • PebHLH35 enhances tolerance to drought by regulating photosynthesis and transpiration. - Abstract: Plant basic helix-loop-helix (bHLH) transcription factors (TFs) are involved in a variety of physiological processes including the regulation of plant responses to various abiotic stresses. However, few drought-responsive bHLH family members in Populus have been reported. In this study, a novel bHLH gene (PebHLH35) was cloned from Populus euphratica. Expression analysis in P. euphratica revealed that PebHLH35 was induced by drought and abscisic acid. Subcellular localization studies using a PebHLH35-GFP fusion showed that the protein was localized to the nucleus. Ectopic overexpression of PebHLH35 in Arabidopsis resulted in a longer primary root, more leaves, and a greater leaf area under well-watered conditions compared with vector control plants. Notably, PebHLH35 overexpression lines showed enhanced tolerance to water-deficit stress. This finding was supported by anatomical and physiological analyses, which revealed a reduced stomatal density, stomatal aperture, transpiration rate, and water loss, and a higher chlorophyll content and photosynthetic rate. Our results suggest that PebHLH35 functions as a positive regulator of drought stress responses by regulating stomatal density, stomatal aperture, photosynthesis and growth.

  2. RAD51 and XRCC3 gene polymorphisms and the risk of developing acute myeloid leukemia.

    PubMed

    Hamdy, Mona S; El-Haddad, Alaa M; Bahaa El-Din, Neveen M; Makhlouf, Manal Mohamed; Abdel-Hamid, Samah M

    2011-10-01

    RAD51 (Rec A homolog of E. coli) is a polymorphic gene and one of the central proteins in homologous recombination-DNA-double-stand breaks (HR-DNA-DSB) repair pathway, which is vital in maintaining genetic stability within a cell. The x-ray repair cross complementing (XRCC3) protein also functions in HR-DNA-DSB repair pathway and directly interacts with and stabilizes RAD51 and the closely related RAD51C. The aim of this study was to determine the prevalence of the RAD51 and XRCC3 repair gene polymorphisms among acute myeloid leukemia (AML) patients and to define their role in development of AML and its correlation with the clinical presentation, laboratory data as well as treatment outcome using polymerase chain reaction-restriction fragment length polymorphism assay in 50 de novo AML patients as well as 30 healthy subjects as a control group. Our study revealed that RAD51 G135C and XRCC3 Thr241Met alleles were associated with increased risk of AML with odds ratio (OR) of 2.833 and 2.909 and 95% confidence interval (CI) of 1.527 to 8.983 and 1.761 to 9.788, respectively. Moreover, when combining the 2 genes polymorphisms, a significant elevation of the risk of AML was found with OR of 3.124 and 95% CI of 1.872 to 11.243. As regards treatment outcome, a highly statistical significant difference was found between XRCC3 genotypes with P value of 0.001, whereas no significant difference was present between RAD51 genotypes with P value of 0.29. This clarifies that XRCC3 gene polymorphisms was found to have a significant impact on the risk of treatment failure with OR of 3.560 and 95% CI of 1.167 to 10.875; however, RAD51 gene polymorphism was not found to have an equivalent effect with OR of 2.813 and 95% CI of 0.933 to 10.828. So XRCC3 gene polymorphism might be considered as a prognostic marker in AML. In conclusion, RAD51 and XRCC3 genes polymorphisms may play an important role in the development of AML.

  3. Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction.

    PubMed

    Münzel, Thomas; Steven, Sebastian; Daiber, Andreas

    2014-12-01

    Given acutely, organic nitrates, such as nitroglycerin (GTN), isosorbide mono- and dinitrates (ISMN, ISDN), and pentaerythrityl tetranitrate (PETN), have potent vasodilator and anti-ischemic effects in patients with acute coronary syndromes, acute and chronic congestive heart failure and arterial hypertension. During long-term treatment, however, side effects such as nitrate tolerance and endothelial dysfunction occur, and therapeutic efficacy of these drugs rapidly vanishes. Recent experimental and clinical studies have revealed that organic nitrates per se are not just nitric oxide (NO) donors, but rather a quite heterogeneous group of drugs considerably differing for mechanisms underlying vasodilation and the development of endothelial dysfunction and tolerance. Based on this, we propose that the term nitrate tolerance should be avoided and more specifically the terms of GTN, ISMN and ISDN tolerance should be used. The present review summarizes preclinical and clinical data concerning organic nitrates. Here we also emphasize the consequences of chronic nitrate therapy on the supersensitivity of the vasculature to vasoconstriction and on the increased autocrine expression of endothelin. We believe that these so far rather neglected and underestimated side effects of chronic therapy with at least GTN and ISMN are clinically important.

  4. Identification of drought-responsive genes in a drought-tolerant cotton (Gossypium hirsutum L.) cultivar under reduced irrigation field conditions and development of candidate gene markers for drought tolerance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cotton productivity is affected by water deficit, and little is known about the molecular basis of drought tolerance in cotton. In this study, microarray analysis was conducted to identify drought-responsive genes in the third topmost leaves of the field-grown drought-tolerant cotton (Gossypium hirs...

  5. Nitazoxanide in Acute Rotavirus Diarrhea: A Randomized Control Trial from a Developing Country

    PubMed Central

    Mahapatro, Samarendra; Mahilary, Nijwm; Satapathy, Amit Kumar

    2017-01-01

    Background. Acute diarrhea is one of the leading causes of childhood mortality, with rotavirus being an important pathogen. Nitazoxanide, an antiparasitic agent, has been shown to inhibit rotavirus. Objective. This double-blind, randomized trial was designed to study the role of nitazoxanide in acute rotavirus diarrhea. Methods. Of 174 children (12 months to 5 years) with acute diarrhea, 50 rotavirus positive cases were randomized. The intervention group received syrup nitazoxanide twice daily (100 mg in 12–47 months, 200 mg in ≥4 yr) for 3 days along with standard treatment of diarrhea. Duration of diarrhea was the primary outcome measure. Results. The median duration (hrs) of diarrhea (54 versus 80; 95% CI: –26 [–13.2 to –38.8]) and hospitalization (68 versus 90; 95% CI: –22 [–12.98 to –31.02]) was significantly shorter in the nitazoxanide group. No significant difference was seen in the median duration (hrs) of fever or vomiting or the proportion of children requiring parenteral rehydration. There was no report of any adverse events. Conclusions. Oral nitazoxanide is effective and safe in the management of acute rotavirus diarrhea in Indian children (CTRI REF/2016/10/012507). PMID:28331496

  6. Development of Chronic and Acute Golden Syrian Hamster Infection Models with Leptospira borgpetersenii serovar Hardjo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The golden Syrian hamster (Mesocricetus auratus) is frequently used as a model to study virulence for several species of Leptospira. Onset of an acute, lethal infection following infection with several pathogenic Leptospira species has been widely adopted for vaccine testing. An important exceptio...

  7. Development of Hamster Models for Acute and Chronic Infections with Leptospira borgpetersenii serovar Hardjo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Golden Syrian hamster is frequently used as a small animal model to study acute leptospirosis. However, use of this small animal model to study Leptospira borgpetersenii serovar Hardjo infections has not been well documented. Cattle are the normal maintenance hosts of L. borgpetersenii serovar...

  8. Language Choice in an Acutely Multilingual Society: Communication and Development in Papua New Guinea.

    ERIC Educational Resources Information Center

    Smith, Geoff P.

    Acute intercultural communication problems posed by multilingualism in Papua New Guinea are discussed, and ways in which they are being addressed are examined. An introductory section outlines the language situation in Melanesia. It is noted that the area's language diversity and colonization and missionary activity have resulted in the emergence…

  9. Ethanol Tolerance Affects Endogenous Adenosine Signaling in Mouse Hippocampus

    PubMed Central

    Zhang, Dali; Xiong, Wei; Jackson, Michael F.

    2016-01-01

    Ethanol has many pharmacological effects, including increases in endogenous adenosine levels and adenosine receptor activity in brain. Ethanol consumption is associated with both positive and negative health outcomes, but tolerance to the behavioral effects of ethanol can lead to increased consumption, which increases the risk of negative health outcomes. The present study was performed to test whether a 7-day treatment with ethanol is linked to reduced adenosine signaling and whether this is a consequence of reduced ecto-5′-nucleotidase activity. Wild-type (CD73+/+) and ecto-5′-nucleotidase-deficient (CD73−/−) mice were treated with ethanol (2 g/kg) or saline for 7 days. In CD73+/+ mice, repeated ethanol treatment reduced the hypothermic and ataxic effects of acute ethanol, indicating the development of tolerance to the acute effects of ethanol. In CD73+/+ mice, this 7-day ethanol treatment led to increased hippocampal synaptic activity and reduced adenosine A1 receptor activity under both basal and low Mg2+ conditions. These effects of ethanol tolerance were associated with an 18% decrease in activity of ecto-5′-nucleotidase activity in hippocampal cell membranes. In contrast, ethanol treatment was not associated with changes in synaptic activity or adenosine signaling in hippocampus from CD73−/− mice. These data indicate that ethanol treatment is associated with a reduction in adenosine signaling through adenosine A1 receptors in hippocampus, mediated, at least in part, via reduced ecto-5′-nucleotidase activity. PMID:27189965

  10. Using euhalophytes to understand salt tolerance and to develop saline agriculture: Suaeda salsa as a promising model

    PubMed Central

    Song, Jie; Wang, Baoshan

    2015-01-01

    Background As important components in saline agriculture, halophytes can help to provide food for a growing world population. In addition to being potential crops in their own right, halophytes are also potential sources of salt-resistance genes that might help plant breeders and molecular biologists increase the salt tolerance of conventional crop plants. One especially promising halophyte is Suaeda salsa, a euhalophytic herb that occurs both on inland saline soils and in the intertidal zone. The species produces dimorphic seeds: black seeds are sensitive to salinity and remain dormant in light under high salt concentrations, while brown seeds can germinate under high salinity (e.g. 600 mm NaCl) regardless of light. Consequently, the species is useful for studying the mechanisms by which dimorphic seeds are adapted to saline environments. S. salsa has succulent leaves and is highly salt tolerant (e.g. its optimal NaCl concentration for growth is 200 mm). A series of S. salsa genes related to salt tolerance have been cloned and their functions tested: these include SsNHX1, SsHKT1, SsAPX, SsCAT1, SsP5CS and SsBADH. The species is economically important because its fresh branches have high value as a vegetable, and its seed oil is edible and rich in unsaturated fatty acids. Because it can remove salts and heavy metals from saline soils, S. salsa can also be used in the restoration of salinized or contaminated saline land. Scope Because of its economic and ecological value in saline agriculture, S. salsa is one of the most important halophytes in China. In this review, the value of S. salsa as a source of food, medicine and forage is discussed. Its uses in the restoration of salinized or contaminated land and as a source of salt-resistance genes are also considered. PMID:25288631

  11. Development of salinity tolerance in rice by constitutive-overexpression of genes involved in the regulation of programmed cell death.

    PubMed

    Hoang, Thi M L; Moghaddam, Lalehvash; Williams, Brett; Khanna, Harjeet; Dale, James; Mundree, Sagadevan G

    2015-01-01

    Environmental factors contribute to over 70% of crop yield losses worldwide. Of these drought and salinity are the most significant causes of crop yield reduction. Rice is an important staple crop that feeds more than half of the world's population. However among the agronomically important cereals rice is the most sensitive to salinity. In the present study we show that exogenous expression of anti-apoptotic genes from diverse origins, AtBAG4 (Arabidopsis), Hsp70 (Citrus tristeza virus) and p35 (Baculovirus), significantly improves salinity tolerance in rice at the whole plant level. Physiological, biochemical and agronomical analyses of transgenic rice expressing each of the anti-apoptotic genes subjected to salinity treatment demonstrated traits associated with tolerant varieties including, improved photosynthesis, membrane integrity, ion and ROS maintenance systems, growth rate, and yield components. Moreover, FTIR analysis showed that the chemical composition of salinity-treated transgenic plants is reminiscent of non-treated, unstressed controls. In contrast, wild type and vector control plants displayed hallmark features of stress, including pectin degradation upon subjection to salinity treatment. Interestingly, despite their diverse origins, transgenic plants expressing the anti-apoptotic genes assessed in this study displayed similar physiological and biochemical characteristics during salinity treatment thus providing further evidence that cell death pathways are conserved across broad evolutionary kingdoms. Our results reveal that anti-apoptotic genes facilitate maintenance of metabolic activity at the whole plant level to create favorable conditions for cellular survival. It is these conditions that are crucial and conducive to the plants ability to tolerate/adapt to extreme environments.

  12. Alteration of dopamine receptor sensitivity by opiates and the subsequent effect of this alteration on opiate tolerance and dependence

    SciTech Connect

    Martin, J.R.

