Ocean acidification narrows the acute thermal and salinity tolerance of the Sydney rock oyster Saccostrea glomerata.

PubMed

Parker, Laura M; Scanes, Elliot; O'Connor, Wayne A; Coleman, Ross A; Byrne, Maria; Pörtner, Hans-O; Ross, Pauline M

2017-09-15

Coastal and estuarine environments are characterised by acute changes in temperature and salinity. Organisms living within these environments are adapted to withstand such changes, yet near-future ocean acidification (OA) may challenge their physiological capacity to respond. We tested the impact of CO 2 -induced OA on the acute thermal and salinity tolerance, energy metabolism and acid-base regulation capacity of the oyster Saccostrea glomerata. Adult S. glomerata were acclimated to three CO 2 levels (ambient 380μatm, moderate 856μatm, high 1500μatm) for 5weeks (24°C, salinity 34.6) before being exposed to a series of acute temperature (15-33°C) and salinity (34.2-20) treatments. Oysters acclimated to elevated CO 2 showed a significant metabolic depression and extracellular acidosis with acute exposure to elevated temperature and reduced salinity, especially at the highest CO 2 of 1500μatm. Our results suggest that the acute thermal and salinity tolerance of S. glomerata and thus its distribution will reduce as OA continues to worsen. Copyright © 2017 Elsevier Ltd. All rights reserved.

Liver size, bodyweight, and tolerance to acute complete occlusion of congenital extrahepatic portosystemic shunts in dogs.

PubMed

Doran, Ivan P; Barr, Frances J; Hotston Moore, Alasdair; Knowles, Toby G; Holt, Peter E

2008-10-01

To investigate the relationship between preoperative liver size, bodyweight, and tolerance to shunt occlusion in dogs with congenital extrahepatic portosystemic shunt(s) (CPSS). Longitudinal cohort study. Dogs with CPSS (n=35). Ultrasonography was used to measure preoperative maximum transverse dimension of the liver (TS) of each dog. Intraoperative portal pressures were measured, before and after CPSS occlusion, via a jejunal vein catheter. Tolerance to shunt occlusion was judged on gross visceral observations, and on changes in portal pressure, central venous and mean arterial pressures. TS was significantly related to bodyweight (P<.05). Mean ratios for TS/bodyweight were calculated for dogs tolerant and intolerant of acute complete shunt occlusion. Dogs tolerant to occlusion had significantly higher TS/bodyweight ratios than dogs intolerant to occlusion (P=.025). Dogs with a TS/bodyweight ratio of >7 were more likely to tolerate CPSS occlusion than dogs with a TS/bodyweight ratio of <5 (P=.036). A model was generated to predict portal pressure rise after shunt occlusion, based on liver dimensions and bodyweight (R=0.668). Intestinal oxygenation did not correlate significantly with tolerance to CPSS occlusion (P=.29). In dogs with CPSS, liver size (relative to bodyweight) is significantly greater (P=.025) in dogs that are tolerant of full ligation than intolerant of occlusion. Preoperative measurement of bodyweight and liver size help indicate the likelihood of tolerance to acute complete occlusion of CPSS in dogs.

Supraspinally administered agmatine prevents the development of supraspinal morphine analgesic tolerance.

PubMed

Kitto, Kelley F; Fairbanks, Carolyn A

2006-04-24

We have determined the effect of intracerebroventricularly (i.c.v.) administered decarboxylated arginine (agmatine) on supraspinally induced chronic morphine analgesic tolerance. Mice pre-treated with a schedule of chronic i.c.v administration of morphine (10 nmol, b.i.d. 3 days) show a 12-fold reduction in the potency of acutely administered i.c.v morphine compared to saline injected controls. Co-administration of agmatine (10 nmol) with one of the two daily morphine injections completely prevents the reduction in i.c.v morphine analgesia. Mice injected with agmatine once daily (but no morphine) do not show a increase in morphine analgesic potency relative to saline controls, indicating that a mere potentiation of acute morphine analgesia cannot account for the agmatine-mediated anti-tolerance effect in those mice subjected to the morphine tolerance induction schedule. These observations agree with previous reports that systemically and intrathecally administered agmatine prevent opioid tolerance, and extend these results to include a supraspinal site of action.

Reversal of oxycodone and hydrocodone tolerance by diazepam.

PubMed

Gonek, Maciej; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L

2017-11-01

The Centers for Disease Control has declared opioid abuse to be an epidemic. Overdose deaths are largely assumed to be the result of excessive opioid consumption. In many of these cases, however, opioid abusers are often polydrug abusers. Benzodiazepines are one of the most commonly co-abused substances and pose a significant risk to opioid users. In 2016, the FDA required boxed warnings - the FDA's strongest warning - for prescription opioid analgesics and benzodiazepines about the serious risks associated with using these medications at the same time. The point of our studies was to evaluate the interactions between these two classes of drugs. We investigated whether diazepam adds to the depressant effects of opioids or do they alter the levels of tolerance to opioids. In the present study, we have found that the antinociceptive tolerance that developed to repeated administration of oxycodone was reversed by an acute dose of diazepam. Antinociceptive tolerance to hydrocodone was also reversed by acute injection of diazepam; however, a fourfold higher dose of diazepam was required when compared to reversal of oxycodone-induced tolerance. These doses of diazepam did not potentiate the acute antinociceptive effect of either opioid. The same dose of diazepam that reversed oxycodone antinociceptive tolerance also reversed oxycodone locomotor tolerance while having no potentiating effects. These studies show that diazepam does not potentiate the acute effect of prescription opioids but reverses the tolerance developed after chronic administration of the drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparative effects of cyclo-oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance

PubMed Central

Powell, Kelly J; Hosokawa, Akiko; Bell, Andrew; Sutak, Maaja; Milne, Brian; Quirion, Remi; Jhamandas, Khem

1999-01-01

This study examined the effects of the COX inhibitors, ketorolac and ibuprofen, and the NOS inhibitor L-NAME for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. Repeated administration of intrathecal morphine (15 μg), once daily, resulted in a progressive decline of antinociceptive effect and an increase in the ED50 value in the tailflick and paw pressure tests. Co-administration of ketorolac (30 and 45 μg) or S(+) ibuprofen (10 μg) with morphine (15 μg) prevented the decline of antinociceptive effect and increase in ED50 value. Similar treatment with L-NAME (100 μg) exerted weaker effects. Administration of S(+) but not R(−) ibuprofen (10 mg kg−1) had similar effects on systemic administration of morphine (15 mg kg−1). Intrathecal or systemic administration of the COX or NOS inhibitors did not alter the baseline responses in either tests. Acute keterolac or S(+) ibuprofen also did not potentiate the acute actions of spinal or systemic morphine, but chronic intrathecal administration of these agents increased the potency of acute morphine. In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 μg) with morphine (15 μg) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance. Intrathecal L-NAME (100 μg) exerted a weaker effect. These data suggest that spinal COX activity, and to a lesser extent NOS activity, contributes to the development and expression of opioid tolerance. Inhibition of COX may represent a useful approach for the prevention as well as reversal of opioid tolerance. PMID:10401553

AMPA receptor positive allosteric modulators attenuate morphine tolerance and dependence.

PubMed

Hu, Xiaoyu; Tian, Xuebi; Guo, Xiao; He, Ying; Chen, Haijun; Zhou, Jia; Wang, Zaijie Jim

2018-04-25

Development of opioid tolerance and dependence hinders the use of opioids for the treatment of chronic pain. In searching for the mechanism and potential intervention for opioid tolerance and dependence, we studied the action of two positive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR PAMs). In mice treated with morphine (100 mg/kg, s.c.), acute morphine tolerance and dependence developed in 4-6 h. Treatment with aniracetam, a well-established AMPAR PAM, was able to completely prevent and reverse the development of acute antinociceptive tolerance to morphine. Partial, but significant, effects of aniracetam on acute morphine induced-physical dependence were also observed. Moreover, aniracetam significantly reversed the established morphine tolerance and dependence in a chronic model of morphine tolerance and dependence produced by intermittent morphine (10 mg/kg, s.c. for 5d). In addition, HJC0122, a new AMPAR PAM was found to have similar effects as aniracetam but with a higher potency. These previously undisclosed actions of AMPAR PAMs are intriguing and may shed lights on understanding the APMA signaling pathway in opioid addiction. Moreover, these data suggest that AMPAR PAMs may have utility in preventing and treating morphine tolerance and dependence. Copyright © 2018. Published by Elsevier Ltd.

Development of Novel Local Analgesics for Management of Acute Tissue Injury Pain

DTIC Science & Technology

2017-09-01

assess biodistribution, tolerance and toxicity of candidate NCEs. 15% complete The goal of our project is to develop a new approach to the management ... Project Manager Boston Biomedical Innovation Center 215 First Street, Suite 500; Cambridge, MA 02142 857-307-2441 | rblackman1@partners.org | b...AWARD NUMBER: W81XWH-15-1-0480 TITLE: Development of Novel Local Analgesics for Management of Acute Tissue Injury Pain PRINCIPAL

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

Effects of Acute Alcohol Tolerance on Perceptions of Danger and Willingness to Drive after Drinking

PubMed Central

Amlung, Michael T.; Morris, David H.; McCarthy, Denis M.

2014-01-01

Rationale Drinking and driving is associated with elevated rates of motor vehicle accidents and fatalities. Previous research suggests that alcohol impairs judgments about the dangers of risky behaviors; however, how alcohol affects driving-related judgments is less clear. Impairments have also been shown to differ across limbs of the blood alcohol concentration (BAC) curve, which is known as acute tolerance. Objectives Examine whether perceptions about the dangerousness of driving after drinking and willingness to drive differed across ascending and descending limbs of the BAC curve. Test whether reductions in perceived danger were associated with willingness to drive on the descending limb. Methods Fifty-six participants were randomly assigned to receive either a moderate dose of alcohol (peak BAC = 0.10 g%) or placebo. We assessed perceived dangerousness and willingness to drive at matched BACs (~0.067-0.068 g%) on the ascending and descending limbs. Results Both perceived danger and willingness to drive showed acute tolerance in the alcohol group. Participants judged driving to be significantly less dangerous and were more willing to drive on the descending limb compared to the ascending limb. The magnitude of change in perceived danger significantly predicted willingness to drive on the descending limb. Conclusions Decreased impairment associated with acute tolerance may lead individuals to underestimate the dangerousness of driving after drinking and in turn make poor decisions regarding driving. This study further emphasizes the descending limb as a period of increased risk and offers support for enhancing prevention efforts by targeting drivers at declining BAC levels. PMID:24752657

Effects of acute alcohol tolerance on perceptions of danger and willingness to drive after drinking.

PubMed

Amlung, Michael T; Morris, David H; McCarthy, Denis M

2014-11-01

Drinking and driving is associated with elevated rates of motor vehicle accidents and fatalities. Previous research suggests that alcohol impairs judgments about the dangers of risky behaviors; however, how alcohol affects driving-related judgments is less clear. Impairments have also been shown to differ across limbs of the blood alcohol concentration (BAC) curve, which is known as acute tolerance. The objectives of this study were to examine whether perceptions about the dangerousness of driving after drinking and willingness to drive differed across the ascending and descending limbs of the BAC curve and to test whether reductions in perceived danger were associated with willingness to drive on the descending limb. Fifty-six participants were randomly assigned to receive either a moderate dose of alcohol (peak BAC = 0.10 g%) or placebo. We assessed perceived dangerousness and willingness to drive at matched BACs (~0.067-0.068 g%) on the ascending and descending limbs. Both perceived danger and willingness to drive showed acute tolerance in the alcohol group. Participants judged driving to be significantly less dangerous and were more willing to drive on the descending limb compared to the ascending limb. The magnitude of change in perceived danger significantly predicted willingness to drive on the descending limb. Decreased impairment associated with acute tolerance may lead individuals to underestimate the dangerousness of driving after drinking and in turn make poor decisions regarding driving. This study further emphasizes the descending limb as a period of increased risk and offers support for enhancing prevention efforts by targeting drivers at declining BAC levels.

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.

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

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

Decrement in operant performance produced by NMDA receptor antagonists in the rat: tolerance and cross-tolerance.

PubMed

Dravolina, O A; Zvartau, E E; Bespalov, A Y

2000-04-01

Current perspectives on the clinical use of NMDA receptor antagonists infer repeated administration schedules for the management of different pathological states. The development of tolerance and cross-tolerance between different NMDA receptor antagonists may be an important factor contributing to the clinical efficacy of these drugs. The present study aimed to characterize the development of tolerance and cross-tolerance to the ability of various site-selective NMDA receptor antagonists to produce a decrement of operant responding (multiple extinction 9 s fixed-interval 1-s schedule of water reinforcement). Acute administration of D-CPPen (SDZ EAA 494; 1-5.6 mg/kg), dizocilpine (MK-801; 0.03-0.3 mg/kg), memantine (0.3-17 mg/kg), ACEA-1021 (10-56 mg/kg), and eliprodil (1-30 mg/kg) differentially affected operant responding. Both increases and decreases in response rates and accuracy of responding were observed. Repeated preexposure to D-CPPen (5.6 mg/kg, once a day for 7 days) attenuated a behavioral disruption produced by an acute challenge with D-CPPen or ACEA-1021, but potentiated the effects of dizocilpine, memantine, and eliprodil. Based on the present results, one can suggest that the repeated administration of a competitive NMDA receptor antagonist differentially affects the functional activity of various sites on NMDA receptor complex.

Nitrendipine decreases benzodiazepine withdrawal seizures but not the development of benzodiazepine tolerance or withdrawal signs.