    1985-01-01

    The present study was undertaken to determine whether there is an alteration of dopamine receptor sensitivity following opiate administration, and whether this alteration has any influence on the development of opiate tolerance and dependence. Behavioral hypersensitivity to direct-acting dopamine agonists was observed in mice following acute or chronic morphine administration. Acute levorphanol administration also resulted in potentiation of dopamine agonist-induced behaviors. An increase in density of dopamine receptors, as measured by (/sup 3/H)butyrophenone binding accompanied the development of behavioral hypersensitivity. This increase was localized to the striatum, an area important in the mediation of dopamine-agonist induced behaviors. Naloxone or LiCl coadministered with the opiates prevented the development of hypersensitivity and the increase in density of dopamine receptors. Coadministration of lithium enhanced the development of acute and chronic tolerance. Lithium enhanced the development of dependence as determined by naloxone-induced hypothermia in chronically morphine-treated mice. Apomorphine enhanced naloxone-induced withdrawal in acutely dependent mice. This enhancement was blocked by coadministration of lithium with the opiates. These results suggest that dopamine receptor supersensitivity influences the degree of tolerance and dependence.

  13. Countermeasure development : Specific Immunoprophylaxis and Immunotherapy of Combined Acute Radiation Syndromes.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Slava

    Introduction: Combined Acute Radiation Syndromes (CARS) are extremely severe injuries. Combination of Radiation and Thermal factors induce development of the acute pathologi-cal processes in irradiated mammals: systemic inflammatory response syndrome (SIRS), toxic multiple organ injury (TMOI), toxic multiple organ dysfunction syndromes (TMOD), toxic multiple organ failure (TMOF). Also, high doses of Radiation and Thermal injury induce for-mation of following Toxin groups: A. Specific Radiation Toxins; B. Specific Thermal Toxins; C. Nonspecific Histiogenic Pro-inflammatory and Inflammatory Toxins (NHIT). Specific Radi-ation Toxins (SRT) include four major group of Toxins: Cerebrovascular Radiation Toxins (Cv RT), Cardiovascular Radiation Toxins (Cr RT), Gastrointestinal Radiation Toxins (Gi RT), and Hematopoietic Radiation Toxins (Hp RT). CvRT, Cr RT, Gi RT groups of toxins are defined as Neurotoxins and Hp RT group is defined as Hematotoxins. Specific Thermal Toxins (STT) were isolated from the burned skin (Voul S., Colker I. 1972). The group of Nonspecific Histio-genic Inflammatory Toxins (NHIT) includes high amount of tissue toxins which are peptides with medium molecular weight. This group of polypeptides can be a significant factor as a part of developing of the general inflammation reaction. However, NHIT toxins can't induce many reactions and changes which are specific for radiation. Specific Radiation Toxins (SRT) can induce specific processes and reactions such as clonogenic cell death -programmed apoptotic necrosis. Although besides high doses of radiation, other forms of cell death such as Pyroptosis or Oncosis should be considered. We postulate that NHIT toxins are similar for high doses of radiation and thermal injury. Specific Radiation Toxins (SRT) are induced by high doses of radiation. Specific Thermal Toxins (STT) toxins which formation is induced by a Thermal Factor are different from SRT. Administration of STT toxins or NHIT toxins (IV or IM) to

  14. Acute rheumatic fever and its consequences: a persistent threat to developing nations in the 21st century.

    PubMed

    Lee, Jennifer L; Naguwa, Stanley M; Cheema, Gurtej S; Gershwin, M Eric

    2009-12-01

    Acute rheumatic fever (ARF) is an autoimmune, multi-system response secondary to molecular mimicry following Lancefield group A streptococcus (GAS) pharyngitis; it is now most commonly found in the pediatric populations of developing nations. The major source of morbidity and mortality of ARF stems from rheumatic heart disease (RHD), although the cardinal symptoms of the disease also include polyarthritis, Sydenham's chorea, subcutaneous nodules, and erythema marginatum. Therapy is aimed towards treating the initial GAS infection, using anti-inflammatory medications for acute symptoms and surgery to correct RHD. Secondary prevention is crucial, given the high risk of recurrence, and includes long-term antibiotic prophylaxis. However, vaccination towards GAS may soon be on the horizon, which may assist in both decreasing the risk of initial infection in naïve patients and helping to lower the risk of recurrence.

  15. Deconstructing tolerance with clobazam

    PubMed Central

    Wechsler, Robert T.; Sankar, Raman; Montouris, Georgia D.; White, H. Steve; Cloyd, James C.; Kane, Mary Clare; Peng, Guangbin; Tworek, David M.; Shen, Vivienne; Isojarvi, Jouko

    2016-01-01

    Objective: To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome. Methods: Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg−1·d−1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg−1·d−1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ≥40% and increasing seizure rates. Results: Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ≥75% responders demonstrated a consistent response over time. Few patients had a dosage increase ≥40% associated with an increase in seizure rates. Conclusions: Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated. ClinicalTrials.gov identifier: NCT00518713 and NCT01160770. Classification of evidence: This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment. PMID:27683846

  16. Central role of the flowering repressor ZCCT2 in the redox control of freezing tolerance and the initial development of flower primordia in wheat

    PubMed Central

    2014-01-01

    Background As both abiotic stress response and development are under redox control, it was hypothesised that the pharmacological modification of the redox environment would affect the initial development of flower primordia and freezing tolerance in wheat (Triticum aestivum L.). Results Pharmacologically induced redox changes were monitored in winter (T. ae. ssp. aestivum cv. Cheyenne, Ch) and spring (T. ae. ssp. spelta; Tsp) wheat genotypes grown after germination at 20/17°C for 9 d (chemical treatment: last 3 d), then at 5°C for 21 d (chemical treatment: first 4 d) and subsequently at 20/17°C for 21 d (recovery period). Thiols and their disulphide forms were measured and based on these data reduction potentials were calculated. In the freezing-tolerant Ch the chemical treatments generally increased both the amount of thiol disulphides and the reduction potential after 3 days at 20/17°C. In the freezing-sensitive Tsp a similar effect of the chemicals on these parameters was only observed after the continuation of the treatments for 4 days at 5°C. The applied chemicals slightly decreased root fresh weight and increased freezing tolerance in Ch, whereas they increased shoot fresh weight in Tsp after 4 days at 5°C. As shown after the 3-week recovery at 20/17°C, the initial development of flower primordia was accelerated in Tsp, whereas it was not affected by the treatments in Ch. The chemicals differently affected the expression of ZCCT2 and that of several other genes related to freezing tolerance and initial development of flower primordia in Ch and Tsp after 4 d at 5°C. Conclusions Various redox-altering compounds and osmotica had differential effects on glutathione disulphide content and reduction potential, and consequently on the expression of the flowering repressor ZCCT2 in the winter wheat Ch and the spring wheat Tsp. We propose that the higher expression of ZCCT2 in Ch may be associated with activation of genes of cold acclimation and its lower

  17. The role of leptin in the development of pulmonary neutrophilia in infection and Acute Lung Injury

    PubMed Central

    Ubags, Niki D.; Vernooy, Juanita H.; Burg, Elianne; Hayes, Catherine; Bement, Jenna; Dilli, Estee; Zabeau, Lennart; Abraham, Edward; Poch, Katie R.; Nick, Jerry A.; Dienz, Oliver; Zuñiga, Joaquin; Wargo, Matthew J.; Mizgerd, Joseph P.; Tavernier, Jan; Rincón, Mercedes; Poynter, Matthew E.; Wouters, Emiel F.M.; Suratt, Benjamin T.

    2014-01-01

    Objective One of the hallmarks of severe pneumonia and associated Acute Lung Injury (ALI) is neutrophil recruitment to the lung. Leptin is thought to be up-regulated in the lung following injury and to exert diverse effects on leukocytes, influencing both chemotaxis and survival. We hypothesized that pulmonary leptin contributes directly to the development of pulmonary neutrophilia during pneumonia and ALI. Design Controlled human and murine in vivo and ex vivo experimental studies. Settings Research laboratory of a university hospital. Subjects Healthy human volunteers and subjects hospitalized with bacterial and H1N1 pneumonia. C57Bl/6 and db/db mice were also used. Interventions Lung samples from patients and mice with either bacterial or H1N1 pneumonia and associated ALI were immunostained for leptin. Human bronchoalveolar-lavage (BAL) samples obtained after lipopolysaccharide (LPS)-induced lung injury were assayed for leptin. C57Bl/6 mice were examined after oropharyngeal aspiration of recombinant leptin alone or in combination with E.coli- or K.pneumonia-induced pneumonia. Leptin-resistant (db/db) mice were also examined using the E.coli model. BAL neutrophilia and cytokine levels were measured. Leptin-induced chemotaxis was examined in human blood- and murine marrow-derived neutrophils in vitro. Measurements and Main Results Injured human and murine lung tissue showed leptin induction compared to normal lung, as did human BAL following LPS instillation. BAL neutrophilia in uninjured and infected mice was increased and lung bacterial-load decreased by airway leptin administration, whereas BAL neutrophilia in infected leptin-resistant mice was decreased. In sterile lung injury by LPS, leptin also appeared to decrease airspace neutrophil apoptosis. Both human and murine neutrophils migrated towards leptin in vitro, and this required intact signaling through the JAK2/PI3K pathway. Conclusion We demonstrate that pulmonary leptin is induced in injured human and

  18. Does breast feeding provide protection against acute appendicitis? A case-control study.

    PubMed

    Alves, João Guilherme Bezerra; Figueiroa, José Natal; Barros, Isabela

    2008-10-01

    Breast feeding stimulates a more tolerant lymphoid tissue at the base of the appendix and this could provide protection against acute appendicitis. Two studies reported that children and adolescents with appendicitis were less likely to have been breast fed. In a case-control study of 200 children with histologically confirmed acute appendicitis matched by 200 siblings with the same sex and difference age - up to three-year-old - we found breast feeding in at least the first two months of life and for more than four months provides protection against acute appendicitis. These findings suggesting that breast feeding may possibly give protection against the development of appendicitis.

  19. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance.

    PubMed

    Steinman, Ralph Marvin; Nussenzweig, Michel C

    2002-01-08

    The immune system generally avoids horror autotoxicus or autoimmunity, an attack against the body's own constituents. This avoidance requires that self-reactive T cells be actively silenced or tolerized. We propose that dendritic cells (DCs) play a critical role in establishing tolerance, especially in the periphery, after functioning T cells have been produced in the thymus. In the steady state, meaning in the absence of acute infection and inflammation, DCs are in an immature state and not fully differentiated to carry out their known roles as inducers of immunity. Nevertheless, immature DCs continuously circulate through tissues and into lymphoid organs, capturing self antigens as well as innocuous environmental proteins. Recent experiments have provided direct evidence that antigen-loaded immature DCs silence T cells either by deleting them or by expanding regulatory T cells. This capacity of DCs to induce peripheral tolerance can work in two opposing ways in the context of infection. In acute infection, a beneficial effect should occur. The immune system would overcome the risk of developing autoimmunity and chronic inflammation if, before infection, tolerance were induced to innocuous environmental proteins as well as self antigens captured from dying infected cells. For chronic or persistent pathogens, a second but dire potential could take place. Continuous presentation of a pathogen by immature DCs, HIV-1 for example, may lead to tolerance and active evasion of protective immunity. The function of DCs in defining immunologic self provides a new focus for the study of autoimmunity and chronic immune-based diseases.

  20. Phenological development stages variation versus mercury tolerance, accumulation, and allocation in salt marsh macrophytes Triglochin maritima and Scirpus maritimus prevalent in Ria de Aveiro coastal lagoon (Portugal).

    PubMed

    Anjum, Naser A; Ahmad, Iqbal; Válega, Mónica; Figueira, Etelvina; Duarte, Armando C; Pereira, Eduarda

    2013-06-01

    Efficient and sustainable management of rapidly mounting environmental issues has been the focus of current intensive research. The present study aimed to investigate the impact of plant phenological development stage variation on mercury (Hg) tolerance, accumulation, and allocation in two salt marsh macrophytes Triglochin maritima and Scirpus maritimus prevalent in historically Hg-contaminated Ria de Aveiro coastal lagoon (Portugal). Both plant samples and the sediments vegetated by monospecific stands of T. maritima and S. maritimus were collected from reference (R) and sites with moderate (M) and high (H) Hg contamination in Laranjo bay within Ria de Aveiro lagoon. Hg tolerance, uptake, and allocation in T. maritima and S. maritimus, physico-chemical traits (pH, redox potential, and organic matter content) and Hg concentrations in sediments vegetated by these species were impacted differentially by phenological development stages variation irrespective of the Hg contamination level. In T. maritima, Hg concentration increased with increase in Hg contamination gradient where root displayed significantly higher Hg followed by rhizome and leaf maximally at H. However, in S. maritimus, the highest Hg concentration was perceptible in rhizome followed by root maximally at M. Between the two studied plant species, S. maritimus displayed higher Hg tolerance index (depicted by higher plant dry mass allocated to reproductive stage) and higher available Hg at M (during all growth stages) and H (during senescent stage) when compared to T. maritimus. Both plant species proved to be Hg excluder (low root/rhizome-leaf Hg translocation). Additionally, T. maritima also acted as Hg stabilizer while, S. maritimus as Hg accumulator. It can be inferred from the study that (a) the plant phenological development stage variations significantly influenced plant Hg sensitivity by impacting sediment chemistry, plant growth (in terms of plant dry mass), Hg accumulation, and its subsequent

  1. Enhancement of chronic acceleration tolerance by selection

    NASA Technical Reports Server (NTRS)

    Smith, A. H.