PubMed Central

Dolin, S. J.; Patch, T. L.; Rabbani, M.; Siarey, R. J.; Bowhay, A. R.; Little, H. J.

1990-01-01

1. The effects of the calcium channel blocking agent, nitrendipine, were studied on seizures in mice produced during withdrawal from chronic benzodiazepine treatment and on the development of tolerance to benzodiazepines. 2. Nitrendipine produced a dose-dependent decrease in seizure incidence, when seizures were produced by the partial inverse agonist FG7142 during withdrawal from seven days treatment with flurazepam. 3. Nitrendipine did not raise the seizure thresholds in naïve mice to the full inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), or to the gamma-aminobutyric acid (GABA) antagonist, bicuculline. 4. When given concurrently with flurazepam for seven days, nitrendipine did not affect the incidence of seizures during flurazepam withdrawal. 5. When given concurrently with the benzodiazepines, nitrendipine did not prevent the development of tolerance to midazolam general anaesthesia or tolerance to the ataxic actions of flurazepam or midazolam. 6. Chronic treatment with flurazepam for seven days did not affect the Kd or Bmax of [3H]-nimodipine binding in mouse whole brain or cerebral cortex. 7. These results with benzodiazepines are partially in contrast with those for ethanol, where nitrendipine not only decreased ethanol withdrawal seizures when given acutely, but also prevented the development of tolerance and withdrawal signs when given concurrently with ethanol. However, they do confirm the selectivity of nitrendipine for withdrawal-induced seizures. PMID:1963805

Open-label Bendamustine Monotherapy for Pediatric Patients With Relapsed or Refractory Acute Leukemia: Efficacy and Tolerability

PubMed Central

Brown, Patrick; Megason, Gail; Ahn, Hyo Seop; Cho, Bin; Kirov, Ivan; Frankel, Lawrence; Aplenc, Richard; Bensen-Kennedy, Debra; Munteanu, Mihaela; Weaver, Jennifer; Harker-Murray, Paul

2014-01-01

This open-label, single-arm, phase I/II, dose-escalation study was designed to determine the recommended phase II dose (RP2D), pharmacokinetics, tolerability, and efficacy of bendamustine in pediatric patients (age ranging from 1 to 20 y) with histologically proven relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Patients (27 with ALL, 16 with AML) received intravenous bendamustine on days 1 and 2 of each treatment cycle. Phase I involved planned dose escalation of bendamustine to establish the RP2D for phase II. Objectives included overall response rate, duration of response, and tolerability. Eleven patients were treated in phase I, and the RP2D was 120 mg/m2. In phase II, 32 patients received bendamustine 120 mg/m2. Two patients with ALL (bendamustine 90 mg/m2) experienced complete response (CR). Among patients who received bendamustine 120 mg/m2, 2 experienced partial response (PR); 7 had stable disease. The overall response rate (CR+CR without platelet recovery [CRp]) was 4.7% and biological activity rate (CR+CRp+PR) was 9.3%. No AML patients responded. The most common adverse events were anemia, neutropenia, thrombocytopenia, pyrexia, nausea, vomiting, and diarrhea. Bendamustine monotherapy has acceptable tolerability in heavily pretreated children with relapsed/refractory ALL or AML and appears to have some activity in ALL, warranting further studies in combination trials. PMID:24072240

Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone.

PubMed

Jacob, Joanna C; Poklis, Justin L; Akbarali, Hamid I; Henderson, Graeme; Dewey, William L

2017-07-01

This study compared the development of tolerance to two orally bioavailable prescription opioids, oxycodone and hydrocodone, to that of morphine, and the reversal of this tolerance by ethanol. Oxycodone (s.c.) was significantly more potent in the mouse tail-withdrawal assay than either morphine or hydrocodone. Oxycodone was also significantly more potent in this assay than hydrocodone when administered orally. Tolerance was seen following chronic subcutaneous administration of each of the three drugs and by the chronic administration of oral oxycodone, but not following the chronic oral administration of hydrocodone. Ethanol (1 g/kg i.p.) significantly reversed the tolerance to the subcutaneous administration of each of the three opioids that developed when given 30 minutes prior to challenge doses. It took twice as much ethanol, when given orally, to reverse the tolerance to oxycodone. We investigated whether the observed tolerance to oxycodone and its reversal by ethanol were due to biodispositional changes or reflected a true neuronal tolerance. As expected, a relationship between brain oxycodone concentrations and activity in the tail-immersion test existed following administration of acute oral oxycodone. Following chronic treatment, brain oxycodone concentrations were significantly lower than acute concentrations. Oral ethanol (2 g/kg) reversed the tolerance to chronic oxycodone, but did not alter brain concentrations of either acute or chronic oxycodone. These studies show that there is a metabolic component of tolerance to oxycodone; however, the reversal of that tolerance by ethanol is not due to an alteration of the biodisposition of oxycodone, but rather is neuronal in nature. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

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

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. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

Local Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance Induction Protocol

DTIC Science & Technology

2016-10-01

Chimerism Vascularized Composite Allograft Tolerance Induction Protocol PRINCIPAL INVESTIGATORS: Dr. Curtis L. Cetrulo CONTRACTING ORGANIZATION...Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance...tacrolimus, FK506, vascularized composite allografts , immune rejection, preclinical, transplant, nonhuman primate model, degradable polymer, tyrosine

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

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.

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

Development of an acute toxicity test with the tropical marine amphipod Parhyale hawaiensis.

PubMed

Artal, Mariana Coletty; Dos Santos, Amanda; Henry, Theodore Burdick; Umbuzeiro, Gisela de Aragão

2018-03-01

There is a lack of suitable tropical marine species for ecotoxicity tests. An attractive model organism for ecotoxicology is the marine amphipod Parhyale hawaiensis, which is already a model for genetic and developmental studies. This species is widespread, can tolerate changes in salinity, is easy to handle and is representative of circumtropical regions. The aim of this work was to describe standardized procedures for laboratory husbandry, define conditions for acute toxicity tests, and to provide acute toxicity test results for some reference toxicants. Culturing conditions for the organism in the laboratory were established in reconstituted seawater (30 ± 2 salinity), 24 ± 2 °C, photoperiod 12/12 h light/dark. Acute toxicity test procedures were developed for 96 h-exposure time, and organisms at ages <7 days. The miniaturized version of the test, based on 96-well microplates and 200 µL of exposure media provided consistent results compared to larger exposure volumes (80-mL vials protocol). Acute toxicity of Ag, Cd, Cu, Zn and ammonia determined for P. hawaiensis were consistent to previous results for other marine amphipods. We conclude that P. hawaiensis can be successfully cultured in standardized conditions and be effectively used in acute toxicity testing. Further development and use of this model will enable standardized and reproducible ecotoxicology investigations in understudied and vulnerable tropical marine ecosystems.

Physiological determinants of human acute hypoxia tolerance.

DOT National Transportation Integrated Search

2013-11-01

AbstractIntroduction. We investigated possible physiological determinants of variability in hypoxia tolerance in subjects given a 5-minute normobaric exposure to 25,000 ft equivalent. Physiological tolerance to hypoxia was defined as the magnitude of...

The gut-brain interaction in opioid tolerance.

PubMed

Akbarali, Hamid I; Dewey, William L

2017-12-01

The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function. Copyright © 2017 Elsevier Ltd. All rights reserved.

Desensitization and Tolerance of Mu Opioid Receptors on Pontine Kölliker-Fuse Neurons.

PubMed

Levitt, Erica S; Williams, John T

2018-01-01

Acute desensitization of mu opioid receptors is thought to be an initial step in the development of tolerance to opioids. Given the resistance of the respiratory system to develop tolerance, desensitization of neurons in the Kölliker-Fuse (KF), a key area in the respiratory circuit, was examined. The activation of G protein-coupled inwardly rectifying potassium current was measured using whole-cell voltage-clamp recordings from KF and locus coeruleus (LC) neurons contained in acute rat brain slices. A saturating concentration of the opioid agonist [Met 5 ]-enkephalin (ME) caused significantly less desensitization in KF neurons compared with LC neurons. In contrast to LC, desensitization in KF neurons was not enhanced by activation of protein kinase C or in slices from morphine-treated rats. Cellular tolerance to ME and morphine was also lacking in KF neurons from morphine-treated rats. The lack of cellular tolerance in KF neurons correlates with the relative lack of tolerance to the respiratory depressant effect of opioids. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Spinal Ceramide and Neuronal Apoptosis in Morphine Antinociceptive Tolerance

PubMed Central

Bryant, Leesa; Doyle, Tim; Chen, Zhoumo; Cuzzocrea, Salvatore; Masini, Emanuela; Vinci, M. Cristina; Esposito, Emanuela; Mazzon, Emanuela; Petrusca, Daniela Nicoleta; Petrache, Irina; Salvemini, Daniela

2009-01-01

Opiates, like morphine, are the most effective analgesics for treating acute and chronic severe pain, but their use is limited by the development of analgesic tolerance and hypersensitivity to innocuous and noxious stimuli. Because opioids are a mainstay of pain management, restoring their efficacy has great clinical importance. We have recently demonstrated that spinal ceramide, a sphingolipid signaling molecule plays a central role in the development of morphine antinociceptive tolerance. We now report that ceramide up-regulation in dorsal horn tissues in response to chronic morphine administration is associated with significant neuronal apoptosis. Inhibition of ceramide biosynthesis attenuated both the increase in neuronal apoptosis and the development of antinociceptive tolerance. These findings indicate that spinal ceramide upregulation is a key pro-apoptotic event that occurs upstream of the development of morphine antinociceptive tolerance and support the rationale for development of inhibitors of ceramide biosynthesis as adjuncts to opiates for the management of chronic pain. PMID:19631718

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

PubMed

Weafer, Jessica; Fillmore, Mark T

2012-04-01

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. 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. 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. 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. 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.

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

Absence of MyD88 Signaling Induces Donor-Specific Kidney Allograft Tolerance

PubMed Central

Noordmans, Gerda A.; O’Brien, Maya R.; Ma, Jin; Zhao, Cathy Y.; Zhang, Geoff Y.; Kwan, Tony K.T.; Alexander, Stephen I.; Chadban, Steven J.

2012-01-01

Toll-like receptors (TLRs) play a fundamental role in innate immunity and provide a link between innate and adaptive responses to an allograft; however, whether the development of acute and chronic allograft rejection requires TLR signaling is unknown. Here, we studied TLR signaling in a fully MHC-mismatched, life-sustaining murine model of kidney allograft rejection. Mice deficient in the TLR adaptor protein MyD88 developed donor antigen-specific tolerance, which protected them from both acute and chronic allograft rejection and increased their survival after transplantation compared with wild-type controls. Administration of an anti-CD25 antibody to MyD88-deficient recipients depleted CD4+CD25+FoxP3+ cells and broke tolerance. In addition, defective development of Th17 immune responses to alloantigen both in vitro and in vivo occurred, resulting in an increased ratio of Tregs to Th17 effectors. Thus, MyD88 deficiency was associated with an altered balance of Tregs over Th17 cells, promoting tolerance instead of rejection. This study provides evidence that targeting innate immunity may be a clinically relevant strategy to facilitate transplantation tolerance. PMID:22878960

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.

Comparative tolerability of treatments for acute migraine: A network meta-analysis.

PubMed

Thorlund, Kristian; Toor, Kabirraaj; Wu, Ping; Chan, Keith; Druyts, Eric; Ramos, Elodie; Bhambri, Rahul; Donnet, Anne; Stark, Richard; Goadsby, Peter J

2017-09-01

Introduction Migraine headache is a neurological disorder whose attacks are associated with nausea, vomiting, photophobia and phonophobia. Treatments for migraine aim to either prevent attacks before they have started or relieve attacks (abort) after onset of symptoms and range from complementary therapies to pharmacological interventions. A number of treatment-related adverse events such as somnolence, fatigue, and chest discomfort have previously been reported in association with triptans. The comparative tolerability of available agents for the abortive treatment of migraine attacks has not yet been systematically reviewed and quantified. Methods We performed a systematic literature review and Bayesian network meta-analysis for comparative tolerability of treatments for migraine. The literature search targeted all randomized controlled trials evaluating oral abortive treatments for acute migraine over a range of available doses in adults. The primary outcomes of interest were any adverse event, treatment-related adverse events, and serious adverse events. Secondary outcomes were fatigue, dizziness, chest discomfort, somnolence, nausea, and vomiting. Results Our search yielded 141 trials covering 15 distinct treatments. Of the triptans, sumatriptan, eletriptan, rizatriptan, zolmitriptan, and the combination treatment of sumatriptan and naproxen were associated with a statistically significant increase in odds of any adverse event or a treatment-related adverse event occurring compared with placebo. Of the non-triptans, only acetaminophen was associated with a statistically significant increase in odds of an adverse event occurring when compared with placebo. Overall, triptans were not associated with increased odds of serious adverse events occurring and the same was the case for non-triptans. For the secondary outcomes, with the exception of vomiting, all triptans except for almotriptan and frovatriptan were significantly associated with increased risk for all

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. Copyright © 2014 Elsevier Inc. All rights reserved.

Development of imidazolinone herbicide tolerant borage (Borago officinalis L.).

PubMed

Song, Dongyan; Wu, Guohai; Vrinten, Patricia; Qiu, Xiao

2017-09-01

Borage (Borago officinalis) is an annual herb that produces a high level of gamma-linolenic acid (GLA) in its seed oil. Due to the recognized health benefits of GLA, borage is now commercially cultivated worldwide. However, an herbicide-tolerant variety for effective weed management has not yet been developed. Here we report the generation and characterization of ethyl methanesulfonate (EMS) induced borage mutant lines tolerant to the herbicide imidazolinone. An EMS-mutagenized borage population was generated by using a series of concentrations of EMS to treat mature borage seeds. Screening of the M2 and M3 borage plants using an herbicide treatment resulted in the identification of two imidazolinone-tolerant lines. Sequence analysis of two acetohydroxyacid synthase (AHAS) genes, AHAS1 and AHAS2, from the mutant (tolerant) and wild type (susceptible) borage plants showed that single nucleotide substitutions which resulted in amino acid changes occurred in AHAS1 and AHAS2, respectively in the two tolerant lines. A KASP marker was then developed to differentiate the homozygous susceptible, homozygous tolerant and heterozygous borage plants. An in vitro assay showed that homozygous tolerant borage carrying the AHAS1 mutation retained significantly higher AHAS activity than susceptible borage across different imazamox concentrations. A herbicide dose response test indicated that the line with the AHAS1 mutation could tolerate four times the normally used field concentration of "Solo" herbicide. Copyright © 2017. Published by Elsevier B.V.

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

PubMed

Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose

Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats

PubMed Central

He, Shao-Qiu; Yang, Fei; Perez, Federico M.; Xu, Qian; Shechter, Ronen; Cheong, Yong-Kwan; Carteret, Alene F.; Dong, Xinzhong; Sweitzer, Sarah M.; Raja, Srinivasa N.; Guan, Yun

2013-01-01

Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5 mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75 to 6.0 mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150 µg/50 µL intraplantarly) and D-Ala2-MePhe4-Glyol5 enkephalin (300 µg/50 µL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5 mg/kg intraperitoneally) and MK-801 (0.2 mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3 mg/kg subcutaneously), but not loperamide (3 mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca2+]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3 µM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide’s inhibition of KCl-elicited [Ca2+]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug

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.

[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.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 developmentmore » 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.« less

Acute heat tolerance of cardiac excitation in the brown trout (Salmo trutta fario).

PubMed

Vornanen, Matti; Haverinen, Jaakko; Egginton, Stuart

2014-01-15

The upper thermal tolerance and mechanisms of heat-induced cardiac failure in the brown trout (Salmo trutta fario) was examined. The point above which ion channel function and sinoatrial contractility in vitro, and electrocardiogram (ECG) in vivo, started to fail (break point temperature, BPT) was determined by acute temperature increases. In general, electrical excitation of the heart was most sensitive to heat in the intact animal (electrocardiogram, ECG) and least sensitive in isolated cardiac myocytes (ion currents). BPTs of Ca(2+) and K(+) currents of cardiac myocytes were much higher (>28°C) than BPT of in vivo heart rate (23.5 ± 0.6°C) (P<0.05). A striking exception among sarcolemmal ion conductances was the Na(+) current (INa), which was the most heat-sensitive molecular function, with a BPT of 20.9 ± 0.5°C. The low heat tolerance of INa was reflected as a low BPT for the rate of action potential upstroke in vitro (21.7 ± 1.2°C) and the velocity of impulse transmission in vivo (21.9 ± 2.2°C). These findings from different levels of biological organization strongly suggest that heat-dependent deterioration of Na(+) channel function disturbs normal spread of electrical excitation over the heart, leading to progressive variability of cardiac rhythmicity (missed beats, bursts of fast beating), reduction of heart rate and finally cessation of the normal heartbeat. Among the cardiac ion currents INa is 'the weakest link' and possibly a limiting factor for upper thermal tolerance of electrical excitation in the brown trout heart. Heat sensitivity of INa may result from functional requirements for very high flux rates and fast gating kinetics of the Na(+) channels, i.e. a trade-off between high catalytic activity and thermal stability.

Evaluation of Emergency Department Management of Opioid-Tolerant Cancer Patients With Acute Pain.

PubMed

Patel, Pina M; Goodman, Lauren F; Knepel, Sheri A; Miller, Charles C; Azimi, Asma; Phillips, Gary; Gustin, Jillian L; Hartman, Amber

2017-10-01

There are no previously published studies examining opioid doses administered to opioid-tolerant cancer patients during emergency department (ED) encounters. To determine if opioid-tolerant cancer patients presenting with acute pain exacerbations receive adequate initial doses of as needed (PRN) opioids during ED encounters based on home oral morphine equivalent (OME) use. We performed a retrospective cohort study of opioid-tolerant cancer patients who received opioids in our ED over a two-year period. The percentage of patients who received an adequate initial dose of PRN opioid (defined as ≥10% of total 24-hour ambulatory OME) was evaluated. Logistic regression was used to establish the relationship between 24-hour ambulatory OME and initial ED OME to assess whether higher home usage was associated with higher likelihood of being undertreated. Out of 216 patients, 61.1% of patients received an adequate initial PRN dose of opioids in the ED. Of patients taking <200 OMEs per day at home, 77.4% received an adequate initial dose; however, only 3.2% of patients taking >400 OMEs per day at home received an adequate dose. Patients with ambulatory 24-hour OME greater than 400 had 99% lower odds of receiving an adequate initial dose of PRN opioid in the ED compared to patients with ambulatory 24-hour OME less than 100 (OR <0.01, CI 0.00-0.02, P < 0.001). Patients with daily home use less than 200 OMEs generally received adequate initial PRN opioid doses during their ED visit. However, patients with higher home opioid usage were at increased likelihood of being undertreated. Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Liver microRNA profile of induced allograft tolerance

PubMed Central

Vitalone, Matthew James; Wai, Liang; Fujiki, Masato; Lau, Audrey H.; Littau, Erik; Esquivel, Carlos; Martinez, Olivia M.; Krams, Sheri M.

2016-01-01

Introduction Although the liver is less immunogenic than other solid organs, most liver transplant recipients receive lifelong immunosuppression. In both experimental models and clinical transplantation, total Lymphoid Irradiation (TLI) has been shown to induce allograft tolerance. Our goal was to identify the microRNAs (miRNAs) expressed in tolerant liver allograft recipients in an experimental model of TLI-induced tolerance. Methods To identify the miRNAs associated with TLI-induced tolerance we examined syngeneic recipients (Lewis→Lewis) and allogeneic recipients (DA→Lewis) of orthotropic liver transplants that received post-transplant TLI, allogeneic recipients that were not treated post-transplantation and experienced acute rejection, and native DA livers. QPCR miRNA array cards were used to profile liver grafts. Results We identified 12 miRNAs that were specifically and significantly increased during acute rejection. In early tolerance, 33 miRNAs were altered compared to syngeneic livers, with 80% of the miRNAs increased. In established tolerance 42 miRNAs were altered. In addition, miR-142-5p and miR-181a demonstrated increased expression in tolerant livers (both early and established tolerance) as compared to syngeneic livers. A principal component analysis of all miRNAs assayed, demonstrated a profile in established tolerance that was closely related to that seen in syngeneic livers. Conclusions The miRNA profile of established tolerant allografts is very similar to syngeneic grafts suggesting tolerance may be a return to an immunological state of quiescence. PMID:26950716

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jon Carmack; Frank Goldner; Shannon M. Bragg-Sitton

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 ormore » 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

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

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

PubMed Central

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

2013-01-01

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. PMID:23500188

Multiscale Multiphysics Developments for Accident Tolerant Fuel Concepts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gamble, K. A.; Hales, J. D.; Yu, J.

2015-09-01

U 3Si 2 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 U 3Si 2 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, andmore » 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.« less

Opioid tolerance and dependence -- do they matter?

PubMed

Jage, Jürgen

2005-04-01

The use of opioids has long been accepted as the standard of care in patients with cancer and acute pain. Opioids can further be used effectively in specific subgroups of patients with chronic nonmalignant pain states. While the development of tolerance and physical dependence are known effects of opioids in cancer and noncancer pain populations, these patients can not be regarded as addicted. However, long-term therapy with short-acting opioids predisposes to tolerance and addiction. Recent research has confirmed the important role of psychopathologic and psychosocial conditions as predictors of failed opioid effectiveness in a significant number of noncancer pain subgroups. The clinical picture of failed therapy may be complicated by noncompliance, concealed consumption of psychotropic substances, and diversion of prescribed opioids for various purposes as, e.g., selling for profit, or sharing excess opioids with others. This article discusses the effects of opioid therapy, including tolerance, physical dependence, drug-aberrant behavior, drug history, psychopathology, and somatization.

[Relationship between single nucleotide polymorphisms in thiopurine methyltransferase gene and tolerance to thiopurines in acute leukemia].

PubMed

Ma, Xiao-li; Zhu, Ping; Wu, Min-yuan; Li, Zhi-gang; Hu, Ya-mei

2003-12-01

For the purpose of clarifying the influence of thiopurine methyltransferase (TPMT) gene single nucleotide polymorphisms (SNPs) on the efficacy of thiopurines and risk for its toxicity and therefore improving the safety and efficacy of thiopurines, the authors investigated TPMT genotype in acute leukemia in children who were intolerant to the treatment with 6-mercap topurine (6-MP). TPMT genotype was determined in an unrelated population of 250 Chinese healthy blood donors and 280 children with acute leukemia. TPMT genotyping assay was based on polymerase chain reaction (PCR), restriction digestion of PCR products, denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing in the TPMT * 2 (G238C), TPMT * 3A (G460A, A719G) and TPMT * 3C (A719G). There were 10 TPMT * 1/TPMT * 3C heterozygotes in 280 children. The frequency of the polymorphism was 3.6%. All the involved alleles were TPMT * 3C. Of the 160 children acute leukemia evaluated, 45 (26%) were intolerant to 6-MP. Presentations included hepatotoxicity and hematological toxicity. Six out of 45 children were heterozygous, while the other 39 were wild type homozygous. Before dosage adjustments for thiopurine, the hematologic toxicity and hepatotoxicity in TPMT heterozygous individuals occurred more frequently than in homozygous. Therefore, cases of TPMT heterozygotes experienced more missed doses of 6-MP. TPMT genotype is associated with tolerance in acute leukemia in children. The heterozygote individuals have low TPMT activity. Therefore the frequencies of hemtopoietic toxicity and hepatoxicity are high after using 6-MP. Detection of SNPs in the TPMT genes is useful in identifying children before administration of 6-MP.

Estimation of maximum tolerated dose for long-term bioassays from acute lethal dose and structure by QSAR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gombar, V.K.; Enslein, K.; Hart, J.B.

1991-09-01

A quantitative structure-activity relationship (QSAR) model has been developed to estimate maximum tolerated doses (MTD) from structural features of chemicals and the corresponding oral acute lethal doses (LD50) as determined in male rats. The model is based on a set of 269 diverse chemicals which have been tested under the National Cancer Institute/National Toxicology Program (NCI/NTP) protocols. The rat oral LD50 value was the strongest predictor. Additionally, 22 structural descriptors comprising nine substructural MOLSTAC(c) keys, three molecular connectivity indices, and sigma charges on 10 molecular fragments were identified as endpoint predictors. The model explains 76% of the variance and ismore » significant (F = 35.7) at p less than 0.0001 with a standard error of the estimate of 0.40 in the log (1/mol) units used in Hansch-type equations. Cross-validation showed that the difference between the average deleted residual square (0.179) and the model residual square (0.160) was not significant (t = 0.98).« less

Effect of Bacopasides on acquisition and expression of morphine tolerance.

PubMed

Rauf, Khalid; Subhan, Fazal; Abbas, Muzaffar; Badshah, Amir; Ullah, Ihsan; Ullah, Sami

2011-07-15

Opioids are extensively used for the management of both chronic malignant and non malignant pains. One major serious limitation associated with chronic use of opioids is the development of tolerance to its analgesic effect. The effect of Bacopa monnieri, a renowned ayurvedic medicine for acquisition and expression of morphine tolerance in mice, was investigated. Bacopa monnieri, n-Butanol fraction was analyzed on High performance liquid chromatography (HPLC), for Bacopaside A major components i.e. Bacoside A(3), Bacopaside ll and Bacosaponin C. Antinociceptive effect of n-Butanol extract of Bacopa monnieri (n Bt-ext BM) (5, 10 and 15 mg/kg) was assessed on hot plate. Effect of different doses of n Bt-ext BM on morphine antinociception was also assessed. n Bt-ext BM was also screened for development of tolerance to antinociceptive effect of Bacopa monnieri by administering 15 mg/kg n Bt-ext BM for seven days. Tolerance to morphine analgesia was induced in mice by administering intraperitoneally (I.P.) 20 mg/kg morphine twice daily for five days. Acute and Chronic administration of 5, 10 and 15 mg/kg n Bt-ext BM significantly reduced both expression and development of tolerance to morphine analgesia in mice. Additionally, Bacopa monnieri was found to enhance antinociceptive effect of morphine in intolerant animals. However, no tolerance to Bacopa monnieri antinociceptive effect was observed in seven days treatment schedule. These findings indicate effectiveness of Bacopa monnieri for management of morphine tolerance. Copyright © 2011 Elsevier GmbH. All rights reserved.

Effects of Shilajit on the development of tolerance to morphine in mice.