    1982-01-01

    A review is presented of experiments concerning the physiological consequences of chronic acceleration and of studies of selection for acceleration tolerance over many generations. It is shown that acceleration selection is effective in improving chronic acceleration tolerance. However, it is determined that the variable selection procedure employed in developing this acceleration-tolerant line limits the confidence in the quantitative evaluation of the procedure.

  2. Viral Infection in the Development and Progression of Pediatric Acute Respiratory Distress Syndrome

    PubMed Central

    Nye, Steven; Whitley, Richard J.; Kong, Michele

    2016-01-01

    Viral infections are an important cause of pediatric acute respiratory distress syndrome (ARDS). Numerous viruses, including respiratory syncytial virus (RSV) and influenza A (H1N1) virus, have been implicated in the progression of pneumonia to ARDS; yet the incidence of progression is unknown. Despite acute and chronic morbidity associated with respiratory viral infections, particularly in “at risk” populations, treatment options are limited. Thus, with few exceptions, care is symptomatic. In addition, mortality rates for viral-related ARDS have yet to be determined. This review outlines what is known about ARDS secondary to viral infections including the epidemiology, the pathophysiology, and diagnosis. In addition, emerging treatment options to prevent infection, and to decrease disease burden will be outlined. We focused on RSV and influenza A (H1N1) viral-induced ARDS, as these are the most common viruses leading to pediatric ARDS, and have specific prophylactic and definitive treatment options. PMID:27933286

  3. Bilateral acute angle closure developing due to use of ipratropium bromide and salbutamol.

    PubMed

    Kola, Mehmet; Hacıoğlu, Dilek; Erdöl, Hidayet; Türk, Adem

    2017-02-06

    Acute angle closure can be seen as a side effect of some medications that can be used systemically. In this article, clinical characteristics of 54-year-old female patient who applied to our clinic with bilateral acute angle closure and has been received nebulized form of salbutamol and ipratropium bromide due to asthma for 4 days was evaluated. Right and left eye IOP were measured as 50 and 48 mmHg. IOP was reduced with anti-glaucomatous treatment. and peripheral iridectomy was done, and then the patient was discharged. It is necessary to be careful to prevent contact with the eye of nebulized form of these drugs which may result in angle closure glaucoma when used systemically.

  4. Viral Infection in the Development and Progression of Pediatric Acute Respiratory Distress Syndrome.

    PubMed

    Nye, Steven; Whitley, Richard J; Kong, Michele

    2016-01-01

    Viral infections are an important cause of pediatric acute respiratory distress syndrome (ARDS). Numerous viruses, including respiratory syncytial virus (RSV) and influenza A (H1N1) virus, have been implicated in the progression of pneumonia to ARDS; yet the incidence of progression is unknown. Despite acute and chronic morbidity associated with respiratory viral infections, particularly in "at risk" populations, treatment options are limited. Thus, with few exceptions, care is symptomatic. In addition, mortality rates for viral-related ARDS have yet to be determined. This review outlines what is known about ARDS secondary to viral infections including the epidemiology, the pathophysiology, and diagnosis. In addition, emerging treatment options to prevent infection, and to decrease disease burden will be outlined. We focused on RSV and influenza A (H1N1) viral-induced ARDS, as these are the most common viruses leading to pediatric ARDS, and have specific prophylactic and definitive treatment options.

  5. Assessment of Air Pollution Tolerance Index of some plants to develop vertical gardens near street canyons of a polluted tropical city.

    PubMed

    Pandey, Ashutosh Kumar; Pandey, Mayank; Tripathi, B D

    2016-12-01

    The aim of the present study was to examine Air Pollution Tolerance Index (APTI) of some climber plant species to develop vertical gardens in Varanasi city which has characteristics of tall building and narrow roads. This condition results in street canyon like structure and hinders the vertical dispersal of air pollutants. We have selected 24 climber plant species which are commonly found in of Varanasi city. Chosen plants can be easily grown either in planter boxes or directly in the ground, with a vertical support they can climb on walls to form green walls or vertical garden. Air Pollution Tolerance Index (APTI) of the selected plant species was calculated and plants with higher APTI are recommended for the development of Vertical garden. Highest APTI was noted for Ipomoea palmata (25.39) followed by Aristolochia elegans (23.28), Thunbergia grandiflora (23.14), Quisqualis indica (22.42), and Clerodendrum splendens (22.36). However, lowest APTI value (8.75) was recorded for the species Hemidesmus indicus. Moreover, the linear regression analysis has revealed a high positive correlation between APTI and ascorbic acid content (R(2)=0.8837) and positive correlation between APTI and Chlorophyll content (R(2)=0.6687). On the basis of higher APTI values (greater than 17), nine species of climber plants viz. I. palmata, T. grandiflora, C. splendens, A. elegans, Q. indica, Petria volubilis, Antigonon leptopus, Cryptolepis buchuanni and Tinospora cordifolia have been recommended to develop vertical greenery systems in a compact tropical city.

  6. FR-H3: a new QTL to assist in the development of fall-sown barley with superior low temperature tolerance.

    PubMed

    Fisk, Scott P; Cuesta-Marcos, Alfonso; Cistué, Luis; Russell, Joanne; Smith, Kevin P; Baenziger, Stephen; Bedo, Zoltán; Corey, Ann; Filichkin, Tanya; Karsai, Ildikó; Waugh, Robbie; Hayes, Patrick M

    2013-02-01

    Fall-sown barley will be increasingly important in the era of climate change due to higher yield potential and efficient use of water resources. Resistance/tolerance to abiotic stresses will be critical, and foremost among the abiotic stresses is low temperature. Simultaneous gene discovery and breeding will accelerate the development of agronomically relevant fall-sown barley germplasm with resistance to low temperature. We developed two doubled haploid mapping populations using two lines from the University of Nebraska (NE) and one line from Oregon State University (OR): NB3437f/OR71 (facultative × facultative) and NB713/OR71 (winter × facultative). Both were genotyped with a custom 384 oligonucleotide pool assay (OPA). QTL analyses were performed for low temperature tolerance (LTT) and vernalization sensitivity (VS). The role of VRN-H2 in VS was confirmed and a novel alternative winter allele at VRN-H3 was discovered in the Nebraska germplasm. FR-H2 was identified as a probable determinant of LTT and a new QTL, FR-H3, was discovered on chromosome 1H that accounted for up to 48 % of the phenotypic variation in field survival at St. Paul, MN, USA. The discovery of FR-H3 is a significant advancement in barley LTT genetics and will assist in developing the next generation of fall-sown varieties.

  7. Gene Expression Changes during the Development of Acute Lung Injury Role of Transforming Growth Factor β

    PubMed Central

    Wesselkamper, Scott C.; Case, Lisa M.; Henning, Lisa N.; Borchers, Michael T.; Tichelaar, Jay W.; Mason, John M.; Dragin, Nadine; Medvedovic, Mario; Sartor, Maureen A.; Tomlinson, Craig R.; Leikauf, George D.

    2005-01-01

    Rationale: Acute lung injury can occur from multiple causes, resulting in high mortality. The pathophysiology of nickel-induced acute lung injury in mice is remarkably complex, and the molecular mechanisms are uncertain. Objectives: To integrate molecular pathways and investigate the role of transforming growth factor β (TGF-β) in acute lung injury in mice. Methods: cDNA microarray analyses were used to identify lung gene expression changes after nickel exposure. MAPPFinder analysis of the microarray data was used to determine significantly altered molecular pathways. TGF-β1 protein in bronchoalveolar lavage fluid, as well as the effect of inhibition of TGF-β, was assessed in nickel-exposed mice. The effect of TGF-β on surfactant-associated protein B (Sftpb) promoter activity was measured in mouse lung epithelial cells. Measurements and Main Results: Genes that decreased the most after nickel exposure play important roles in lung fluid absorption or surfactant and phospholipid synthesis, and genes that increased the most were involved in TGF-β signaling. MAPPFinder analysis further established TGF-β signaling to be significantly altered. TGF-β–inducible genes involved in the regulation of extracellular matrix function and fibrinolysis were significantly increased after nickel exposure, and TGF-β1 protein was also increased in the lavage fluid. Pharmacologic inhibition of TGF-β attenuated nickel-induced protein in bronchoalveolar lavage. In addition, treatment with TGF-β1 dose-dependently repressed Sftpb promoter activity in vitro, and a novel TGF-β–responsive region in the Sftpb promoter was identified. Conclusions: These data suggest that TGF-β acts as a central mediator of acute lung injury through the alteration of several different molecular pathways. PMID:16100012

  8. [Microflora of gastric mucosa, its properties and role in the development of acute and chronic gastritis].

    PubMed

    Tsimmerman, Ia S; Zakharova, Iu A; Vedernikov, V E

    2012-01-01

    Gastric microflora was studied in 28 patients suffering acute and chronic gastritis with reference to the factors of pathogenicity and sensitivity to antibacterial preparations. A total of 55 bacterial species were isolated The microflora was dominated by streptoccoci while Helicobacter pylori occurred rather rarely 27.3 +/- 6.5% of the isolated strains showed urease activity 36.3 +/- 6.5% natural or acquired virulence, 45.5 +/- 6.7% resistance to eradication therapy.

  9. Respiratory syncytial virus, adenoviruses, and mixed acute lower respiratory infections in children in a developing country.

    PubMed

    Rodríguez-Martínez, Carlos E; Rodríguez, Diego Andrés; Nino, Gustavo

    2015-05-01

    There is growing evidence suggesting greater severity and worse outcomes in children with mixed as compared to single respiratory virus infections. However, studies that assess the risk factors that may predispose a child to a mixture of respiratory syncytial virus (RSV) and adenoviral infections, are scarce. In a retrospective cohort study, the study investigated the epidemiology of RSV and adenovirus infections and predictors of mixed RSV-adenoviral infections in young children hospitalized with acute lower respiratory infection in Bogota, Colombia, South America, over a 2-year period 2009-2011. Of a total of 5,539 children admitted with a diagnosis of acute lower respiratory infection, 2,267 (40.9%) who were positive for RSV and/or adenovirus were selected. Out the total number of cases, 1,416 (62.5%) infections occurred during the 3-month period from March to May, the first rainy season of Bogota, Colombia. After controlling for gender, month when the nasopharyngeal sample was taken, and other pre-existing conditions, it was found that an age greater than 6 months (OR:1.74; CI 95%:1.05-2.89; P = 0.030) and malnutrition as a comorbidity (OR:9.92; CI 95%:1.01-100.9; P = 0.049) were independent predictors of mixed RSV-adenoviral infections in the sample of patients. In conclusion, RSV and adenovirus are significant causes of acute lower respiratory infection in infants and young children in Bogota, Colombia, especially during the first rainy season. The identified predictors of mixed RSV-adenoviral infections should be taken into account when planning intervention, in order to reduce the burden of acute lower respiratory infection in young children living in the country.

  10. Differences in flooding tolerance between species from two wetland habitats with contrasting hydrology: implications for vegetation development in future floodwater retention areas

    PubMed Central

    Banach, Katarzyna; Banach, Artur M.; Lamers, Leon P. M.; De Kroon, Hans; Bennicelli, Riccardo P.; Smits, Antoine J. M.; Visser, Eric J. W.