PubMed

Tiwari, P; Ramarao, P; Ghosal, S

2001-03-01

Effects of concomitant administration of Processed Shilajit (PS, 0.1 and 1 mg/kg, i.p.), in Swiss mice were evaluated on the development of tolerance to morphine induced analgesia in the hot plate test. Chronic administration of morphine (10 mg/kg, i.p., b.i.d.) to mice over a duration of 10 days resulted in the development of tolerance to the analgesic effect of morphine. Concomitant administration of PS with morphine, from day 6 to day 10, resulted in a significant inhibition of the development of tolerance to morphine (10 mg/kg, i.p.) induced analgesia. Processed Shilajit per se, in the doses used, did not elicit any significant analgesia in mice; nor did the chronic concomitant administration of Processed Shilajit alter the morphine-induced analgesia. These findings with Processed Shilajit indicate its potential as a prospective modifier of analgesic tolerance to morphine. Copyright 2001 John Wiley & Sons, Ltd.

Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effectiveness, tolerability, safety, and future applications

PubMed Central

Chou, Timothy Y; Hong, Bennett Y

2014-01-01

Eye disease due to herpes simplex virus (HSV) is a leading cause of ocular morbidity and the number one infectious cause of unilateral corneal blindness in the developed parts of the globe. Recurrent keratitis can result in progressive corneal scarring, thinning, and vascularization. Antiviral agents employed against HSV have primarily been nucleoside analogs. Early generation drugs included idoxuridine, iododesoxycytidine, vidarabine, and trifluridine. While effective, they tended to have low bioavailability and measurable local cellular toxicity due to their nonselective mode of action. Acyclovir 0.3% ointment is a more selective agent, and had become a first-line topical drug for acute HSV keratitis in Europe and other places outside of the US. Ganciclovir 0.15% gel is the most recently approved topical treatment for herpes keratitis. Compared to acyclovir 0.3% ointment, ganciclovir 0.15% gel has been shown to be better tolerated and no less effective in several Phase II and III trials. Additionally, topical ganciclovir does not cause adverse systemic side effects and is therapeutic at lower concentrations. Based on safety, efficacy, and tolerability, ganciclovir 0.15% gel should now be considered a front-line topical drug in the treatment of dendritic herpes simplex epithelial keratitis. Topics of future investigation regarding other potential uses for ganciclovir gel may include the prophylaxis of recurrent HSV epithelial keratitis, treatment of other forms of ocular disease caused by herpesviruses and adenovirus, and ganciclovir gel as an adjunct to antitumor therapy. PMID:25187721

Comparison of tizanidine and morphine with regard to tolerance-developing ability to antinociceptive action.

PubMed

Nabeshima, T; Yamada, S; Sugimoto, A; Matsuno, K; Kameyama, T

1986-10-01

The antinociceptive, tolerance-developing and anti-withdrawal activities of tizanidine [5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzo-thiadiazole] were investigated by comparing its effects with those of morphine and clonidine in tail-flick-, hot plate-, acetic acid-induced writhing-, and naloxone-precipitated withdrawal jumping-tests. The antinociceptive action of tizanidine was not altered by naloxone, while that of morphine was antagonized. Tolerance to the tizanidine-induced antinociceptive action and to motor incoordination was developed by successive administration of tizanidine. In the tizanidine-tolerant mice, the antinociceptive action of morphine was significantly decreased, but not sleeping time induced by pentobarbital. The action of tizanidine was not modified in the morphine-tolerant mice. Tizanidine failed to induce morphine-withdrawal jumping and to inhibit naloxone-precipitated withdrawal jumping in the morphine-dependent mice. Cross tolerance to the antinociceptive action induced by tizanidine and clonidine was developed. These results suggest that alpha 2-adrenoreceptors may be involved in the action mechanism of tizanidine, but not opioid receptors. Functional tolerance to tizanidine action may be developed by successive administration of tizanidine.

Genetic variance of tolerance and the toxicant threshold model.

PubMed

Tanaka, Yoshinari; Mano, Hiroyuki; Tatsuta, Haruki

2012-04-01

A statistical genetics method is presented for estimating the genetic variance (heritability) of tolerance to pollutants on the basis of a standard acute toxicity test conducted on several isofemale lines of cladoceran species. To analyze the genetic variance of tolerance in the case when the response is measured as a few discrete states (quantal endpoints), the authors attempted to apply the threshold character model in quantitative genetics to the threshold model separately developed in ecotoxicology. The integrated threshold model (toxicant threshold model) assumes that the response of a particular individual occurs at a threshold toxicant concentration and that the individual tolerance characterized by the individual's threshold value is determined by genetic and environmental factors. As a case study, the heritability of tolerance to p-nonylphenol in the cladoceran species Daphnia galeata was estimated by using the maximum likelihood method and nested analysis of variance (ANOVA). Broad-sense heritability was estimated to be 0.199 ± 0.112 by the maximum likelihood method and 0.184 ± 0.089 by ANOVA; both results implied that the species examined had the potential to acquire tolerance to this substance by evolutionary change. Copyright © 2012 SETAC.

Levetiracetam as a possible contributor to acute kidney injury.

PubMed

Spengler, Danielle C; Montouris, Georgia D; Hohler, Anna D

2014-08-01

Levetiracetam is an antiepileptic medication that has been reported to be both well-tolerated and effective in treating generalized tonic-clonic, myoclonic, and partial-onset seizures. The adverse effects most commonly reported in tolerability trials include somnolence, fatigue/asthenia, headaches, dizziness, and nausea. However, there have been a few reports suggesting possible detrimental effects of levetiracetam on renal function. Here we describe the case of a previously healthy 23-year-old female patient who developed acute kidney injury 1 day after the initiation of levetiracetam therapy for new-onset seizures. Based on the time course of the patient's rise in serum creatinine and the exclusion of other causes, this case suggests that levetiracetam use contributed to the acute kidney injury. Levetiracetam is a widely used drug that has been reported to be generally tolerable and effective; however, it has the potential to negatively affect renal function. This potential consequence of therapy should be considered when deciding whether or not to prescribe this medication, and renal function should be monitored during treatment. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

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.).

Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury

PubMed Central

Li, Li; Huang, Liping; Ye, Hong; Song, Steven P.; Bajwa, Amandeep; Lee, Sang Ju; Moser, Emily K.; Jaworska, Katarzyna; Kinsey, Gilbert R.; Day, Yuan J.; Linden, Joel; Lobo, Peter I.; Rosin, Diane L.; Okusa, Mark D.

2012-01-01

DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important antiinflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR–induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI. PMID:23093781

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.

Role of dietary immunomodulatory factors in the development of immune tolerance.

PubMed

Prescott, Susan L

2009-01-01

The development of oral tolerance occurs during critical early stages of immune development. Rising rates of food allergy and other immune-mediated food reactions are an indication that oral tolerance is highly susceptible to environmental change. There is growing evidence that this many not be due food allergens per se, but rather to changing exposure to other key immunomodulatory exposures in this critical period. Successful tolerance appears to depend on many concurrent environmental influences during the period of first allergen encounter, including favorable gut colonization, and the presence of key immunomodulatory factors in breast milk and the infant diet. This review explores the potential effects of early dietary and nutritional factors in tolerogenic immune processes that are normally initiated during initial food allergen encounter. Copyright 2009 Nestec Ltd., Vevey/S. Karger AG, Basel.

Ethanol Reversal of Cellular Tolerance to Morphine in Rat Locus Coeruleus Neurons

PubMed Central

Llorente, Javier; Withey, Sarah; Rivero, Guadalupe; Cunningham, Margaret; Cooke, Alex; Saxena, Kunal; McPherson, Jamie; Oldfield, Sue; Dewey, William L.; Bailey, Chris P.; Kelly, Eamonn; Henderson, Graeme

2013-01-01

Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala2,N-MePhe4,Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have revealed a role for protein kinase C (PKC)α in μ-opioid receptor (MOPr) desensitization by morphine and in the induction and maintenance of morphine tolerance, but we have been unable to demonstrate that 20 mM ethanol produces significant inhibition of PKCα. The ability of ethanol to reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293 cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine. Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the efficacy of morphine for G-protein activation as measured by guanosine 5′-O-(3-[35S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying morphine cellular tolerance. PMID:23716621

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.

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. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

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 Central

Withey, Sarah L.; Hill, Rob; Lyndon, Abigail; Dewey, William L.; Kelly, Eamonn

2017-01-01

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. PMID:28130265

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

Ethanol Tolerance Affects Endogenous Adenosine Signaling in Mouse Hippocampus.

PubMed

Zhang, Dali; Xiong, Wei; Jackson, Michael F; Parkinson, Fiona E

2016-07-01

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 Mg(2+) 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. Copyright © 2016 The Author(s).

Augmentation of the development of behavioral tolerance to cannabinoid administration through pavlovian conditioning.

PubMed

Hill, Matthew N; Gorzalka, Boris B; Choi, Joyce W

2004-01-01

This investigation examined the effects, in female rats, of a Pavlovian conditioning paradigm on the development of tolerance to hypolocomotion induced by the cannabinoid agonist HU-210. Rats were administered HU-210 and placebo in either an associative or a nonassociative fashion. The results indicated that rats in the associative paradigm developed tolerance significantly faster than those in the nonassociative group (p < 0.03). Subsequently, once tolerance had developed, the associative group of rats was administered HU-210 and placebo in the opposite environments. There were no differences found in locomotion between the CS+ and CS- environments following administration of HU-210. However, when the placebo was administered in the CS+ environment, there was a trend towards increased activity levels (p = 0.06), suggesting withdrawal-like behavior. These findings indicate that the underlying physiological mechanisms of tolerance development in the cannabinoid system are hastened by conditioning, but that these physiological alterations are not contingent upon the associative parameters used for drug administration. Copyright 2004 S. Karger AG, Basel

Markers of inflammation and tolerance development in allergic proctocolitis.

PubMed

Nacaroglu, Hikmet T; Bahceci Erdem, Semiha; Durgun, Ersin; Karaman, Sait; Baris Erdur, Cahit; Unsal Karkmer, Canan S; Can, Demet

2018-02-01

Today, as a result of an increase in the frequency of food protein-induced allergic proctocolitis (FPIAP), there is a need for studies not only to enlighten the pathophysiology of the disease but also to determine simple, non-invasive markers in both diagnosis, and evaluation of the development of tolerance. No study has been found in the literature about the place of neutrophil/lymphocyte ratio (NLR) and mean platelet volume (MPV), which are easy to calculate and non-invasive markers. The purpose is to determine the relation between NLR and MPV with the diagnosis and development of tolerance in children with FPIAP. In this retrospective cross-sectional study, clinical, demographic symptoms and laboratory findings of patients, monitored with FPIAP diagnosis in allergy and gastroenterology clinics, were acquired from the patient record system. Hemogram values at the time of diagnosis were compared with the values of healthy children of the same age and gender. Among 59 patients diagnosed with FPIAP, males constitute 47.4% and females constitute 52.6%. MPV and platelet crit (PCT) values were significantly high when compared to the control group (n: 67) in FPIAP cases (p < 0.001). Also, MPV and PCT values were significantly high in non-tolerance developing cases when compared to developing ones (p= 0.01). Contrary to NLR, MPV and PCT values have been considered to be good markers in predicting prognosis in cases with FPIAP since they are quick, cost effective and easy to calculate. Sociedad Argentina de Pediatría

Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts.

PubMed

Azuma, H; Isaka, Y; Li, X; Hünig, T; Sakamoto, T; Nohmi, H; Takabatake, Y; Mizui, M; Kitazawa, Y; Ichimaru, N; Ibuki, N; Ubai, T; Inamoto, T; Katsuoka, Y; Takahara, S

2008-10-01

The ultimate goal of organ transplantation is to establish graft tolerance where CD4+CD25+FOXP3+ regulatory T (Treg) cells play an important role. We examined whether a superagonistic monoclonal antibody specific for CD28 (CD28 SA), which expands Treg cells in vivo, would prevent acute rejection and induce tolerance using our established rat acute renal allograft model (Wistar to Lewis). In the untreated or mouse IgG-treated recipients, graft function significantly deteriorated with marked destruction of renal tissue, and all rats died by 13 days with severe azotemia. In contrast, 90% of recipients treated with CD28 SA survived over 100 days, and 70% survived with well-preserved graft function until graft recovery at 180 days. Analysis by flow cytometry and immunohistochemistry demonstrated that CD28 SA induced marked infiltration of FOXP3+ Treg cells into the allografts. Furthermore, these long-surviving recipients showed donor-specific tolerance, accepting secondary (donor-matched) Wistar cardiac allografts, but acutely rejecting third-party BN allografts. We further demonstrated that adoptive transfer of CD4+CD25+ Treg cells, purified from CD28 SA-treated Lewis rats, significantly prolonged allograft survival and succeeded in inducing donor-specific tolerance. In conclusion, CD28 SA treatment successfully induces donor-specific tolerance with the involvement of Treg cells, and thus the therapeutic value of this approach warrants further investigation and preclinical studies.

Immunoneutralization of Agmatine Sensitizes Mice to μ-Opioid Receptor Tolerance

PubMed Central

Wade, Carrie L.; Eskridge, Lori L.; Nguyen, H. Oanh X.; Kitto, Kelley F.; Stone, Laura S.; Wilcox, George

2009-01-01

Systemically or centrally administered agmatine (decarboxylated arginine) prevents, moderates, or reverses opioid-induced tolerance and self-administration, inflammatory and neuropathic pain, and sequelae associated with ischemia and spinal cord injury in rodents. These behavioral models invoke the N-methyl-d-aspartate (NMDA) receptor/nitric-oxide synthase cascade. Agmatine (AG) antagonizes the NMDA receptor and inhibits nitric-oxide synthase in vitro and in vivo, which may explain its effect in models of neural plasticity. Agmatine has been detected biochemically and immunohistochemically in the central nervous system. Consequently, it is conceivable that agmatine operates in an anti-glutamatergic manner in vivo; the role of endogenous agmatine in the central nervous system remains minimally defined. The current study used an immunoneutralization strategy to evaluate the effect of sequestration of endogenous agmatine in acute opioid analgesic tolerance in mice. First, intrathecal pretreatment with an anti-AG IgG (but not normal IgG) reversed an established pharmacological effect of intrathecal agmatine: antagonism of NMDA-evoked behavior. This result justified the use of anti-AG IgG to sequester endogenous agmatine in vivo. Second, intrathecal pretreatment with the anti-AG IgG sensitized mice to induction of acute spinal tolerance of two μ-opioid receptor-selective agonists, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin and endomorphin-2. A lower dose of either agonist that, under normal conditions, produces moderate or no tolerance was tolerance-inducing after intrathecal pretreatment of anti-AG IgG (but not normal IgG). The effect of the anti-AG IgG lasted for at least 24 h in both NMDA-evoked behavior and the acute opioid tolerance. These results suggest that endogenous spinal agmatine may moderate glutamate-dependent neuroplasticity. PMID:19684255

Immunoneutralization of agmatine sensitizes mice to micro-opioid receptor tolerance.

PubMed

Wade, Carrie L; Eskridge, Lori L; Nguyen, H Oanh X; Kitto, Kelley F; Stone, Laura S; Wilcox, George; Fairbanks, Carolyn A

2009-11-01

Systemically or centrally administered agmatine (decarboxylated arginine) prevents, moderates, or reverses opioid-induced tolerance and self-administration, inflammatory and neuropathic pain, and sequelae associated with ischemia and spinal cord injury in rodents. These behavioral models invoke the N-methyl-D-aspartate (NMDA) receptor/nitric-oxide synthase cascade. Agmatine (AG) antagonizes the NMDA receptor and inhibits nitric-oxide synthase in vitro and in vivo, which may explain its effect in models of neural plasticity. Agmatine has been detected biochemically and immunohistochemically in the central nervous system. Consequently, it is conceivable that agmatine operates in an anti-glutamatergic manner in vivo; the role of endogenous agmatine in the central nervous system remains minimally defined. The current study used an immunoneutralization strategy to evaluate the effect of sequestration of endogenous agmatine in acute opioid analgesic tolerance in mice. First, intrathecal pretreatment with an anti-AG IgG (but not normal IgG) reversed an established pharmacological effect of intrathecal agmatine: antagonism of NMDA-evoked behavior. This result justified the use of anti-AG IgG to sequester endogenous agmatine in vivo. Second, intrathecal pretreatment with the anti-AG IgG sensitized mice to induction of acute spinal tolerance of two micro-opioid receptor-selective agonists, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin and endomorphin-2. A lower dose of either agonist that, under normal conditions, produces moderate or no tolerance was tolerance-inducing after intrathecal pretreatment of anti-AG IgG (but not normal IgG). The effect of the anti-AG IgG lasted for at least 24 h in both NMDA-evoked behavior and the acute opioid tolerance. These results suggest that endogenous spinal agmatine may moderate glutamate-dependent neuroplasticity.

Mitochondrial Sirtuin 4 Resolves Immune Tolerance in Monocytes by Rebalancing Glycolysis and Glucose Oxidation Homeostasis

PubMed Central

Tao, Jie; Zhang, Jingpu; Ling, Yun; McCall, Charles E.; Liu, Tie Fu

2018-01-01

The goal of this investigation was to define the molecular mechanism underlying physiologic conversion of immune tolerance to resolution of the acute inflammatory response, which is unknown. An example of this knowledge gap and its clinical importance is the broad-based energy deficit and immunometabolic paralysis in blood monocytes from non-survivors of human and mouse sepsis that precludes sepsis resolution. This immunometabolic dysregulation is biomarked by ex vivo endotoxin tolerance to increased glycolysis and TNF-α expression. To investigate how tolerance switches to resolution, we adapted our previously documented models associated with acute inflammatory, immune, and metabolic reprogramming that induces endotoxin tolerance as a model of sepsis in human monocytes. We report here that mitochondrial sirtuin 4 (SIRT4) physiologically breaks tolerance and resolves acute inflammation in human monocytes by coordinately reprogramming of metabolism and bioenergetics. We find that increased SIRT4 mRNA and protein expression during immune tolerance counters the increase in pyruvate dehydrogenase kinase 1 (PDK1) and SIRT1 that promote tolerance by switching glucose-dependent support of immune resistance to fatty acid oxidation support of immune tolerance. By decreasing PDK1, pyruvate dehydrogenase complex reactivation rebalances mitochondrial respiration, and by decreasing SIRT1, SIRT4 represses fatty acid oxidation. The precise mechanism for the mitochondrial SIRT4 nuclear feedback is unclear. Our findings are consistent with a new concept in which mitochondrial SIRT4 directs the axis that controls anabolic and catabolic energy sources. PMID:29593712

Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans

PubMed Central

Sagoo, Pervinder; Perucha, Esperanza; Sawitzki, Birgit; Tomiuk, Stefan; Stephens, David A.; Miqueu, Patrick; Chapman, Stephanie; Craciun, Ligia; Sergeant, Ruhena; Brouard, Sophie; Rovis, Flavia; Jimenez, Elvira; Ballow, Amany; Giral, Magali; Rebollo-Mesa, Irene; Le Moine, Alain; Braudeau, Cecile; Hilton, Rachel; Gerstmayer, Bernhard; Bourcier, Katarzyna; Sharif, Adnan; Krajewska, Magdalena; Lord, Graham M.; Roberts, Ian; Goldman, Michel; Wood, Kathryn J.; Newell, Kenneth; Seyfert-Margolis, Vicki; Warrens, Anthony N.; Janssen, Uwe; Volk, Hans-Dieter; Soulillou, Jean-Paul; Hernandez-Fuentes, Maria P.; Lechler, Robert I.

2010-01-01

Identifying transplant recipients in whom immunological tolerance is established or is developing would allow an individually tailored approach to their posttransplantation management. In this study, we aimed to develop reliable and reproducible in vitro assays capable of detecting tolerance in renal transplant recipients. Several biomarkers and bioassays were screened on a training set that included 11 operationally tolerant renal transplant recipients, recipient groups following different immunosuppressive regimes, recipients undergoing chronic rejection, and healthy controls. Highly predictive assays were repeated on an independent test set that included 24 tolerant renal transplant recipients. Tolerant patients displayed an expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, a lack of donor-specific antibodies, donor-specific hyporesponsiveness of CD4+ T cells, and a high ratio of forkhead box P3 to α-1,2-mannosidase gene expression. Microarray analysis further revealed in tolerant recipients a bias toward differential expression of B cell–related genes and their associated molecular pathways. By combining these indices of tolerance as a cross-platform biomarker signature, we were able to identify tolerant recipients in both the training set and the test set. This study provides an immunological profile of the tolerant state that, with further validation, should inform and shape drug-weaning protocols in renal transplant recipients. PMID:20501943

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...

[A patient with acute Philadelphia-chromosome-positive mixed phenotype leukemia developing ecthyma gangrenosum while undergoing combined imatinib mesylate chemotherapy].

PubMed

Suzuki, Kei; Sekine, Takao

2014-05-01

A 67-year-old woman with acute Philadelphia-chromosome-positive mixed phenotype leukemia developed bilateral periorbital ecthyma gangrenousum (EG) subsequent to periorbital edema while undergoing combined imatinib mesylate (imatinib) chemotherapy. Although initial periorbital edema was considered an imatinib side effect, the lesion deteriorated rapidly with high fever in the neutropenic phase, and the woman died of septic shock. Cultures from blood and exudative fluid grew Pseudomonas aeruginosa, after which EG was diagnosed. EG is a well-recognized emergent cutaneous infection most commonly associated with Pseudomonas aeruginosa bactremia. Because some patients present with EG a few days prior to developing life-threatening septicemia, it is important that EG be diagnosed correctly. Imatinib side effects such as edema are usually tolerable, and imatinib is widely used to treat Philadelphia-chromosome-positive leukemia, particularly in those with acute lymphoblastic leukemia, and neutropenic patients undergoing imatinib therapy are expected to increase in number. Delay in initiating appropriate therapy is correlated with poor outcome, so drug side effects and EG must be carefully differentiated when skin edema with surrounding erythema is noted in neutropenic patients undergoing imatinib therapy.

The impact of acute lymphocytic leukemia on diabetic retinopathy.

PubMed

Melberg, N S; Grand, M G; Rup, D

1995-02-01

A 16 year-old girl with a 9-year history of insulin-dependent diabetes mellitus developed acute lymphocytic leukemia. The patient's vision deteriorated from normal to legal blindness within 6 months as her ophthalmologic examination progressed from minimal background diabetic retinopathy to severe proliferative diabetic retinopathy. The accelerated course of diabetic eye disease is attributable to the moderate anemia resulting from the leukemia and its treatment. Although anemia is usually well tolerated by young patients, it is not well tolerated by the diabetic retina. Diabetic patients require close ophthalmologic follow-up and aggressive management to maintain normal hemoglobin levels.

Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance

PubMed Central

Steinman, Ralph Marvin; Nussenzweig, Michel C.

2002-01-01

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. PMID:11773639

The outcomes of children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference.

PubMed

Quasney, Michael W; López-Fernández, Yolanda M; Santschi, Miriam; Watson, R Scott

2015-06-01

To provide additional details and evidence behind the recommendations for outcomes assessment of patients with pediatric acute respiratory distress syndrome from the Pediatric Acute Lung Injury Consensus Conference. Consensus conference of experts in pediatric acute lung injury. A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The outcomes subgroup comprised four experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was used. The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, seven of which related to outcomes after pediatric acute respiratory distress syndrome. All seven recommendations had strong agreement. Children with acute respiratory distress syndrome continue to have a high mortality, specifically, in relation to certain comorbidities and etiologies related to pediatric acute respiratory distress syndrome. Comorbid conditions, such as an immunocompromised state, increase the risk of mortality even further. Likewise, certain etiologies, such as non-pulmonary sepsis, also place children at a higher risk of mortality. Significant long-term effects were reported in adult survivors of acute respiratory distress syndrome: diminished lung function and exercise tolerance, reduced quality of life, and diminished neurocognitive function. Little knowledge of long-term outcomes exists in children who survive pediatric acute respiratory distress syndrome. Characterization of the longer term consequences of pediatric acute respiratory distress syndrome in children is vital to help identify opportunities for improved therapeutic and rehabilitative strategies that will lessen the long-term burden of pediatric acute

77 FR 73940 - Flubendiamide; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-12

... in c/o Nichino America, Inc. (U.S. subsidiary of Nihon Nohyaku Co., Ltd.), P.O. Box 12014, Research... increases in the tolerances for pome fruit and wet apple pomace as follows: i. Acute exposure. Quantitative... level residues, assuming 100% of crops were treated. In addition, experimental processing (where...

Transcription factors involved in drought tolerance and their possible role in developing drought tolerant cultivars with emphasis on wheat (Triticum aestivum L.).

PubMed

Gahlaut, Vijay; Jaiswal, Vandana; Kumar, Anuj; Gupta, Pushpendra Kumar

2016-11-01

TFs involved in drought tolerance in plants may be utilized in future for developing drought tolerant cultivars of wheat and some other crops. Plants have developed a fairly complex stress response system to deal with drought and other abiotic stresses. These response systems often make use of transcription factors (TFs); a gene encoding a specific TF together with -its target genes constitute a regulon, and take part in signal transduction to activate/silence genes involved in response to drought. Since, five specific families of TFs (out of >80 known families of TFs) have gained widespread attention on account of their significant role in drought tolerance in plants, TFs and regulons belonging to these five multi-gene families (AP2/EREBP, bZIP, MYB/MYC, NAC and WRKY) have been described and their role in improving drought tolerance discussed in this brief review. These TFs often undergo reversible phosphorylation to perform their function, and are also involved in complex networks. Therefore, some details about reversible phosphorylation of TFs by different protein kinases/phosphatases and the co-regulatory networks, which involve either only TFs or TFs with miRNAs, have also been discussed. Literature on transgenics involving genes encoding TFs and that on QTLs and markers associated with TF genes involved in drought tolerance has also been reviewed. Throughout the review, there is a major emphasis on wheat as an important crop, although examples from the model cereal rice (sometimes maize also), and the model plant Arabidopsis have also been used. This knowledge base may eventually allow the use of TF genes for development of drought tolerant cultivars, particularly in wheat.

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

Effect of Peripheral μ-, δ-, and κ-Opioid Ligands on the Development of Tolerance to Ethanol-Induced Analgesia.

PubMed

Sudakov, S K; Alekseeva, E V; Nazarova, G A

2017-06-01

We studied the rate of development of tolerance to the ethanol-induced analgesia under the effect of μ-, δ-, and κ-opioid agonists and antagonists not crossing the blood-brain barrier and rapidly inactivated by gastric and duodenal proteolytic enzymes. Activation of gastric κ-opioid receptors eliminated the analgesic effect of ethanol and accelerated the development of tolerance to ethanol-induced analgesia. In contrast, activation of gastric μ-opioid receptors decelerated the development of this tolerance. Activation of gastric δ-opioid receptors produced no effect on examined tolerance. μ-Opioid receptor antagonist decelerated and δ-opioid receptor antagonist accelerated the development of tolerance to ethanol-induced analgesia. Thus, the state of gastric opioid receptors affects the manifestation of ethanol-induced analgesia and the development of tolerance to this effect.

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

RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice.