    2009-01-01

    Background and Aims Plants need different survival strategies in habitats differing in hydrological regimes. This probably has consequences for vegetation development when former floodplain areas that are currently confronted with soil flooding only, will be reconnected to the highly dynamical river bed. Such changes in river management are increasingly important, especially at locations where increased water retention can prevent flooding events in developed areas. It is therefore crucial to determine the responses of plant species from relatively low-dynamic wetlands to complete submergence, and to compare these with those of species from river forelands, in order to find out what the effects of such landscape-scale changes on vegetation would be. Methods To compare the species' tolerance to complete submergence and their acclimation patterns, a greenhouse experiment was designed with a selection of 19 species from two contrasting sites: permanently wet meadows in a former river foreland, and frequently submerged grasslands in a current river foreland. The plants were treated with short (3 weeks) and long (6 weeks) periods of complete submergence, to evaluate if survival, morphological responses, and changes in biomass differed between species of the two habitats. Key Results All tested species inhabiting river forelands were classified as tolerant to complete submergence, whereas species from wet meadows showed either relatively intolerant, intermediate or tolerant responses. Species from floodplains showed in all treatments stronger shoot elongation, as well as higher production of biomass of leaves, stems, fine roots and taproots, compared with meadow species. Conclusions There is a strong need for the creation of temporary water retention basins during high levels of river discharge. However, based on the data presented, it is concluded that such reconnection of former wetlands (currently serving as meadows) to the main river bed will strongly influence plant

  11. Comparative acute freshwater hazard assessment and preliminary PNEC development for eight fluorinated acids.

    PubMed

    Hoke, Robert A; Bouchelle, Laurie D; Ferrell, Barbra D; Buck, Robert C

    2012-05-01

    Short-term 48, 72 and 96-h aquatic toxicity tests were conducted to evaluate the acute toxicity of eight fluorinated acids to the cladoceran, Daphnia magna, the green alga, Pseudokirchneriella subcapitata, and the rainbow trout, Oncorhynchus mykiss or the fathead minnow, Pimephales promelas. The eight fluorinated acids studied were tridecafluorohexyl ethanoic acid (6:2 FTCA), heptadecafluorooctyl ethanoic acid (8:2 FTCA), 2H-dodecafluoro-2-octenoic acid (6:2 FTUCA), 2H-hexadecafluoro-2-decenoic acid (8:2 FTUCA), 2H,2H,3H,3H-undecafluoro octanoic acid (5:3 acid), 2H,2H,3H,3H-pentadecafluoro decanoic acid (7:3 acid), n-perfluoropentanoic acid (PFPeA) and n-perfluorodecanoic acid (PFDA). The results of the acute toxicity tests conducted during this study suggest that the polyfluorinated acids, 8:2 FTCA, 8:2 FTUCA, 6:2 FTCA, 6:2 FTUCA, 7:3 acid and 5:3 acid, and the perfluorinated acids PFPeA and PFDA, are generally of low to medium concern based on evaluation of their acute freshwater toxicity (EC/LC50s typically between 1 and >100 mg L(-1)) using the USEPA TSCA aquatic toxicity evaluation paradigm. For the polyfluorinated acids, aquatic toxicity generally decreased as the number of fluorinated carbons decreased and as the overall carbon chain length decreased from 12 to 8. Acute aquatic toxicity of the 5 and 10 carbon perfluorocarboxylic acids (EC/LC50s between 10.6 and >100 mg L(-1)) was greater or similar to that of the 6-9 carbon perfluorocarboxylic acids (EC/LC50s>96.5 mg L(-1)). This study also provides the first report of the acute aquatic toxicity of the 5:3 acid (EC/LC50s of 22.5 to >103 mg L(-1)) which demonstrated less aquatic toxicity than the 7:3 acid (EC/LC50s of 0.4-32 mg L(-1)). The cladoceran, D. magna and the green alga, P. subcapitata had generally similar EC50 values for a given substance while fish were typically equally or less sensitive with the exception that PFPeA was most toxic to fish. Predicted no-effect concentrations (PNECs) were

  12. Development and Preliminary Randomized Controlled Trial of a Distress Tolerance Treatment for Smokers With a History of Early Lapse

    PubMed Central

    2013-01-01

    Introduction: An inability to tolerate distress is a significant predictor of early smoking lapse following a cessation attempt. We conducted a preliminary randomized controlled trial to compare a distress tolerance (DT) treatment that incorporated elements of exposure-based therapies and Acceptance and Commitment Therapy to standard smoking cessation treatment (ST). Methods: Smokers with a history of early lapse in prior quit attempts received either DT (N = 27; 9 2-hr group and 6 50-min individual sessions) or ST (N = 22; 6 90-min group and 1 20-min individual session), plus 8 weeks of transdermal nicotine patch. Results: At the end of behavioral treatment, odds of abstinence among participants receiving DT were 6.46 times greater than among participants receiving ST (66.7% vs. 31.8%), equivalent to a medium- to large-effect size. Odds of abstinence for DT were still 1.73 times greater at 8 weeks, corresponding to a small- to medium-effect size, although neither this difference nor those at 13 and 26 weeks were statistically significant. Furthermore, of those who lapsed to smoking during the first week postquit, DT participants had more than 4 times greater odds of abstinence than ST participants at the end of treatment. Relative to ST, DT participants also reported a larger decrease in experiential avoidance, a hypothesized DT treatment mediator, prior to quit day. The trajectory of negative mood and withdrawal symptoms in DT differed from ST and was largely consistent with hypotheses. Conclusions: Reasons for the decrease in abstinence in DT after treatment discontinuation and suggestions for future research are discussed. PMID:23884317

  13. Fault tolerant magnetic bearings

    SciTech Connect

    Maslen, E.H.; Sortore, C.K.; Gillies, G.T.; Williams, R.D.; Fedigan, S.J.; Aimone, R.J.

    1999-07-01

    A fault tolerant magnetic bearing system was developed and demonstrated on a large flexible-rotor test rig. The bearing system comprises a high speed, fault tolerant digital controller, three high capacity radial magnetic bearings, one thrust bearing, conventional variable reluctance position sensors, and an array of commercial switching amplifiers. Controller fault tolerance is achieved through a very high speed voting mechanism which implements triple modular redundancy with a powered spare CPU, thereby permitting failure of up to three CPU modules without system failure. Amplifier/cabling/coil fault tolerance is achieved by using a separate power amplifier for each bearing coil and permitting amplifier reconfiguration by the controller upon detection of faults. This allows hot replacement of failed amplifiers without any system degradation and without providing any excess amplifier kVA capacity over the nominal system requirement. Implemented on a large (2440 mm in length) flexible rotor, the system shows excellent rejection of faults including the failure of three CPUs as well as failure of two adjacent amplifiers (or cabling) controlling an entire stator quadrant.

  14. Tolerant (parallel) Programming

    NASA Technical Reports Server (NTRS)

    DiNucci, David C.; Bailey, David H. (Technical Monitor)

    1997-01-01

    In order to be truly portable, a program must be tolerant of a wide range of development and execution environments, and a parallel program is just one which must be tolerant of a very wide range. This paper first defines the term "tolerant programming", then describes many layers of tools to accomplish it. The primary focus is on F-Nets, a formal model for expressing computation as a folded partial-ordering of operations, thereby providing an architecture-independent expression of tolerant parallel algorithms. For implementing F-Nets, Cooperative Data Sharing (CDS) is a subroutine package for implementing communication efficiently in a large number of environments (e.g. shared memory and message passing). Software Cabling (SC), a very-high-level graphical programming language for building large F-Nets, possesses many of the features normally expected from today's computer languages (e.g. data abstraction, array operations). Finally, L2(sup 3) is a CASE tool which facilitates the construction, compilation, execution, and debugging of SC programs.

  15. Constitutive Expression of Rice MicroRNA528 Alters Plant Development and Enhances Tolerance to Salinity Stress and Nitrogen Starvation in Creeping Bentgrass1[OPEN

    PubMed Central

    Yuan, Shuangrong; Li, Zhigang; Li, Dayong; Yuan, Ning; Hu, Qian; Luo, Hong

    2015-01-01

    MicroRNA528 (miR528) is a conserved monocot-specific small RNA that has the potential of mediating multiple stress responses. So far, however, experimental functional studies of miR528 are lacking. Here, we report that overexpression of a rice (Oryza sativa) miR528 (Osa-miR528) in transgenic creeping bentgrass (Agrostis stolonifera) alters plant development and improves plant salt stress and nitrogen (N) deficiency tolerance. Morphologically, miR528-overexpressing transgenic plants display shortened internodes, increased tiller number, and upright growth. Improved salt stress resistance is associated with increased water retention, cell membrane integrity, chlorophyll content, capacity for maintaining potassium homeostasis, CATALASE activity, and reduced ASCORBIC ACID OXIDASE (AAO) activity; while enhanced tolerance to N deficiency is associated with increased biomass, total N accumulation and chlorophyll synthesis, nitrite reductase activity, and reduced AAO activity. In addition, AsAAO and COPPER ION BINDING PROTEIN1 are identified as two putative targets of miR528 in creeping bentgrass. Both of them respond to salinity and N starvation and are significantly down-regulated in miR528-overexpressing transgenics. Our data establish a key role that miR528 plays in modulating plant growth and development and in the plant response to salinity and N deficiency and indicate the potential of manipulating miR528 in improving plant abiotic stress resistance. PMID:26224802

  16. Constitutive Expression of Rice MicroRNA528 Alters Plant Development and Enhances Tolerance to Salinity Stress and Nitrogen Starvation in Creeping Bentgrass.

    PubMed

    Yuan, Shuangrong; Li, Zhigang; Li, Dayong; Yuan, Ning; Hu, Qian; Luo, Hong

    2015-09-01

    MicroRNA528 (miR528) is a conserved monocot-specific small RNA that has the potential of mediating multiple stress responses. So far, however, experimental functional studies of miR528 are lacking. Here, we report that overexpression of a rice (Oryza sativa) miR528 (Osa-miR528) in transgenic creeping bentgrass (Agrostis stolonifera) alters plant development and improves plant salt stress and nitrogen (N) deficiency tolerance. Morphologically, miR528-overexpressing transgenic plants display shortened internodes, increased tiller number, and upright growth. Improved salt stress resistance is associated with increased water retention, cell membrane integrity, chlorophyll content, capacity for maintaining potassium homeostasis, CATALASE activity, and reduced ASCORBIC ACID OXIDASE (AAO) activity; while enhanced tolerance to N deficiency is associated with increased biomass, total N accumulation and chlorophyll synthesis, nitrite reductase activity, and reduced AAO activity. In addition, AsAAO and COPPER ION BINDING PROTEIN1 are identified as two putative targets of miR528 in creeping bentgrass. Both of them respond to salinity and N starvation and are significantly down-regulated in miR528-overexpressing transgenics. Our data establish a key role that miR528 plays in modulating plant growth and development and in the plant response to salinity and N deficiency and indicate the potential of manipulating miR528 in improving plant abiotic stress resistance.

  17. Overexpression of rice NAC gene SNAC1 improves drought and salt tolerance by enhancing root development and reducing transpiration rate in transgenic cotton.

    PubMed

    Liu, Guanze; Li, Xuelin; Jin, Shuangxia; Liu, Xuyan; Zhu, Longfu; Nie, Yichun; Zhang, Xianlong

    2014-01-01

    The SNAC1 gene belongs to the stress-related NAC superfamily of transcription factors. It was identified from rice and overexpressed in cotton cultivar YZ1 by Agrobacterium tumefaciens-mediated transformation. SNAC1-overexpressing cotton plants showed more vigorous growth, especially in terms of root development, than the wild-type plants in the presence of 250 mM NaCl under hydroponic growth conditions. The content of proline was enhanced but the MDA content was decreased in the transgenic cotton seedlings under drought and salt treatments compared to the wild-type. Furthermore, SNAC1-overexpressing cotton plants also displayed significantly improved tolerance to both drought and salt stresses in the greenhouse. The performances of the SNAC1-overexpressing lines under drought and salt stress were significantly better than those of the wild-type in terms of the boll number. During the drought and salt treatments, the transpiration rate of transgenic plants significantly decreased in comparison to the wild-type, but the photosynthesis rate maintained the same at the flowering stage in the transgenic plants. These results suggested that overexpression of SNAC1 improve more tolerance to drought and salt in cotton through enhanced root development and reduced transpiration rates.