PubMed

Yasuda, Makiko; Gan, Lin; Chen, Brenden; Kadirvel, Senkottuvelan; Yu, Chunli; Phillips, John D; New, Maria I; Liebow, Abigail; Fitzgerald, Kevin; Querbes, William; Desnick, Robert J

2014-05-27

The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias.

Tolerance and sensitization to inhaled 1,1,1-trichloroethane in mice: results from open-field behavior and a functional observational battery.

PubMed

Bowen, Scott E; Balster, Robert L

2006-05-01

1,1,1-Trichloroethane (TCE), a representative abused solvent, has well described acute behavioral effects in animals. Much less is known about repeated high-concentration exposures as would be encountered in inhalant abusers. Tolerance has been demonstrated in some, but not all, studies with TCE while sensitization has also been seen with other abused solvents. The present study was designed to further characterize changes in the effects of repeated exposure to TCE on a variety of mouse behaviors. Mice were tested using locomotor activity as well as a functional observational battery (FOB) both before and after a regimen of daily exposures to various concentrations of TCE. The initial locomotor effects of acute 30-min exposures to TCE were biphasic with concentration-dependent increases in activity at lower concentrations and decreases observed at higher concentrations. The profile of acute effects as measured by the FOB included changes in posture, decreased arousal, disturbances in gait, delayed righting reflexes, and decreased sensorimotor reactivity. Animals were then divided into five groups and exposed 30 min/day to either air or one of four concentrations of TCE (2,000, 6,000, 10,000, or 13,300 ppm) for 15 consecutive days. The TCE concentration used primarily affected the magnitude of change, not whether tolerance or sensitization occurred. Tolerance developed on the measures of forelimb grip strength, inverted screen, and number of rears. Conversely, sensitization developed to measures of locomotor activity. Depending on the behavioral measure, both tolerance and sensitization can occur in mice with repeated exposure to TCE. Both of these phenomena are characteristic of drugs of abuse.

The research and development of damage tolerant carbon fiber composites

NASA Astrophysics Data System (ADS)

Miranda, John Armando

This record of study takes a first hand look at corporate research and development efforts to improve the damage tolerance of two unique composite materials used in high performance aerospace applications. The professional internship with The Dow Chemical Company---Dow/United Technologies joint venture describes the intern's involvement in developing patentable process technologies for interleave toughening of high temperature resins and their composites. The subsequent internship with Hexcel Corporation describes the intern's involvement in developing the damage tolerance of novel and existing honeycomb sandwich structure technologies. Through the Doctor of Engineering professional internship experience this student exercised fundamental academic understanding and methods toward accomplishing the corporate objectives of the internship sponsors in a resource efficient and cost-effective manner. Also, the student gained tremendous autonomy through exceptional training in working in focused team environments with highly trained engineers and scientists in achieving important corporate objectives.

11C choline PET guided salvage radiotherapy with volumetric modulation arc therapy and hypofractionation for recurrent prostate cancer after HIFU failure: preliminary results of tolerability and acute toxicity.

PubMed

Alongi, Filippo; Liardo, Rocco L E; Iftode, Cristina; Lopci, Egesta; Villa, Elisa; Comito, Tiziana; Tozzi, Angelo; Navarria, Pierina; Ascolese, Anna M; Mancosu, Pietro; Tomatis, Stefano; Bellorofonte, Carlo; Arturo, Chiti; Scorsetti, Marta

2014-10-01

The purpose of this work was to evaluate tolerance, feasibility and acute toxicity in patients undergoing salvage radiotherapy after high-intensity focused ultrasound (HIFU) failure. From 2005 to 2011 a total of 15 patients were treated with HIFU as primary radical treatment. Between July 2011 and February 2013, all 15 patients presented biochemical relapse after HIFU and 11C choline PET documenting intrapostatic-only failure. Salvage EBRT was performed with moderate hypofractionation schedule in 28 fractions with volumetric modulation arc therapy (VMAT). Genito-urinary (GU) and rectal and bowel toxicity were scored by common terminology criteria for adverse events version 4 (CTCAE V.4) scale. Biochemical response was assessed by ASTRO Phoenix criteria. Median age of patients was 67 years (range: 53-85). The median Gleason score was 7 (range: 6-9). The median prostate specific antigen (PSA) at the time of biochemical relapse after HIFU was 5.2 ng/mL (range: 2-64.2). Seven of the 15 patients received androgen deprivation therapy (ADT) started after HIFU failure, interrupted before 11C choline PET and radiotherapy. Median prescribed dose was 71.4 Gy (range: 71.4-74.2 Gy) in 28 fractions. No radiation related major upper gastrointestinal (GI), rectal and GU toxicity were experienced. GU, acute grade 1 and grade 2 toxicities were recorded in 7/15 and 4/15 respectively; bowel acute grade 1 and grade 2 toxicities in 4/15 and 1/15; rectal acute grade 1 and grade 2 toxicities in 3/15 and 2/15 respectively. No grade 3 or greater acute or late toxicities occurred. Biochemical control was assessed in 12/15 (80%) patients. With a median follow up of 12 months, three out of 15 patients, with biochemical relapse, showed lymph-nodal recurrence. Our early clinical results and biochemical data confirm the feasibility and show a good tolerance of the 11C choline PET guided salvage radiation therapy after HIFU failure. The findings of low acute toxicity is encouraging, but longer

Linking transcriptional responses to organismal tolerance reveals mechanisms of thermal sensitivity in a mesothermal endangered fish.

PubMed

Komoroske, Lisa M; Connon, Richard E; Jeffries, Ken M; Fangue, Nann A

2015-10-01

Forecasting species' responses to climate change requires understanding the underlying mechanisms governing environmental stress tolerance, including acclimation capacity and acute stress responses. Current knowledge of these physiological processes in aquatic ectotherms is largely drawn from eurythermal or extreme stenothermal species. Yet many species of conservation concern exhibit tolerance windows and acclimation capacities in between these extremes. We linked transcriptome profiles to organismal tolerance in a mesothermal endangered fish, the delta smelt (Hypomesus transpacificus), to quantify the cellular processes, sublethal thresholds and effects of thermal acclimation on acute stress responses. Delta smelt initiated rapid molecular changes in line with expectations of theoretical thermal limitation models, but also exhibited diminished capacity to modify the expression of some genes and cellular mechanisms key to coping with acute thermal stress found in eurytherms. Sublethal critical thresholds occurred 4-6 °C below their upper tolerance limits, and thermal acclimation shifted the onset of acute thermal stress and tolerance as predicted. However, we found evidence that delta smelt's limited thermal plasticity may be partially due to an inability of individuals to effectively make physiological adjustments to truly achieve new homoeostasis under heightened temperatures, resulting in chronic thermal stress. These findings provide insight into the physiological basis of the diverse patterns of thermal tolerances observed in nature. Moreover, understanding how underlying molecular mechanisms shape thermal acclimation capacity, acute stress responses and ultimately differential phenotypes contributes to a predictive framework to deduce species' responses in situ to changes in selective pressures due to climate change. © 2015 John Wiley & Sons Ltd.

Acute Effects of Zolpidem Extended-Release on Cognitive Performance and Sleep in Healthy Males After Repeated Nightly Use

PubMed Central

Kleykamp, Bethea A.; Griffiths, Roland R.; McCann, Una D.; Smith, Michael T.; Mintzer, Miriam Z.

2012-01-01

The extended-release formulation of zolpidem (Ambien CR®) is approved for the treatment of insomnia without a treatment duration limit. Acutely zolpidem impairs performance, and no research to date has examined whether tolerance develops to these performance impairments during nighttime awakening. The present double-blind, placebo-controlled study examined whether tolerance develops to zolpidem-induced acute performance impairment after repeated (22–30 days) nightly use. Effects of bedtime administration of zolpidem extended-release (ZOL; 12.5 mg) were tested on a battery of performance measures assessed during a forced nighttime awakening in 15 healthy male volunteers who completed overnight polysomnographic recording sessions in our laboratory at baseline and after approximately a month of at-home ZOL. As expected, bedtime ZOL administration was associated with changes in sleep architecture and impairments across all performance domains during nighttime testing (psychomotor function, attention, working memory, episodic memory, metacognition) with no residual next morning impairment. Tolerance did not develop to the observed ZOL-related impairments on any outcome. Possible evidence of acute abstinence effects following discontinuation of ZOL was observed on some performance and sleep outcomes. Overall, these findings suggest that performance is significantly impaired during nighttime awakening even after a month of nightly ZOL administration and these impairments could significantly impact safety should nighttime awakening require unimpaired functioning (e.g., driving; combat-related activities in the military). PMID:21928913

Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review.

PubMed

Kim, Sang Hun; Stoicea, Nicoleta; Soghomonyan, Suren; Bergese, Sergio D

2014-01-01

The use of opioids has been increasing in operating room and intensive care unit to provide perioperative analgesia as well as stable hemodynamics. However, many authors have suggested that the use of opioids is associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) in experimental studies and clinical observations in dose and/or time dependent exposure even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management during anesthesia as well as in the intensive care units because of its rapid onset and offset. Search of the available literature to assess remifentanil AOT and OIH based on available published data. We reviewed articles analyzing remifentanil AOT and OIH, and focused our literature search on evidence based information. Experimental and clinical studies were identified using electronic searches of Medline (PubMed, Ovid, Springer, and Elsevier, ClinicalKey). Our results showed that the development of remifentanil AOT and OIH is a clinically significant phenomenon requiring further research. AOT - defined as an increase in the required opioid dose to maintain adequate analgesia, and OIH - defined as decreased pain threshold after chronic opioid treatment, should be suspected with any unexplained pain report unassociated with the disease progression. The clinical significance of these findings was evaluated taking into account multiple methodological issues including the dose and duration of opioids administration, the different infusion mode, the co-administrated anesthetic drug's effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion. Future studies need to investigate the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process.

Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments.

PubMed

Elhabazi, K; Trigo, J M; Mollereau, C; Moulédous, L; Zajac, J-M; Bihel, F; Schmitt, M; Bourguignon, J J; Meziane, H; Petit-demoulière, B; Bockel, F; Maldonado, R; Simonin, F

2012-01-01

BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments

PubMed Central

Elhabazi, K; Trigo, JM; Mollereau, C; Moulédous, L; Zajac, J-M; Bihel, F; Schmitt, M; Bourguignon, JJ; Meziane, H; Petit-demoulière, B; Bockel, F; Maldonado, R; Simonin, F

2012-01-01

BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence. PMID:21718302

Proinflammatory cytokines oppose opioid induced acute and chronic analgesia

PubMed Central

Hutchinson, Mark R.; Coats, Benjamen D.; Lewis, Susannah S.; Zhang, Yingning; Sprunger, David B.; Rezvani, Niloofar; Baker, Eric M.; Jekich, Brian M.; Wieseler, Julie L.; Somogyi, Andrew A.; Martin, David; Poole, Stephen; Judd, Charles M.; Maier, Steven F.; Watkins, Linda R.

2008-01-01

Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring ≤5 minutes after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia. PMID:18599265

Modulation of morphine antinociceptive tolerance and physical dependence by co-administration of simvastatin.

PubMed

Mansouri, Mohammad Taghi; Khodayar, Mohammad Javad; Tabatabaee, Amirhossein; Ghorbanzadeh, Behnam; Naghizadeh, Bahareh

2015-10-01

Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, are widely used in the management of different diseases beyond their primary indication for lowering cholesterol. Previous studies have demonstrated the neuroprotective effects of simvastatin in different animal models. In the present study, we examined the effects of simvastatin (30, 60, 100 and 300mg/kg, p.o.) on the development and expression of morphine-induced tolerance and dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10mg/kg, s.c.) for 5 consecutive days. Tolerance was evaluated by the hot-plate test and physical dependence by naloxone challenge, on the sixth day. The results showed that oral administration of simvastatin produced antinociceptive activity in a dose-dependent way. Co-administration of simvastatin with morphine did not affect the acute morphine-induced analgesia (10mg/kg, s.c.). However, repeated co-administration of simvastatin with morphine significantly attenuated the development of tolerance to the analgesic effect of morphine and inhibited the naloxone (5mg/kg, s.c.)-precipitated withdrawal signs (jumping and body weight loss). Also, simvastatin at doses of 100 and 300mg/kg attenuated the expression of morphine-induced tolerance and dependence. These data indicated that, while simvastatin can alleviate both development and expression of morphine-induced tolerance, it cannot enhance morphine-induced antinociception. Taken together, simvastatin may be used as an adjutant therapeutic agent in combination with morphine and or other opioids in patients with severe chronic pain. Copyright © 2015 Elsevier Inc. All rights reserved.

Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues

PubMed Central

Kant, Cavit D.; Akiyama, Yoshinobu; Tanaka, Katsunori; Shea, Susan; Yamada, Yohei; Connolly, Sarah E; Marino, Jose; Tocco, Georges; Benichou, Gilles

2014-01-01

In this study, we show that aly/aly mice, which are devoid of lymph nodes and Peyer’s patches, rejected acutely fully allogeneic skin and heart grafts. They mounted potent inflammatory direct alloresponses but failed to develop indirect alloreactivity after transplantation. Remarkably, skin allografts were also rejected acutely by splenectomized aly/aly mice (aly/aly-spl−) devoid of all secondary lymphoid organs. In these recipients, the rejection was mediated by alloreactive CD8+ T cells presumably primed in the bone marrow. In contrast, cardiac transplants were not rejected in aly/aly-spl− mice. Actually, aly/aly-spl− mice having spontaneously accepted a heart allotransplant displayed donor-specific tolerance also accepted skin grafts from the same but not a third-party donor via a mechanism involving CD4+ regulatory T cells producing IL-10 cytokine. Therefore, direct priming of alloreactive T cells, as well as rejection and regulatory tolerance of allogeneic transplants, can occur in recipient mice lacking secondary lymphoid organs. PMID:25535285

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

Gastric Helicobacter Infection Inhibits Development of Oral Tolerance to Food Antigens in Mice

PubMed Central

Matysiak-Budnik, Tamara; van Niel, Guillaume; Mégraud, Francis; Mayo, Kathryn; Bevilacqua, Claudia; Gaboriau-Routhiau, Valérie; Moreau, Marie-Christiane; Heyman, Martine

2003-01-01

The increase in the transcellular passage of intact antigens across the digestive epithelium infected with Helicobacter pylori may interfere with the regulation of mucosal immune responses. The aim of this work was to study the capacity of Helicobacter infection to inhibit the development of oral tolerance or to promote allergic sensitization and the capacity of a gastro-protective agent, rebamipide, to interfere with these processes in mice. Oral tolerance to ovalbumin (OVA) was studied in 48 C3H/He 4-week-old mice divided into four groups: (i) OVA-sensitized mice; (ii) OVA-“tolerized” mice (that is, mice that were rendered immunologically tolerant); (iii) H. felis-infected, OVA-tolerized mice; (iv) and H. felis-infected, OVA-tolerized, rebamipide-treated mice. Oral sensitization to hen egg lysozyme (HEL) was studied in 48 mice divided into four groups: (i) controls; (ii) HEL-sensitized mice; (iii) H. felis-infected, HEL-sensitized mice; and (iv) H. felis-infected, HEL-sensitized, rebamipide-treated mice. Specific anti-OVA or anti-HEL immunoglobulin E (IgE) and IgG1/IgG2a serum titers were measured by enzyme-linked immunosorbent assay. Additionally, the capacity of rebamipide to interfere with antigen presentation and T-cell activation in vitro, as well as absorption of rebamipide across the epithelial monolayer, was tested. H. felis infection led to the inhibition of oral tolerance to OVA, but rebamipide prevented this inhibitive effect of H. felis. H. felis infection did not enhance the sensitization to HEL, but rebamipide inhibited the development of this sensitization. Moreover, rebamipide inhibited in a dose-dependent manner antigen presentation and T-cell activation in vitro and was shown to be able to cross the epithelium at a concentration capable of inducing this inhibitory effect. We conclude that H. felis can inhibit the development of oral tolerance to OVA in mice and that this inhibition is prevented by rebamipide. PMID:12933867

78 FR 18504 - Emamectin Benzoate; Pesticide Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-27

... vegetable crop group 9. Interregional Research Project Number 4 (IR-4) requested this tolerance under the... and/or quantitative sensitivity of rat pups was seen in the reproductive toxicity and in the.... Quantitative acute dietary exposure and risk assessments are performed for a food-use pesticide, if a...

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

Light at night acutely impairs glucose tolerance in a time-, intensity- and wavelength-dependent manner in rats.

PubMed

Opperhuizen, Anne-Loes; Stenvers, Dirk J; Jansen, Remi D; Foppen, Ewout; Fliers, Eric; Kalsbeek, Andries

2017-07-01

Exposure to light at night (LAN) has increased dramatically in recent decades. Animal studies have shown that chronic dim LAN induced obesity and glucose intolerance. Furthermore, several studies in humans have demonstrated that chronic exposure to artificial LAN may have adverse health effects with an increased risk of metabolic disorders, including type 2 diabetes. It is well-known that acute exposure to LAN affects biological clock function, hormone secretion and the activity of the autonomic nervous system, but data on the effects of LAN on glucose homeostasis are lacking. This study aimed to investigate the acute effects of LAN on glucose metabolism. Male Wistar rats were subjected to i.v. glucose or insulin tolerance tests while exposed to 2 h of LAN in the early or late dark phase. In subsequent experiments, different light intensities and wavelengths were used. LAN exposure early in the dark phase at ZT15 caused increased glucose responses during the first 20 min after glucose infusion (p < 0.001), whereas LAN exposure at the end of the dark phase, at ZT21, caused increased insulin responses during the first 10 min (p < 0.01), indicating that LAN immediately induces glucose intolerance in rats. Subsequent experiments demonstrated that the effect of LAN was both intensity- and wavelength-dependent. White light of 50 and 150 lx induced greater glucose responses than 5 and 20 lx, whereas all intensities other than 5 lx reduced locomotor activity. Green light induced glucose intolerance, but red and blue light did not, suggesting the involvement of a specific retina-brain pathway. Together, these data show that exposure to LAN has acute adverse effects on glucose metabolism in a time-, intensity- and wavelength-dependent manner.

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

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.

[Fenspiride in patients with acute bronchitis].

PubMed

Płusa, Tadeusz; Ochwat, Agnieszka

2005-07-01

Fenspiride is an anti-inflammatory drug that may have a role in inhibition of histamine receptor H1 and influence a production of archidonic acid metabolites. The efficacy and tolerance of fenspiride therapy have been performed in patients with acute bronchitis. 597 patients, 51% females and 49% males, aged 39+/-18 years, were observed because of acute bronchitis. Fenspiride (Eurespal, Servier) was given in a dose of 240 mg per day (80 mg three times daily) for 14 consecutive days. During two following medical examinations - after 7 and 14 days of treatment, clinical symptoms of disease, therapy efficacy and tolerance were determined. Mean duration of acute bronchitis before fenspiride therapy was 2.3+/-1.3 days. In most of the patients (72%) a moderate, and in 27% mild degree of disease was diagnosed. Only 1% of patients were diagnosed as severe. Total evaluation of fenspiride efficacy in examined patients with acute bronchitis showed complete relief of symptoms after 7 days of therapy in 24% and after 14 days in 87% of patients. In 6% of patients after 7 days and in 1% after 14 days of fenspiride therapy no improvement was obtained. 28 adverse reactions were determined in 26 patients (4.3%): vertigo in 7, nausea in 6, somnolence in 5, palpitations in 4, fatigue in 2, abdominal pain in 2 and other symptoms in 2 patients. In 8 patients the therapy was discontinued after 7 days because of adverse reactions. In performed observations in patients with acute bronchitis the high clinical efficacy of fenspiride therapy. In 12% of patients an antibiotic support was necessary to obtain relief of the symptoms. Very good tolerance of the 14 days therapy was determined and it is recommended for safe clinical application.

Nicotine Activation of α4* Receptors: Sufficient for Reward, Tolerance, and Sensitization

NASA Astrophysics Data System (ADS)

Tapper, Andrew R.; McKinney, Sheri L.; Nashmi, Raad; Schwarz, Johannes; Deshpande, Purnima; Labarca, Cesar; Whiteaker, Paul; Marks, Michael J.; Collins, Allan C.; Lester, Henry A.

2004-11-01

The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with α4 nicotinic subunits containing a single point mutation, Leu9' --> Ala9' in the pore-forming M2 domain, rendering α4* receptors hypersensitive to nicotine. Selective activation of α4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of α4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.

A Case of Acute Pancreatitis developing after Extracorporeal Shock Wave Lithotripsy.

PubMed

Goral, Vedat; Sahin, Erkan; Arslan, Murat

2015-01-01

Extracorporeal shock wave lithotripsy (ESWL) is a standard treatment method used for the treatment of renal calculi and upper ureteral calculi. Acute pancreatitis is a serious condition which develops due to multiple etiologic factors and is characterized by autodigestion of the pancreas. A case of acute pancreatitis which developed following ESWL performed for right renal calculi treatment is presented here. Goral V, Sahin E, Arslan M. A Case of Acute Pancreatitis developing after Extracorporeal Shock Wave Lithotripsy. Euroasian J Hepato-Gastroenterol 2015;5(1):52-54.

Influences on cocaine tolerance assessed under a multiple conjunctive schedule of reinforcement.

PubMed

Yoon, Jin Ho; Branch, Marc N

2009-11-01

Under multiple schedules of reinforcement, previous research has generally observed tolerance to the rate-decreasing effects of cocaine that has been dependent on schedule-parameter size in the context of fixed-ratio (FR) schedules, but not under the context of fixed-interval (FI) schedules of reinforcement. The current experiment examined the effects of cocaine on key-pecking responses of White Carneau pigeons maintained under a three-component multiple conjunctive FI (10 s, 30 s, & 120 s) FR (5 responses) schedule of food presentation. Dose-effect curves representing the effects of presession cocaine on responding were assessed in the context of (1) acute administration of cocaine (2) chronic administration of cocaine and (3) daily administration of saline. Chronic administration of cocaine generally resulted in tolerance to the response-rate decreasing effects of cocaine, and that tolerance was generally independent of relative FI value, as measured by changes in ED50 values. Daily administration of saline decreased ED50 values to those observed when cocaine was administered acutely. The results show that adding a FR requirement to FI schedules is not sufficient to produce schedule-parameter-specific tolerance. Tolerance to cocaine was generally independent of FI-parameter under the present conjunctive schedules, indicating that a ratio requirement, per se, is not sufficient for tolerance to be dependent on FI parameter.

Tolerance to repeated nicotine administration on performance, subjective, and physiological responses in nonsmokers.

PubMed

Heishman, S J; Henningfield, J E

2000-10-01

When administered acutely to nonsmokers, nicotine's effects on performance are inconsistent, perhaps because of suboptimal dosing or initial dysphoria that could interfere with performance. The purpose of this study was to determine if a range of nicotine doses administered for 8 days to nonsmokers would enhance psychomotor and cognitive abilities and to document the development of nicotine tolerance or sensitization. Twelve male volunteers, who reported ever smoking five cigarettes or less, participated in 8 consecutive experimental days in which they were administered four doses of nicotine polacrilex gum each day in this order: 0, 2, 4, and 8 mg. Performance, subjective, and physiological measures were assessed before and after each dose. Plasma nicotine concentration ranged from 6.9 to 11.5 ng/ml following the 8 mg dose. Nicotine increased rate of responding and decreased response time on working memory (digit recall); however, accuracy was impaired. Nicotine also decreased accuracy on visual scanning and attention (two-letter search), and the 8 mg dose impaired gross motor coordination (circular lights). Tolerance did not develop to the performance impairing effects of nicotine. Nicotine produced dose-related increases in ratings of dysphoria and negative mood, including tension, anxiety, nervousness, turning of stomach, and sedation. Tolerance developed to some, but not all, of these aversive effects. Tolerance also was not observed to the increased cardiovascular measures. Although tolerance developed to some of the aversive effects of nicotine, performance enhancement was not observed. These data do not support the hypothesis that nicotine-induced performance enhancement contributes to the reinforcing effects of tobacco use during the early stages of dependence development.

Tolerance to the antinociceptive effects of chronic morphine requires c-Jun N-terminal kinase.

PubMed

Marcus, David J; Zee, Michael; Hughes, Alex; Yuill, Matthew B; Hohmann, Andrea G; Mackie, Ken; Guindon, Josée; Morgan, Daniel J

2015-06-12

Morphine and fentanyl are opioid analgesics in wide clinical use that act through the μ-opioid receptor (MOR). However, one limitation of their long-term effectiveness is the development of tolerance. Receptor desensitization has been proposed as a putative mechanism driving tolerance to G protein-coupled receptor (GPCR) agonists. Recent studies have found that tolerance to morphine is mediated by the c-Jun N-terminal Kinase (JNK) signaling pathway. The goal of the present study was to test the hypotheses that: 1) JNK inhibition will be antinociceptive on its own; 2) JNK inhibition will augment morphine antinociception and; 3) JNK mediates chronic tolerance for the antinociceptive effects of morphine using acute (hotplate and tail-flick), inflammatory (10 μl of formalin 2.5%) and chemotherapy (cisplatin 5 mg/kg ip once weekly)-induced neuropathic pain assays. We found that JNK inhibition by SP600125 (3 mg/kg) produces a greater antinociceptive effect than morphine (6 mg/kg) alone in the formalin test. Moreover, co-administration of morphine (6 mg/kg) with SP600125 (3 mg/kg) produced a sub-additive antinociceptive effect in the formalin test. We also show that pre-treatment with SP600125 (3 or 10 mg/kg), attenuates tolerance to the antinociceptive effects of morphine (10 mg/kg), but not fentanyl (0.3 mg/kg), in the tail-flick and hotplate tests. Pre-treatment with SP600125 also attenuates tolerance to the hypothermic effects of both morphine and fentanyl. We also examined the role of JNK in morphine tolerance in a cisplatin-induced model of neuropathic pain. Interestingly, treatment with SP600125 (3 mg/kg) alone attenuated mechanical and cold allodynia in a chemotherapy-induced pain model using cisplatin. Strikingly, SP600125 (3 mg/kg) pre-treatment prolonged the anti-allodynic effect of morphine by several days (5 and 7 days for mechanical and cold, respectively). These results demonstrate that JNK signaling plays a crucial role in mediating antinociception as

Long-term tolerance to kidney allografts in a preclinical canine model.

PubMed

Kuhr, Christian S; Yunusov, Murad; Sale, George; Loretz, Carol; Storb, Rainer

2007-08-27

Durable immune tolerance supporting vascularized allotransplantation offers the possibility of extending graft survival and avoiding harmful complications of chronic immunosuppression. Immune tolerance to renal allografts was induced in a preclinical canine model through engraftment of donor hematopoietic cells using a combination of low-dose total body irradiation and a short course of immunosuppression. Subsequently, donor renal allografts were transplanted accompanied by bilateral native nephrectomies. With 5-year follow up, we found normal renal function in all recipients and no histological evidence of acute or chronic rejection. This tolerance does not extend universally to donor skin grafts, however, with two of four animals rejecting delayed donor skin grafts. Hematopoietic chimerism produces durable and robust immune tolerance to kidney allografts, although incomplete tolerance to donor skin grafting.