  18. The NLRP3 Inflammasome Is Required for the Development of Hypoxemia in LPS/Mechanical Ventilation Acute Lung Injury

    PubMed Central

    Jones, Heather D.; Crother, Timothy R.; Gonzalez-Villalobos, Romer A.; Jupelli, Madhulika; Chen, Shuang; Dagvadorj, Jargalsaikhan; Shimada, Kenichi

    2014-01-01

    IL-1β is a potent proinflammatory cytokine that is implicated in the pathogenesis of acute respiratory distress syndrome. We hypothesized that LPS and mechanical ventilation (MV) together could lead to IL-1β secretion and the development of acute lung injury (ALI), and that this process would be dependent on caspase-1 and the nucleotide binding domain and leucine-rich repeat (NLR) pyrin domain containing 3 (NLRP3) inflammasome activation. The objectives of this study were to determine the specific role of IL-1β, caspase-1, and the NLRP3 inflammasome in a two-hit model of ALI due to LPS plus MV. We used a two-hit murine model of ALI in which both inhaled LPS and MV were required for the development of hypoxemia, pulmonary neutrophil infiltration, and alveolar leakage. Nlrp3-deficent and Casp1-deficient mice had significantly diminished IL-1β levels in bronchoalveolar lavage fluid, and were specifically protected from hypoxemia, despite similar alveolar neutrophil infiltration and leakage. The IL-1 receptor antagonist, Anakinra, significantly improved the specific development of hypoxemia without significant effects on neutrophil infiltration or alveolar leakage. MV resulted in increased bronchoalveolar lavage extracellular ATP and alveolar macrophage apoptosis as triggers of NLRP3 inflammasome activation. NLRP3 inflammasome activation and IL-1β production play a key role in ALI caused by the combination of LPS and MV, particularly in the hypoxemia associated with acute respiratory distress syndrome. Blocking IL-1 signaling in this model specifically ameliorates hypoxemia, without affecting neutrophil infiltration and alveolar leakage, disassociating these readouts of ALI. MV causes alveolar macrophage apoptosis, a key step in the activation of NLRP3 inflammasome and production of IL-1β. PMID:24007300

  19. Joint Influence of Protein Supplements, Soft Drinks and Extreme Physical Activity on the Development of Acute Renal Failure and Hypokalaemia.

    PubMed

    Djordjevic, S; Kitic, D; Kostic, M; Apostolovic, B; Brankovic, S; Ciric, I M; Velickovic-Radovanovic, R

    2015-11-13

    We present a case of a 33-year old man who complained of weakness, fever and decreased urinating. A personal history revealed a consumption of creatine, protein supplements, soft drinks containing caffeine and stevia, and extreme physical activity which included lifting of heavy weights. The patient developed anuria, uraemia, fatigue, rhabdomyolysis and paradoxical hypokalaemia. After the patient had seven successive dialysis treatments, normal kidney function was restored. The report presents the first case of acute renal failure followed by hypokalaemia due to the combined action of the excessive consumption of supplements, soft drinks with stevia and caffeine, and extreme physical activity.

  20. Interrupted development of dentition in children receiving bone marrow transplantation for acute lymphocytic Leukemia: a case series.

    PubMed

    Rowland, Chris; Kaste, Sue; Owens, Amber

    2013-01-01

    This case series depicts dental anomalies that may develop in children who have undergone bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL). The most common finding in these patients was root stunting; other abnormalities included microdontia, hypodontia, taurodontia, caries, enamel pearls, and pulpal calcification. Recognition of these adverse effects of BMT on odontogenesis, as demonstrated on panoramic radiograph images, will allow healthcare providers to explain to parents and patients the possible dental outcomes associated with BMT and to optimize their dental health regimen.

  1. Methodological issues in current practice may lead to bias in the development of biomarker combinations for predicting acute kidney injury

    PubMed Central

    Meisner, Allison; Kerr, Kathleen F.; Thiessen-Philbrook, Heather; Coca, Steven G.; Parikh, Chirag R.

    2015-01-01

    Individual biomarkers of renal injury are only modestly predictive of acute kidney injury (AKI). Using multiple biomarkers has the potential to improve predictive capacity. In this systematic review, statistical methods of articles developing biomarker combinations to predict acute kidney injury were assessed. We identified and described three potential sources of bias (resubstitution bias, model selection bias and bias due to center differences) that may compromise the development of biomarker combinations. Fifteen studies reported developing kidney injury biomarker combinations for the prediction of AKI after cardiac surgery (8 articles), in the intensive care unit (4 articles) or other settings (3 articles). All studies were susceptible to at least one source of bias and did not account for or acknowledge the bias. Inadequate reporting often hindered our assessment of the articles. We then evaluated, when possible (7 articles), the performance of published biomarker combinations in the TRIBE-AKI cardiac surgery cohort. Predictive performance was markedly attenuated in six out of seven cases. Thus, deficiencies in analysis and reporting are avoidable and care should be taken to provide accurate estimates of risk prediction model performance. Hence, rigorous design, analysis and reporting of biomarker combination studies are essential to realizing the promise of biomarkers in clinical practice. PMID:26398494

  2. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL.

    PubMed

    Rego, Eduardo M; Kim, Haesook T; Ruiz-Argüelles, Guillermo J; Undurraga, Maria Soledad; Uriarte, Maria del Rosario; Jacomo, Rafael H; Gutiérrez-Aguirre, Homero; Melo, Raul A M; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Fagundes, Evandro M; Chauffaille, Maria de Lourdes; Chiattone, Carlos S; Martinez, Lem; Meillón, Luis A; Gómez-Almaguer, David; Kwaan, Hau C; Garcés-Eisele, Javier; Gallagher, Robert; Niemeyer, Charlotte M; Schrier, Stanley L; Tallman, Martin; Grimwade, David; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C; Lo-Coco, Francesco; Löwenberg, Bob; Sanz, Miguel A

    2013-03-14

    Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries.

  3. Reduced salinity tolerance in the Arctic grayling (Thymallus arcticus) is associated with rapid development of a gill interlamellar cell mass: implications of high-saline spills on native freshwater salmonids

    PubMed Central

    Blair, Salvatore D.; Matheson, Derrick; He, Yuhe; Goss, Greg G.

    2016-01-01

    Arctic grayling (Thymallus arcticus) are salmonids that have a strict freshwater existence in post-glacial North America. Oil and gas development is associated with production of high volumes of hypersaline water. With planned industrial expansion into northern areas of Canada and the USA that directly overlap grayling habitat, the threat of accidental saline water release poses a significant risk. Despite this, we understand little about the responses of grayling to hypersaline waters. We compared the physiological responses and survivability of Arctic grayling and rainbow trout (Oncorhynchus mykiss) to tolerate an acute transfer to higher saline waters. Arctic grayling and rainbow trout were placed directly into 17 ppt salinity and sampled at 24 and 96 h along with control animals in freshwater at 24 h. Serum sodium, chloride and osmolality levels increased significantly in grayling at both 24 and 96 h time points, whereas trout were able to compensate for the osmoregulatory disturbance by 96 h. Sodium–potassium ATPase mRNA expression responses to salinity were also compared, demonstrating the inability of the grayling to up-regulate the seawater isoform nkaα1b. Our results demonstrated a substantially lower salinity tolerance in grayling. We also found a significant salinity-induced morphological gill remodelling by Arctic grayling, as demonstrated by the rapid growth of an interlamellar cell mass by 24 h that persisted at 96 h. We visualized and quantified the appearance of the interlamellar cell mass as a response to high salinity, although the functional significance remains to be understood fully. Compared with rainbow trout, which are used as an environmental regulatory species, Arctic grayling are unable to compensate for the osmotic stressors that would result from a highly saline produced water spill. Given these new data, collaboration between fisheries and the oil and gas industry will be vital in the long-term conservation strategies

  4. 76 FR 82157 - Difenoconazole; Pesticide Tolerances

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-30

    ... sensitizer. Subchronic and chronic studies with difenoconazole in mice and rats showed decreased body weights, decreased body weight gains and effects on the liver. In an acute neurotoxicity study in rats, reduced fore... tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES: This regulation is...

  5. Iron Tolerant Cyanobacteria as an Effective Tool to Study Early Evolution of Life and the Development of Biosignatures

    NASA Technical Reports Server (NTRS)

    Brown, Igor; Mummey, Daniel; Sarkisova, Svetlana; Allen, Carlton; McKay, David S.

    2006-01-01

    We are currently conducting preliminary studies on the diversity of iron-tolerant cyanobacteria (CB) isolated from iron-depositing hot springs in and around Yellowstone National Park (WY, USA). In conclusion, there is no consensus on the divergence of cyanobacteria from a common ancestor for either anoxygenic or oxygenic phototrophs. Anoxygenic photosynthesis may have provided energy for the common ancestor, but it is unclear what environmental pressure induced the evolving of oxygenic phototrophs. It is supposed, however, that predecessors of contemporary CB were capable of oxidizing various substrates other than water , and it is likely that Fe2+ could be one of those substrates . If that were the case, the work of entire photosystems in Precambrian cyanobacteria and/or in their predecessors could follow three scenarios (at least): 1) ferrous iron may have been oxidized in PS II but without significant effects on oxygen evolution, and environmental iron could have been oxidized either enzymatically or chemically; 2) ferrous iron may have been oxidized only enzymatically by PS II, accompanied by the repression of O2 evolution; or 3) ferrous iron may have been oxidized by PS I upon the prevalence of anoxygenic photosynthesis or without any effect on PS II. All of these scenarios will be the subject of our future studies with the aim to understand which line-ages of CB could be typical for Precambrian time.

  6. Development and evaluation of a Fault-Tolerant Multiprocessor (FTMP) computer. Volume 3: FTMP test and evaluation

    NASA Technical Reports Server (NTRS)

    Lala, J. H.; Smith, T. B., III

    1983-01-01

    The experimental test and evaluation of the Fault-Tolerant Multiprocessor (FTMP) is described. Major objectives of this exercise include expanding validation envelope, building confidence in the system, revealing any weaknesses in the architectural concepts and in their execution in hardware and software, and in general, stressing the hardware and software. To this end, pin-level faults were injected into one LRU of the FTMP and the FTMP response was measured in terms of fault detection, isolation, and recovery times. A total of 21,055 stuck-at-0, stuck-at-1 and invert-signal faults were injected in the CPU, memory, bus interface circuits, Bus Guardian Units, and voters and error latches. Of these, 17,418 were detected. At least 80 percent of undetected faults are estimated to be on unused pins. The multiprocessor identified all detected faults correctly and recovered successfully in each case. Total recovery time for all faults averaged a little over one second. This can be reduced to half a second by including appropriate self-tests.

  7. Glucose tolerance in depressed inpatients, under treatment with mirtazapine and in healthy controls.

    PubMed

    Hennings, J M; Ising, M; Grautoff, S; Himmerich, H; Pollmächer, T; Schaaf, L

    2010-02-01

    Impaired glucose tolerance and diabetes have been associated with depression, and antidepressant treatment is assumed to improve impaired glucose tolerance. However, antidepressant treatment is also considered as a risk factor for the development of diabetes. Reports about glucose tolerance under antidepressant treatment frequently lack appropriate control groups. We conducted the oral glucose tolerance test (OGTT) in 10 healthy controls selected from an epidemiological sample with a negative lifetime history of mental Axis I disorder. Controls were carefully matched to a sample of inpatients with major depression that participated in an OGTT before and after antidepressant treatment with mirtazapine. All participants underwent a standard OGTT protocol. In patients, a second (after 2 weeks) and a third (after 4-6 weeks) OGTT was performed under treatment with mirtazapine. Compared to healthy controls, we observed significantly impaired glucose tolerance in acutely depressed patients. Effect size calculation indicated a moderate to large effects on glucose and insulin concentrations in response to an OGTT. Although glucose tolerance improved under mirtazapine treatment, insulin sensitivity was still impaired and remained significantly lower in patients compared to controls.

  8. Non-invasive ventilation for children with acute respiratory failure in the developing world: literature review and an implementation example.

    PubMed

    Balfour-Lynn, R E; Marsh, G; Gorayi, D; Elahi, E; LaRovere, J

    2014-06-01

    Over 2 million children die of acute respiratory infection every year, with around 98% of these deaths occurring in developing countries. Depending upon the clinical status of the patient, supplemental oxygen is usually the first line therapy. However this often proves inadequate for acute respiratory failure (ARF), in which case intubation and mechanical positive pressure ventilation are required. Adult intensive care successfully introduced non-invasive positive pressure ventilation (NIPPV) to treat ARF over a decade ago. This experience, coupled with the use of NIPPV in children with chronic respiratory insufficiency, has led to increasing use of NIPPV to treat ARF in paediatric populations. NIPPV can have similar or improved outcomes to IPPV, but with fewer complications. However there are no controlled trials of its use in children, and most data come from observational studies and retrospective reviews. In a developing world setting, where mortality from ARF is high and the risks of intubation are great and often not feasible, NIPPV can be a simple and cost-effective way to treat these patients. Its implementation in rural Northern Ghana shows NIPPV for ARF can be delivered safely with minimal training, and appears to impact significantly on mortality in those under 5 years.

  9. Development and Application of Acute Exposure Guideline Levels (AEGLs) for Chemical Warfare Nerve and Sulfur Mustard Agents.

    SciTech Connect

    Watson, Annetta Paule; Opresko, Dennis M; Young, Robert A; Hauschild, Veronique

    2006-01-01

    Acute exposure guideline levels (AEGLs) have been developed for the chemical warfare agents GB, GA, GD, GF, VX, and sulfur mustard. These AEGLs were approved by the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances after Federal Register publication and comment, and judged as scientifically valid by the National Research Council Committee on Toxicology Subcommittee on AEGLs. AEGLs represent general public exposure limits for durations ranging from 10 min to 8 h, and for three levels of severity (AEGL-1, AEGL-2, AEGL-3). Mild effects are possible at concentrations greater than AEGL-1, while life-threatening effects are expected at concentrations greater than AEGL-3. AEGLs can be applied to various civilian and national defense purposes, including evacuation and shelter-in-place protocols, reentry levels, protective clothing specifications, and analytical monitoring requirements. This report documents development and derivation of AEGL values for six key chemical warfare agents, and makes recommendations for their application to various potential exposure scenarios.

  10. Clinical decision rule for primary care patient with acute low back pain at risk of developing chronic pain

    PubMed Central

    Mehling, Wolf E.; Ebell, Mark H.; Avins, Andrew L.; Hecht, Frederick M.

    2015-01-01

    Background Context Primary care clinicians need to identify candidates for early interventions to prevent patients with acute pain from developing chronic pain. Purpose We conducted a 2-year prospective cohort study of risk factors for the progression to chronic pain and developed and internally validated a clinical decision rule (CDR) that stratifies patients into low, medium and high-risk groups for chronic pain. Study Design/Setting Prospective cohort study in primary care. Patient Sample Patients with acute low back pain (LBP; ≤30 days duration) Outcome measures Self-reported perceived non-recovery and chronic pain. Methods Patients were surveyed at baseline, 6 months and 2 years. We conducted bivariate and multivariate regression analyses of demographic, clinical and psychosocial variables for chronic pain outcomes, developed a CDR and assessed its performance by calculating the bootstrapped areas under the receiver operating characteristic curve (AUC) and likelihood ratios. This study was supported by NIH/NCCAM grants K23 AT002298, R21 AT004467, NIH/NCCAM K24 AT007827, the Research Evaluation and Allocation Committee (REAC) of the University of California San Francisco, and the Mount Zion Health Fund, San Francisco. The funding agencies played no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors report no conflict of interests. Results 605 patients enrolled. 13% had chronic pain at 6 months, 19% at 2 years. An eight-item CDR was most parsimonious for classifying patients into three risk levels. Bootstrapped AUC was 0.76 (0.70–0.82) for the 6-month CDR. Each 10-point score increase (60-point range) was associated with an odds ratio of 11.1 (10.8–11.4) for developing chronic pain. Using a <5% probability of chronic pain as the cutoff for low risk and a >40% probability for high risk, likelihood ratios were 0.26 (0.14–0.48) and 4

  11. Prospects and strategies for clinical tolerance.

    PubMed

    Monaco, A P

    2004-01-01

    The morbidity and mortality associated with chronic immunosuppression provide a strong motivation for development of clinical tolerance. This paper discusses the definition(s) of clinical (operational) tolerance, the role of chimerism in experimental and clinical tolerance, and the special role of bone marrow in tolerance induction. The states of microchimerism and macrochimerism are defined and related to certain clinical observations in solid organ transplantation. Current clinical strategies already being tested in the clinic are briefly reviewed. Certain principles for induction of clinical (operational) tolerance are elaborated.

  12. 75 FR 32490 - Issues in the Development of Medical Products for the Prophylaxis and/or Treatment of Acute...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-08

    ... Prophylaxis and/or Treatment of Acute Antibody Mediated Rejection in Kidney Transplant Recipients; Public... prophylaxis and/or treatment of acute antibody mediated rejection (AMR) in kidney transplant recipients....

  13. Developments in mechanical thrombectomy devices for the treatment of acute ischemic stroke.

    PubMed

    Mordasini, Pasquale; Gralla, Jan

    2016-01-01

    Several recent prospective randomized controlled trials of endovascular stroke therapy using latest generation thrombectomy devices, so called stent-retrievers, have shown significantly improved clinical outcome compared to the standard treatment with intra-venous thrombolysis using r-tPA alone. Despite some differences in inclusion criteria between these studies, all required non-invasive vessel imaging to proof occlusion of a major brain supplying vessel. Furthermore, in most studies additional imaging techniques were used to exclude patients with already established large cerebral infarction or unfavorable collateral or penumbral status. Patients with small infarct volume, severe neurological deficits and in whom thrombectomy can be initiated within the first 6 hours after symptom onset seem to benefit the most. Therefore, mechanical thrombectomy using stent-retrievers in addition to intra-venous thrombolysis is recommended for the treatment of acute ischemic stroke with proven major vessel occlusion in the anterior circulation.

  14. Transfusion-related acute lung injury (TRALI): A Canadian blood services research and development symposium.

    PubMed

    Saidenberg, Elianna; Petraszko, Tanya; Semple, Elisabeth; Branch, Donald R

    2010-10-01

    Since the first description of transfusion-related acute lung injury (TRALI) more than 2 decades ago, we have only recently begun to learn how this disorder may occur and how to prevent it. Scientists from around the world have made great strides in identifying the possible causes of this condition. Blood banks and transfusion services have risen to the challenges of prevention. Recent introduction of restricting most plasma products to those obtained from male donors only has greatly reduced the incidence of TRALI worldwide. Scientists have recently identified the gene and protein for the human neutrophil antigen-3a associated with most mortality due to TRALI, and this presents an opportunity for a screening assay to prevent future TRALI-associated deaths. Finally, animal models of TRALI have provided insight into the possible mechanisms of this disorder and can be used to explore potential treatment modalities.

  15. Fault tolerant control laws

    NASA Technical Reports Server (NTRS)

    Ly, U. L.; Ho, J. K.

    1986-01-01

    A systematic procedure for the synthesis of fault tolerant control laws to actuator failure has been presented. Two design methods were used to synthesize fault tolerant controllers: the conventional LQ design method and a direct feedback controller design method SANDY. The latter method is used primarily to streamline the full-state Q feedback design into a practical implementable output feedback controller structure. To achieve robustness to control actuator failure, the redundant surfaces are properly balanced according to their control effectiveness. A simple gain schedule based on the landing gear up/down logic involving only three gains was developed to handle three design flight conditions: Mach .25 and Mach .60 at 5000 ft and Mach .90 at 20,000 ft. The fault tolerant control law developed in this study provides good stability augmentation and performance for the relaxed static stability aircraft. The augmented aircraft responses are found to be invariant to the presence of a failure. Furthermore, single-loop stability margins of +6 dB in gain and +30 deg in phase were achieved along with -40 dB/decade rolloff at high frequency.

  16. A Glycine soja 14-3-3 protein GsGF14o participates in stomatal and root hair development and drought tolerance in Arabidopsis thaliana.

    PubMed

    Sun, Xiaoli; Luo, Xiao; Sun, Mingzhe; Chen, Chao; Ding, Xiaodong; Wang, Xuedong; Yang, Shanshan; Yu, Qingyue; Jia, Bowei; Ji, Wei; Cai, Hua; Zhu, Yanming

    2014-01-01

    It is well established that 14-3-3 proteins are key regulators of multiple stress signal transduction cascades. However, the biological functions of soybean 14-3-3 proteins, especially in plant drought response, are not yet known. In this study, we characterized a Glycine soja 14-3-3 gene, GsGF14o, which is involved in plant development and drought response. GsGF14o expression was greatly induced by drought stress, as evidenced by the quantitative real-time PCR and β-glucuronidase (GUS) activity analysis. GsGF14o overexpression in Arabidopsis thaliana resulted in decreased drought tolerance during seed germination and seedling growth. Furthermore, silencing of AtGF14µ, the most homologous 14-3-3 gene of GsGF14o, led to enhanced drought tolerance at both the seed germination and seedling stage. Unexpectedly, GsGF14o transgenic lines showed reduced water loss and transpiration rates compared with wild-type plants, which was demonstrated to be the consequence of the decreased stomatal size. At the same time, the smaller stomata due to GsGF14o overexpression led to a relatively slow net photosynthesis rate, which led to a growth penalty under drought stress. We further demonstrated that GsGF14o overexpression caused deficits in root hair formation and development, and thereby reduced the water intake capacity of the transgenic root system. In addition, GsGF14o overexpression down-regulated the transcript levels of drought-responsive marker genes. Finally, we also investigated the tissue-specific accumulation of GsGF14o by using a GUS activity assay. Collectively, the results presented here confirm that GsGF14o plays a dual role in drought stress responses through its involvement in the regulation of stomatal size and root hair development.

  17. Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation.

    PubMed

    Wong, Simon S; Sun, Nina N; Lantz, R Clark; Witten, Mark L

    2004-10-01

    To characterize the tachykininergic effects in fire smoke (FS)-induced acute respiratory distress syndrome (ARDS), we designed a series of studies in rats. Initially, 20 min of FS inhalation induced a significant increase of substance P (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after insult. Conversely, FS disrupted 51.4, 55.6, 46.3, and 43.0% enzymatic activity of neutral endopeptidase (NEP, a primary hydrolyzing enzyme for SP) 1, 6, 12, and 24 h after insult, respectively. Immunolabeling density of NEP in the airway epithelium largely disappeared 1 h after insult due to acute cell damage and shedding. These changes were also accompanied by extensive influx of albumin and granulocytes/lymphocytes in BALF. Furthermore, levels of BALF SP and tissue NEP activity dose dependently increased and decreased, respectively, following 0, low (10 min), and high (20 min) levels of FS inhalation. However, neither the time-course nor the dose-response study observed a significant change in the highest affinity neurokinin-1 receptor (NK-1R) for SP. Finally, treatment (10 mg/kg im) with SR-140333B, an NK-1R antagonist, significantly prevented 20-min FS-induced hypoxemia and pulmonary edema 24 h after insult. Further examination indicated that SR-140333B (1.0 or 10.0 mg/kg im) fully abolished early (1 h) plasma extravasation following FS. Collectively, these findings suggest that a combination of sustained SP and NEP inactivity induces an exaggerated neurogenic inflammation mediated by NK-1R, which may lead to an uncontrolled influx of protein-rich edema fluid and cells into the alveoli as a consequence of increased vascular permeability.

  18. Arpin contributes to bacterial translocation and development of severe acute pancreatitis

    PubMed Central

    Deng, Wen-Sheng; Zhang, Jian; Ju, Hui; Zheng, Hong-Mei; Wang, Jiang; Wang, Su; Zhang, Dian-Liang

    2015-01-01

    AIM: To assess the impact of Arpin protein and tight junction (TJ) proteins in the intestinal mucosa on bacterial translocation in patients with severe acute pancreatitis (SAP). METHODS: Fifty SAP patients were identified as study objects and then classified into two groups according to the presence of bacterial translocation (BT) in the blood [i.e., BT(+) and BT(-)]. Twenty healthy individuals were included in the control group. BT was analyzed by polymerase chain reaction, colonic mucosal tissue was obtained by endoscopy and the expression of TJ proteins and Arpin protein was determined using immunofluorescence and western blotting. RESULTS: Bacterial DNA was detected in the peripheral blood of 62.0% of patients (31/50) with SAP. The expression of TJ proteins in SAP patients was lower than that in healthy controls. In contrast, Arpin protein expression in SAP patients was higher than in healthy controls (0.38 ± 0.19 vs 0.28 ± 0.16, P < 0.05). Among SAP patients, those positive for BT showed a higher level of claudin-2 expression (0.64 ± 0.27 vs 0.32 ± 0.21, P < 0.05) and a lower level of occludin (OC) (0.61 ± 0.28 vs 0.73 ± 0.32, P < 0.05) and zonula occludens-1 (0.42 ± 0.26 vs 0.58 ± 0.17, P = 0.038) expression in comparison with BT (-) patients. Moreover, the level of Arpin expression in BT (+) patients was higher than in BT (-) patients (0.61 ± 0.28 vs 0.31 ± 0.24, P < 0.05). CONCLUSION: Arpin protein affects the expression of tight junction proteins and may have an impact on BT. These results contribute to a better understanding of the factors involved in bacterial translocation during acute pancreatitis. PMID:25892881

  19. Developing complex interventions: lessons learned from a pilot study examining strategy training in acute stroke rehabilitation

    PubMed Central

    Skidmore, Elizabeth R.; Dawson, Deirdre R.; Whyte, Ellen M.; Butters, Meryl A.; Dew, Mary Amanda; Grattan, Emily S.; Becker, James T.; Holm, Margo B.

    2013-01-01

    Objective To examine the feasibility of a strategy training clinical trial in a small group of adults with stroke-related cognitive impairments in inpatient rehabilitation, and to explore the impact of strategy training on disability. Design Non-randomized two-group intervention pilot study Setting Two inpatient rehabilitation units within an academic health center Participants Individuals with a primary diagnosis of acute stroke, who were admitted to inpatient rehabilitation and demonstrated cognitive impairments were included. Individuals with severe aphasia; dementia; major depressive disorder, bipolar, or psychotic disorder; recent drug or alcohol abuse; and anticipated length of stay less than 5 days were excluded. Intervention Participants received strategy training or an attention control session in addition to usual rehabilitation care. Sessions in both groups were 30–40 minutes daily, 5 days per week, for the duration of inpatient rehabilitation. Main Outcome Measures We assessed feasibility through participants’ recruitment and retention; research intervention session number and duration; participants’ comprehension and engagement; intervention fidelity; and participants’ satisfaction. We assessed disability at study admission, inpatient rehabilitation discharge, 3 and 6 months using the Functional Independence Measure. Results Participants in both groups (5 per group) received the assigned intervention (>92% planned sessions; >94% fidelity) and completed follow-up testing. Strategy training participants in this small sample demonstrated significantly less disability at 6 months [M(SE)=117 (3)] than attention control participants [M(SE)=96 (14); t8=7.87, p=.02]. Conclusions It is feasible and acceptable to administer both intervention protocols as an adjunct to acute inpatient rehabilitation, and strategy training shows promise for reducing disability. PMID:24113727

  20. Damage Tolerance Assessment Branch

    NASA Technical Reports Server (NTRS)

    Walker, James L.

    2013-01-01

    The Damage Tolerance Assessment Branch evaluates the ability of a structure to perform reliably throughout its service life in the presence of a defect, crack, or other form of damage. Such assessment is fundamental to the use of structural materials and requires an integral blend of materials engineering, fracture testing and analysis, and nondestructive evaluation. The vision of the Branch is to increase the safety of manned space flight by improving the fracture control and the associated nondestructive evaluation processes through development and application of standards, guidelines, advanced test and analytical methods. The Branch also strives to assist and solve non-aerospace related NDE and damage tolerance problems, providing consultation, prototyping and inspection services.

  1. Abuse Tolerance Improvements

    SciTech Connect

    Orendorff, Christopher J.; Nagasubramanian, Ganesan; Fenton, Kyle R.; Allcorn, Eric

    2015-10-01

    As lithium-ion battery technologies mature, the size and energy of these systems continues to increase (> 50 kWh for EVs); making safety and reliability of these high energy systems increasingly important. While most material advances for lithium-ion chemistries are directed toward improving cell performance (capacity, energy, cycle life, etc.), there are a variety of materials advancements that can be made to improve lithium-ion battery safety. Issues including energetic thermal runaway, electrolyte decomposition and flammability, anode SEI stability, and cell-level abuse tolerance continue to be critical safety concerns. This report highlights work with our collaborators to develop advanced materials to improve lithium-ion battery safety and abuse tolerance and to perform cell-level characterization of new materials.

  2. Development and Evaluation of New Products for the Far-Forward Care of Combat Casualties With Acute Lung Injury

    DTIC Science & Technology

    2005-02-01

    acute respiratory distress syndrome ( ARDS ) caused by chlorine gas (C12). Background: Toxic industrial chemicals (TICs) have recently been identified as...Batchinsky A, Cancio L. An ovine model of acute respiratory distress syndrome ( ARDS ) secondary to inhalation of chlorine gas. Veterinary Pathology, 2004;41...TERMS 15. NUMBER OF PAGES 27 Chlorine, acute respiratory distress syndrome , inhalation injury 16. PRICECODE 17. SECURITY

  3. Environmental modification of tolerance to morphine discriminative stimulus properties in rats.

    PubMed

    Sannerud, C A; Young, A M

    1987-01-01

    The development of tolerance to the discriminative stimulus properties of morphine was examined in rats trained to discriminate saline and 3.2 mg/kg morphine under a multiple timeout 15 min, 5 min fixed-ratio 30 schedule of food delivery. Generalization gradients were generated by administering increasing doses of morphine before successive timeout periods within the experimental session. Over the course of the study, the minimal discriminable dose (MDD) of morphine under control conditions fluctuated but did not systematically increase or decrease. Acute pretreatments of 3.2-17.8 mg/kg morphine 4-24 h before a generalization test resulted in minor changes in the MDD. To examine development of tolerance, supplemental doses of morphine (17.8 mg/kg) or saline were administered twice daily while discrimination training was either suspended or continued. Tolerance was assessed by weekly generalization tests. Greater tolerance developed to the morphine stimulus when training was suspended than when training was continued. For both training conditions, response rates during generalization tests were markedly suppressed during supplemental morphine administration, and original generalization gradients were recaptured within 2 weeks after termination of supplemental morphine administration. Supplemental saline administration did not alter the discriminative or rate-altering effects of morphine under either training condition. Thus, the magnitude of tolerance to a morphine discriminative stimulus reflected an interaction of supplemental drug treatment with the training conditions imposed during that treatment.

  4. 'Did He Who Made the Lamb Make Thee?' New Developments in Treating the 'Fearful Symmetry' of Acute Myeloid Leukemia.

    PubMed

    Brumatti, Gabriela; Lalaoui, Najoua; Wei, Andrew H; Silke, John

    2017-03-01

    Malignant cells must circumvent endogenous cell death pathways to survive and develop into cancers. Acquired cell death resistance also sets up malignant cells to survive anticancer therapies. Acute Myeloid Leukemia (AML) is an aggressive blood cancer characterized by high relapse rate and resistance to cytotoxic therapies. Recent collaborative profiling projects have led to a greater understanding of the 'fearful symmetry' of the genomic landscape of AML, and point to the development of novel potential therapies that can overcome factors linked to chemoresistance. We review here the most recent research in the genetics of AML and how these discoveries have led, or might lead, to therapies that specifically activate cell death pathways to substantially challenge this 'fearful' disease.

  5. Development of national standardized all-hazard disaster core competencies for acute care physicians, nurses, and EMS professionals.

    PubMed

    Schultz, Carl H; Koenig, Kristi L; Whiteside, Mary; Murray, Rick

    2012-03-01

    The training of medical personnel to provide care for disaster victims is a priority for the physician community, the federal government, and society as a whole. Course development for such training guided by well-accepted standardized core competencies is lacking, however. This project identified a set of core competencies and performance objectives based on the knowledge, skills, and attitudes required by the specific target audience (emergency department nurses, emergency physicians, and out-of-hospital emergency medical services personnel) to ensure they can treat the injuries and illnesses experienced by victims of disasters regardless of cause. The core competencies provide a blueprint for the development or refinement of disaster training courses. This expert consensus project, supported by a grant from the Robert Wood Johnson Foundation, incorporated an all-hazard, comprehensive emergency management approach addressing every type of disaster to minimize the effect on the public's health. An instructional systems design process was used to guide the development of audience-appropriate competencies and performance objectives. Participants, representing multiple academic and provider organizations, used a modified Delphi approach to achieve consensus on recommendations. A framework of 19 content categories (domains), 19 core competencies, and more than 90 performance objectives was developed for acute medical care personnel to address the requirements of effective all-hazards disaster response. Creating disaster curricula and training based on the core competencies and performance objectives identified in this article will ensure that acute medical care personnel are prepared to treat patients and address associated ramifications/consequences during any catastrophic event.

  6. Acute bacterial parotitis following acute stroke.

    PubMed

    Lee, V K; Kimbrough, D J; Jarquin-Valdivia, A A

    2009-06-01

    Acute bacterial parotitis (ABP) is a relatively uncommon condition that tends to occur in debilitated older patients. We report a case of an older woman that presented with an acute intracerebral hemorrhage who developed ABP. This morbidity led to endotracheal intubation, mechanical ventilation, tracheostomy and gastrostomy, all of which were not initially needed. We discuss the proposed physiopathology and etiopathogenesis of ABP in adults.

  7. Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice.

    PubMed

    Withey, Sarah L; Hill, Rob; Lyndon, Abigail; Dewey, William L; Kelly, Eamonn; Henderson, Graeme

    2017-04-01

    Respiratory depression is the major cause of death in opioid overdose. We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al., 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK). We found that although mice treated for up to 6 days with morphine developed tolerance, as measured by the reduced responsiveness to an acute challenge dose of morphine, administration of the brain-penetrant PKC inhibitors tamoxifen and calphostin C restored the ability of acute morphine to produce respiratory depression in morphine-treated mice. Importantly, reversal of opioid tolerance was dependent on the nature of the opioid ligand used to induce tolerance, as these PKC inhibitors did not reverse tolerance induced by prolonged treatment of mice with methadone nor did they reverse the protection to acute morphine-induced respiratory depression afforded by prolonged treatment with buprenorphine. We found no evidence for the involvement of JNK in morphine-induced tolerance to respiratory depression. These results indicate that PKC represents a major mechanism underlying morphine tolerance, that the mechanism of opioid tolerance to respiratory depression is ligand-dependent, and that coadministration of drugs with PKC-inhibitory activity and morphine (as well as heroin, largely metabolized to morphine in the body) may render individuals more susceptible to overdose death by reversing tolerance to the effects of morphine.

  8. The contribution of nursing data to the development of a predictive model for the detection of acute pancreatitis.

    PubMed

    Cho, In Sook; Haug, Peter J

    2006-01-01

    The increasing use of information system has resulted in the accumulation of a large volume of nursing data in electronic medical records. These data have great potential for supporting the various clinical decisions made by physicians, nurses, and managers. However, how to re-use of nursing data remains largely an issue of informatics. The aim of this study was to demonstrate how these nursing data can be used and how much they could contribute to developing a predictive model for an expert system for early detection of acute pancreatitis. We employed a probability-based model consisting of a Bayesian network and trained this model with the patient data retrospectively retrieved from the enterprise data warehouse of a tertiary hospital. The performance of the predictive model was measured based on the error rate and the area under receiver operating characteristics curve, which were 13.89 % and 0.93, respectively. The sensitivity of the acute pancreatitis to the findings from each nursing data was measured using a test of sensitivity. The results showed that the role of nursing data is as important as laboratory data in formulating a model for an expert system.

  9. The effect of rest break schedule on acute low back pain development in pain and non-pain developers during seated work.

    PubMed

    Sheahan, Peter J; Diesbourg, Tara L; Fischer, Steven L

    2016-03-01

    A significant portion of the population (25-50%) is known to develop acute low back pain (LBP) within a bout of prolonged sitting. Previous research has supported the use of frequent rest breaks, from seated office work, in order to reduce self-reported LBP, however, there is limited consensus about the recommended frequency and duration of rest breaks. This may be due to the limited consideration of individual differences in acute LBP development. The purpose of this study was to examine the effect of three different standing rest-break conditions on a group of pain developers (PD) and non-pain developers (NPD) engaged in prolonged seated work. Twenty participants completed four one-hour-long bouts of seated typing: Condition A - no rest; Condition B - 5 min of standing rest every 30 min; Condition C - 2.5 min of standing rest every 15 min; Condition D - 50 s of standing rest every 5 min. Self-reported LBP, self-reported mental fatigue and 30-s samples of EMG were collected every 10 min throughout each session. Eight out of 20 participants (40%) reported LBP during Condition A (classified as PD). Only PD demonstrated clinically relevant increases in LBP across conditions where Conditions B, C, or D provided some relief, but did not restore pain scores to their original level, prior to sitting. PD and NPD developed mental fatigue equally, with Conditions B and D helping to reduce fatigue. No differences in productivity were observed between conditions or groups and no main effects were observed for muscle activity, median power frequency or co-contraction. These data suggests that frequent, short, standing rest breaks may help to reduce symptoms of LBP, however they are only a temporary solution as PD still developed clinically important LBP, even with frequent rest breaks.

  10. Transient activation of microglia following acute alcohol exposure in developing mouse neocortex is primarily driven by BAX-dependent neurodegeneration.

    PubMed

    Ahlers, Katelin E; Karaçay, Bahri; Fuller, Leah; Bonthius, Daniel J; Dailey, Michael E

    2015-10-01

    Fetal alcohol exposure is the most common known cause of preventable mental retardation, yet we know little about how microglia respond to, or are affected by, alcohol in the developing brain in vivo. Using an acute (single day) model of moderate (3 g/kg) to severe (5 g/kg) alcohol exposure in postnatal day (P) 7 or P8 mice, we found that alcohol-induced neuroapoptosis in the neocortex is closely correlated in space and time with the appearance of activated microglia near dead cells. The timing and molecular pattern of microglial activation varied with the level of cell death. Although microglia rapidly mobilized to contact and engulf late-stage apoptotic neurons, apoptotic bodies temporarily accumulated in neocortex, suggesting that in severe cases of alcohol toxicity the neurodegeneration rate exceeds the clearance capacity of endogenous microglia. Nevertheless, most dead cells were cleared and microglia began to deactivate within 1-2 days of the initial insult. Coincident with microglial activation and deactivation, there was a transient increase in expression of pro-inflammatory factors, TNFα and IL-1β, after severe (5 g/kg) but not moderate (3 g/kg) EtOH levels. Alcohol-induced microglial activation and pro-inflammatory factor expression were largely abolished in BAX null mice lacking neuroapoptosis, indicating that microglial activation is primarily triggered by apoptosis rather than the alcohol. Therefore, acute alcohol exposure in the developing neocortex causes transient microglial activation and mobilization, promoting clearance of dead cells and tissue recovery. Moreover, cortical microglia show a remarkable capacity to rapidly deactivate following even severe neurodegenerative insults in the developing brain.

  11. Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency.

    PubMed

    Muñoz-López, Alvaro; Romero-Moya, Damià; Prieto, Cristina; Ramos-Mejía, Verónica; Agraz-Doblas, Antonio; Varela, Ignacio; Buschbeck, Marcus; Palau, Anna; Carvajal-Vergara, Xonia; Giorgetti, Alessandra; Ford, Anthony; Lako, Majlinda; Granada, Isabel; Ruiz-Xivillé, Neus; Rodríguez-Perales, Sandra; Torres-Ruíz, Raul; Stam, Ronald W; Fuster, Jose Luis; Fraga, Mario F; Nakanishi, Mahito; Cazzaniga, Gianni; Bardini, Michela; Cobo, Isabel; Bayon, Gustavo F; Fernandez, Agustin F; Bueno, Clara; Menendez, Pablo

    2016-10-11

    Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming "boosters" also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency.

  12. Large Conductance Voltage- and Ca2+-gated Potassium (BK) Channel β4 Subunit Influences Sensitivity and Tolerance to Alcohol by Altering Its Response to Kinases*

    PubMed Central

    Velázquez-Marrero, Cristina; Seale, Garrett E.; Treistman, Steven N.; Martin, Gilles E.

    2014-01-01

    Tolerance is a well described component of alcohol abuse and addiction. The large conductance voltage- and Ca2+-gated potassium channel (BK) has been very useful for studying molecular tolerance. The influence of association with the β4 subunit can be observed at the level of individual channels, action potentials in brain slices, and finally, drinking behavior in the mouse. Previously, we showed that 50 mm alcohol increases both α and αβ4 BK channel open probability, but only α BK develops acute tolerance to this effect. Currently, we explore the possibility that the influence of the β4 subunit on tolerance may result from a striking effect of β4 on kinase modulation of the BK channel. We examine the influence of the β4 subunit on PKA, CaMKII, and phosphatase modulation of channel activity, and on molecular tolerance to alcohol. We record from human BK channels heterologously expressed in HEK 293 cells composed of its core subunit, α alone (Insertless), or co-expressed with the β4 BK auxiliary subunit, as well as, acutely dissociated nucleus accumbens neurons using the cell-attached patch clamp configuration. Our results indicate that BK channels are strongly modulated by activation of specific kinases (PKA and CaMKII) and phosphatases. The presence of the β4 subunit greatly influences this modulation, allowing a variety of outcomes for BK channel activity in response to acute alcohol. PMID:25190810

  13. Importance of magnesium ions in development of tolerance to ethanol: studies on cultured cerebral vascular smooth muscle cells, type-2 astrocytes and intact rat brain.

    PubMed

    Li, W; Zheng, T; Babu, A N; Altura, B T; Gupta, R K; Altura, B M

    2001-09-15

    This study was designed to examine the roles of intracellular free magnesium ion concentration ([Mg(2+)](i)) in ethanol-induced intoxication and development of tolerance in cultured canine cerebral vascular smooth muscle cells and astrocytes as well as intact rat brain. The basal, resting level of [Mg(2+)](i) in cerebrovascular cells was 732.5 +/- 82.4 microM. Exposure of cultured canine cerebral vascular smooth muscle cells to ethanol (10 and 25 mM) for 24 h reduced the concentrations of [Mg(2+)](i) to 521.1 +/- 59.6 microM, and 308.2 +/- 37.8 microM, respectively. However, exposure of these cultured vascular cells to the same concentrations of ethanol, after initial pretreatment with ethanol for 24 h, failed to interfere with the levels of [Mg(2+)](i). Measurement of [Mg(2+)](i) at 48 h and 72 h indicated that the decreased levels of [Mg(2+)](i) induced by ethanol at 24 h treatment returned toward baseline. Similar experiments were performed in cultured type-2 astrocytes isolated from neonatal rat brain. The basal level of [Mg(2+)](i) in type-2 astrocytes was about 125 microM. Incubation of these cells with 10 mM ethanol for 10 min resulted in a 27% reduction in the level of [Mg(2+)](i), whereas incubation with 25 mM ethanol resulted in almost a 50% reduction in [Mg(2+)](i). The decreased levels of [Mg(2+)](i) lasted around 30 min, until the measurement finished. Continuous incubation of these cultured astrocytes, with ethanol (either 10 mM or 25 mM), for more than 24 h, indicated that the concentrations of [Mg(2+)](i) in type-2 astrocytes were equivalent to those at basal, resting levels. In vivo 31P-NMR spectroscopy, performed on intact rat brains, indicated that an initial administration of 4 mg/kg ethanol ( approximately 20-25 mM blood alcohol level) resulted (after 20-40 min of exposure) in severe deficits in whole brain [Mg(2+)](i) (550 +/- 33 microM to 358 +/- 24 microM). Repeated injections of ethanol (4 mg/kg) over the next 24-72 h resulted in

  14. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute cystitis; Acute bladder infection; Acute bacterial cystitis ... cause. Menopause also increases the risk for a urinary tract infection. The following also increase your chances of having ...

  15. Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function.

    PubMed

    Pan, Ping-Ying; Wang, George X; Yin, Bingjiao; Ozao, Junko; Ku, Teresa; Divino, Celia M; Chen, Shu-Hsia

    2008-01-01

    Tumor growth induced a significant increase of myeloid-derived suppressor cells (MDSCs) in the tumor-bearing host. In our previous study, we showed that MDSCs induced tumor-specific T-cell tolerance and the development of T regulatory cells (Tregs). Tumor-derived factors have been implicated in the accumulation of MDSCs. We hypothesize that reduction of MDSC accumulation in tumor-bearing hosts, through the blockade of tumor factors, can prevent T-cell anergy and Treg development and thereby improve immune therapy for the treatment of advanced tumors. Several tumor-derived factors were identified by gene array analysis. Among the candidate factors, stem- cell factor (SCF) is expressed by various human and murine carcinomas and was selected for further study. Mice bearing tumor cells with SCF siRNA knockdown exhibited significantly reduced MDSC expansion and restored proliferative responses of tumor-infiltrating T cells. More importantly, blockade of SCF receptor (ckit)-SCF interaction by anti-ckit prevented tumor-specific T-cell anergy, Treg development, and tumor angiogenesis. Furthermore, the prevention of MDSC accumulation in conjunction with immune activation therapy showed synergistic therapeutic effect when treating mice bearing large tumors. This information supports the notion that modulation of MDSC development may be required to achieve effective immune-enhancing therapy for the treatment of advanced tumors.

  16. Opioid antinociception, tolerance and dependence: interactions with the N-methyl-D-aspartate system in mice.

    PubMed

    Dykstra, Linda A; Fischer, Bradford D; Balter, Rebecca E; Henry, Fredrick E; Schmidt, Karl T; Miller, Laurence L

    2011-09-01

    This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of μ-opioid agonists. A hot-plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced [knockdown (KD)] to approximately 10%, and in mice treated with the NMDA antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959). The μ opioid agonists, morphine, l-methadone and fentanyl, were approximately three-fold less potent in the NR1 KD mice than in wild-type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and the WT mice. Acute administration of the NMDA antagonist, LY235959, produced dose-dependent, leftward shifts in the morphine dose-effect curve in the WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD or the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in μ opioid tolerance.

  17. Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs.

    PubMed

    Sánchez-Fueyo, Alberto; Strom, Terry B

    2011-01-01

    Transplantation of organs between genetically different individuals of the same species causes a T cell-mediated immune response that, if left unchecked, results in rejection and graft destruction. The potency of the alloimmune response is determined by the antigenic disparity that usually exists between donors and recipients and by intragraft expression of proinflammatory cytokines in the early period after transplantation. Studies in animal models have identified many molecules that, when targeted, inhibit T-cell activation. In addition, some of these studies have shown that certain immunologic interventions induce transplantation tolerance, a state in which the allograft is specifically accepted without the need for chronic immunosuppression. Tolerance is an important aspect of liver transplantation, because livers have a unique microenvironment that promotes tolerance rather than immunity. In contrast to the progress achieved in inducing tolerance in animal models, patients who receive transplanted organs still require nonspecific immunosuppressant drugs. The development of calcineurin inhibitors has reduced the acute rejection rate and improved short-term, but not long-term, graft survival. However, long-term use of immunosuppressive drugs leads to nephrotoxicity and metabolic disorders, as well as manifestations of overimmunosuppression such as opportunistic infections and cancers. The status of pharmacologic immunosuppression in the clinic is therefore not ideal. We review recently developed therapeutic strategies to promote tolerance to transplanted livers and other organs and diagnostic tools that might be used to identify patients most likely to accept or reject allografts.

  18. Retinal vein occlusion and the risk of acute myocardial infarction development: a 12-year nationwide cohort study.

    PubMed

    Rim, Tyler Hyungtaek; Han, John Seungsoo; Oh, Jaewon; Kim, Dong Wook; Kang, Seok-Min; Chung, Eun Jee

    2016-02-29

    The goal of this study was to evaluate the risk of developing acute myocardial infarction (AMI) following retinal vein occlusion (RVO). A retrospective cohort study was performed from the National Health Insurance Service and comprised 1,025,340 random subjects who were followed from 2002 to 2013. Patients with RVO in 2002 were excluded. The RVO group was composed of patients who received an initial RVO diagnosis between January 2003 and December 2007 (n = 1677). The comparison group was selected (five patients per RVO patient; n = 8367) using propensity score matching according to sociodemographic factors and the year of enrolment. Each patient was tracked until 2013. The Cox proportional hazard regression model was used. AMI developed in 7.6% of the RVO group and 5.3% of the comparison group (p < 0.001) for 7.7 median follow-up periods. RVO increased the risk of AMI development [hazard ratio (HR) = 1.25; 95% Confidence Interval (CI) 1.02 to 1.52]. In the subgroup analysis, RVO patients aged <65 years and the males within this age group had an adjusted HR of 1.47 (95% CI 1.10 to 1.98) and an adjusted HR of 2.00 (95% CI 1.38 to 2.91) for AMI development, respectively. RVO was significantly associated with AMI development.

  19. Hsp72-Mediated Suppression of c-Jun N-Terminal Kinase Is Implicated in Development of Tolerance to Caspase-Independent Cell Death

    PubMed Central

    Gabai, Vladimir L.; Yaglom, Julia A.; Volloch, Vladimir; Meriin, Anatoli B.; Force, Thomas; Koutroumanis, Maria; Massie, Bernard; Mosser, Dick D.; Sherman, Michael Y.

    2000-01-01

    Pretreatment with mild heat shock is known to protect cells from severe stress (acquired thermotolerance). Here we addressed the mechanism of this phenomenon by using primary human fibroblasts. Severe heat shock (45°C, 75 min) of the fibroblasts caused cell death displaying morphological characteristics of apoptosis; however, it was caspase independent. This cell death process was accompanied by strong activation of Akt, extracellular signal-regulated kinase 1 (ERK1) and ERK2, p38, and c-Jun N-terminal (JNK) kinases. Suppression of Akt or ERK1 and -2 kinases increased cell thermosensitivity. In contrast, suppression of stress kinase JNK rendered cells thermoresistant. Development of thermotolerance was not associated with Akt or ERK1 and -2 regulation, and inhibition of these kinases did not reduce acquired thermotolerance. On the other hand, acquired tolerance to severe heat shock was associated with downregulation of JNK. Using an antisense-RNA approach, we found that accumulation of the heat shock protein Hsp72 is necessary for JNK downregulation and is critical for thermotolerance. The capability of naive cells to withstand moderate heat treatment also appears to be dependent on the accumulation of Hsp72 induced by this stress. Indeed, exposure to 45°C for 45 min caused only transient JNK activation and was nonlethal, while prevention of Hsp72 accumulation prolonged JNK activation and led to massive cell death. We also found that JNK activation by UV irradiation, interleukin-1, or tumor necrosis factor was suppressed in thermotolerant cells and that Hsp72 accumulation was responsible for this effect. Hsp72-mediated suppression of JNK is therefore critical for acquired thermotolerance and may play a role in tolerance to other stresses. PMID:10958679

  20. Constitutive Expression of a miR319 Gene Alters Plant Development and Enhances Salt and Drought Tolerance in Transgenic Creeping Bentgrass1[W][OA

    PubMed Central

    Zhou, Man; Li, Dayong; Li, Zhigang; Hu, Qian; Yang, Chunhua; Zhu, Lihuang; Luo, Hong

    2013-01-01

    MicroRNA319 (miR319) is one of the first characterized and cons