Regulation of opioid receptor signalling: Implications for the development of analgesic tolerance

PubMed Central

2011-01-01

Opiate drugs are the most effective analgesics available but their clinical use is restricted by severe side effects. Some of these undesired actions appear after repeated administration and are related to adaptive changes directed at counteracting the consequences of sustained opioid receptor activation. Here we will discuss adaptations that contribute to the development of tolerance. The focus of the first part of the review is set on molecular mechanisms involved in the regulation of opioid receptor signalling in heterologous expression systems and neurons. In the second part we assess how adaptations that take place in vivo may contribute to analgesic tolerance developed during repeated opioid administration. PMID:21663702

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

Durapain in symptomatic treatment of severe acute pain: a post-marketing, prospective, multicenter, observational study – PRIME study

PubMed Central

Shah, Kshitij; Chaudhari, Omvijay B; Gupta, Palash; Chaudhuri, R Hom; Kamilya, Ranjan; Kulkarni, Shreedhar S; Subbaiah, S; Sorathia, Zubair H; Billa, Gauri

2017-01-01

Objective To assess the effectiveness, overall tolerability, and gastrointestinal (GI) tolerability of Durapain (fixed dose combination of tramadol hydrochloride immediate release [50 mg] and diclofenac sodium sustained release [75 mg]) in symptomatic treatment of severe acute pain in physician’s routine clinical practice. Materials and methods In this prospective, multicenter, observational, post-marketing study, adult patients (aged 18–60 years) with severe acute pain were treated with tramadol hydrochloride/diclofenac sodium as per approved prescribing information. Evaluation was done at base-line, day 2, and day 5. Primary end point was pain intensity difference from baseline to day 5. Results A total of 351 patients (mean age 44.2 years; male 43%; female 57%) were included. The mean pain score was reduced from 9.2±1.09 at baseline to 2.8±1.73 at day 5 (p<0.0001). The number of patients with severe intensity of pain reduced from 100% at baseline to 18.3% at day 2 and 6.96% at day 5. According to the patient assessment, 68.36% of patients reported tolerability as “very good to good”, whereas according to physician’s assessment, “very good to good” tolerability was reported in 68.27% of patients. Five (1.43 %) patients discontinued the study because of adverse drug reaction. Five patients developed nine GI-related events of moderate intensity. Two patients developed three adverse reactions (burning sensation in urine, giddiness, and urine retention) other than GI events. No serious adverse drug reactions were reported during the study period. Conclusion Tramadol hydrochloride/diclofenac sodium is an effective and well-tolerated treatment in Indian patients with severe acute pain. Treatment with tramadol hydrochloride/diclofenac sodium provides significant pain relief on day 2 and maintained until day 5 without any serious adverse reactions. PMID:28579825

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.

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

PubMed

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

2016-09-15

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.

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

S-adenosyl methionine (SAM) attenuates the development of tolerance to analgesic activity of morphine in rats.

PubMed

Katyal, Jatinder; Kumar, Hemant; Joshi, Dinesh; Gupta, Yogendra Kumar

2017-04-03

Development of tolerance to analgesic effect, on chronic administration of morphine, limits its clinical usefulness in pain management. S-adenosyl methionine (SAM) used for arthritis and approved as a supplement in many countries including United States was evaluated for reducing morphine tolerance. Male 'Wistar' rats were used. The analgesic activity was determined using tail flick analgesiometer (Columbus Instruments, USA). Rats given morphine (7mg/kg), intraperitoneally (i.p.), once daily for 5days developed tolerance to analgesic effect. To evaluate the effect of SAM on morphine tolerance, SAM 800mg/kg was administered orally (p.o.), 45min prior to each dose of morphine. The analgesic activity of SAM and opioidergic component in its activity was also evaluated. Co-administration of morphine and SAM reversed morphine tolerance. SAM exhibited analgesic effect after repeated administration which was reversed by naloxone administration. Since safety of SAM on chronic use is documented it can be a good option in morphine tolerance. Role in drug addiction and withdrawal should also be evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

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...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Development of a Lubricant Therapy to Prevent Development of Osteoarthritis after Acute Injury of Synovial...early-onset osteoarthritis after traumatic joint injury remains a clinical challenge and may be associated with the poor lubricant quality of the

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

PubMed

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

2015-06-22

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. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

COMPARISONS OF ACUTE REFERENCE VALUES IN DEVELOPING AN ACUTE INHALATION ASSESSMENT METHOD

EPA Science Inventory

A method is being developed for performing assessments of human health risk from acute (less than 24 hour) inhalation exposures. The methodology will be flexible in its ability to utilize variously robust data sets of dose-response information. A supporting task is a comparati...

Testing the air pollution tolerances of shade tree cultivars

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karnosky, D.J.

1978-01-01

A program in progress to test the relative air pollution tolerances of some commonly planted shade tree cultivars is described. The relative sulfur dioxide and ozone tolerances of several cultivars of acer, fagus, fraxinus, ginkgo, gleditsia, platanus, and quercus species are being determined by examination of foliar response to short-term, high-concentration fumigations. In a follow-up study, the extent of foliar injury, growth reduction, and mortality caused by air pollution will be examined for the same cultivars grown in test plantings in and around New York City. The correlation of the relative sulfur dioxide and ozone tolerances, as determined by themore » controlled-fumigation tests, with urban survival and growth will be useful in determining the adequacy of acute exposure fumigations in testing the air pollution tolerances of the tree species under study.« less

Can physiological engineering/programming increase multi-generational thermal tolerance to extreme temperature events?

PubMed

Sorby, Kris L; Green, Mark P; Dempster, Tim D; Jessop, Tim S

2018-05-29

Organisms increasingly encounter higher frequencies of extreme weather events as a consequence of global climate change. Currently, few strategies are available to mitigate climate change effects on animals arising from acute extreme high temperature events. We tested the capacity of physiological engineering to influence the intra- and multi-generational upper thermal tolerance capacity of a model organism Artemia , subjected to extreme high temperatures. Enhancement of specific physiological regulators during development could affect thermal tolerances or life-history attributes affecting subsequent fitness. Using experimental Artemia populations we exposed F0 individuals to one of four treatments; heat hardening (28°C to 36°C, 1°C per 10 minutes), heat hardening plus serotonin (0.056 µg ml -1 ), heat hardening plus methionine (0.79 mg ml -1 ), and a control treatment. Regulator concentrations were based on previous literature. Serotonin may promote thermotolerance, acting upon metabolism and life-history. Methionine acts as a methylation agent across generations. For all groups, measurements were collected for three performance traits of individual thermal tolerance (upper sublethal thermal limit, lethal limit, and dysregulation range) over two generations. Results showed no treatment increased upper thermal limit during acute thermal stress, although serotonin-treated and methionine-treated individuals outperformed controls across multiple thermal performance traits. Additionally, some effects were evident across generations. Together these results suggest phenotypic engineering provides complex outcomes; and if implemented with heat hardening can further influence performance in multiple thermal tolerance traits, within and across generations. Potentially, such techniques could be up-scaled to provide resilience and stability in populations susceptible to extreme temperature events. © 2018. Published by The Company of Biologists Ltd.

Acute Effects of Cannabis on Breath-Holding Duration

PubMed Central

Farris, Samantha G.; Metrik, Jane

2016-01-01

Distress intolerance (an individual’s perceived or actual inability to tolerate distressing psychological or physiological states) is associated with cannabis use. It is unknown whether a bio-behavioral index of distress intolerance, breath-holding duration, is acutely influenced (increased or decreased) by cannabis. Such information may further inform understanding of the expression of psychological or physiological distress post-cannabis use. This within-subjects study examined whether smoked marijuana with 2.7–3.0 % delta-9-tetrahydrocannabinol (THC), relative to placebo, acutely changed duration of breath-holding. Participants (n = 88; 65.9% male) were non-treatment seeking frequent cannabis users who smoked placebo or active THC cigarette on two separate study days and completed breath-holding task. Controlling for baseline breath-holding duration and participant sex, THC produced significantly lower breath-holding durations relative to placebo. There was a significant interaction of drug administration x frequency of cannabis use, such that THC decreased breath-holding time among less frequent but not among more frequent users. Findings indicate that cannabis may be exacerbating distress intolerance (via breath-holding duration). As compared to less frequent cannabis users, frequent users display tolerance to cannabis’ acute effects including increased ability to tolerate respiratory distress when holding breath. Objective measures of distress intolerance are sensitive to contextual factors such as acute drug intoxication, and may inform the link between cannabis use and the expression of psychological distress. PMID:27454678

Growth and Development Temperature Influences Level of Tolerance to High Light Stress 1

PubMed Central

Steffen, Kenneth L.; Palta, Jiwan P.

1989-01-01

The influence of growth and development temperature on the relative tolerance of photosynthetic tissue to high light stress at chilling temperatures was investigated. Two tuber-bearing potato species, Solanum tuberosum L. cv Red Pontiac and Solanum commersonii were grown for 4 weeks, at either 12 or 24°C with 12 hours of about 375 micromoles per second per square meter of photosynthetically active radiation. Paired leaf discs were cut from directly across the midvein of leaflets of comparable developmental stage and light environment from each species at each growth temperature treatment. One disc of each pair was exposed to 1°C and about 1000 micromoles per second per square meter photosynthetically active radiation for 4 hours, and the other disc was held at 1°C in total darkness for the same duration. Photosynthetic tissue of S. tuberosum, developed at 12°C, was much more tolerant to high light and low temperature stress than tissue developed under 24°C conditions. Following the high light treatment, 24°C-grown S. tuberosum tissue demonstrated light-limited and light-saturated rates that were approximately 50% of their paired dark controls. In contrast, the 12°C-grown tissue from S. tuberosum that was subjected to the light stress showed only a 18 and 6% reduction in light-limited and light-saturated rates of photosynthetic oxygen evolution, respectively. Tissue from 24°C-grown S. commersonii was much less sensitive to the light stress than was tissue from S. tuberosum grown under the same conditions. The results presented here demonstrate that: (a) acclimation of S. tuberosum to lower temperature growth conditions with a constant light environment, results in the increased capacity of photosynthetic tissue to tolerate high light stress at chilling temperature and (b) following growth and development at relatively high temperatures S. commersonii, a frost- and heat-tolerant wild species, has a much greater tolerance to the high light stress at chilling

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.

Diabetes, insulin, and development of acute lung injury

PubMed Central

Honiden, Shyoko; Gong, Michelle N.

2009-01-01

Objectives Recently, many studies have investigated the immunomodulatory effects of insulin and glucose control in critical illness. This review examines evidence regarding the relationship between diabetes and the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), reviews studies of lung injury related to glycemic and nonglycemic metabolic features of diabetes, and examines the effect of diabetic therapies. Data Sources and Study Selection A MEDLINE/PubMed search from inception to August 1, 2008, was conducted using the search terms acute lung injury, acute respiratory distress syndrome, hyperglycemia, diabetes mellitus, insulin, hydroxymethylglutaryl-CoA reductase inhibitors (statins), angiotensin-converting enzyme inhibitor, and peroxisome proliferator-activated receptors, including combinations of these terms. Bibliographies of retrieved articles were manually reviewed. Data Extraction and Synthesis Available studies were critically reviewed, and data were extracted with special attention to the human and animal studies that explored a) diabetes and ALI; b) hyperglycemia and ALI; c) metabolic nonhyperglycemic features of diabetes and ALI; and d) diabetic therapies and ALI. Conclusions Clinical and experimental data indicate that diabetes is protective against the development of ALI/ARDS. The pathways involved are complex and likely include effects of hyperglycemia on the inflammatory response, metabolic abnormalities in diabetes, and the interactions of therapeutic agents given to diabetic patients. Multidisciplinary, multifaceted studies, involving both animal models and clinical and molecular epidemiology techniques, are essential. PMID:19531947

Tolerability and suitability of brief group mindfulness-oriented interventions in psychiatric inpatients: a pilot study.

PubMed

Nikolitch, Katerina; Laliberté, Vincent; Yu, Ching; Strychowsky, Natalie; Segal, Marilyn; Looper, Karl J; Rej, Soham

2016-09-01

Mindfulness-oriented therapies have a positive impact on patients' overall well-being and alleviate many psychiatric conditions. However, little is known about their use in people with severe mental illness. We aimed to identify which clinical and sociodemographic factors are associated with suitability/tolerability of a brief group mindfulness-oriented therapy. This retrospective study examines pre-/post-data from 40 psychiatric inpatients who underwent one session of a 10-min mindfulness-oriented group intervention between January and March 2014. The main outcome was 'suitability for and tolerating the brief mindfulness-oriented group intervention'. We assessed potential correlates of the main outcome, including female gender, shorter hospitalisation, the absence of psychosis and good pre-morbid functioning. The intervention was well tolerated (92.5%) and 50% of patients met both of our relatively stringent suitability and tolerability criteria. Sociodemographic and clinical variables were not associated with suitability/tolerability. Tai chi was the most suitable/tolerable compared to body scan and mindful eating (76.5% vs. 35.7% vs. 22.2%, Fisher's exact p = 0.01, Bonferroni p < 0.05). Brief group mindfulness therapy interventions are very well tolerated and often suitable for acutely hospitalised psychiatric inpatients, including those with acute psychosis. Mindfulness-oriented intervention with an active component (e.g., tai chi, mindful walking) may potentially be best suited for this population.

An integrative analysis of ethanol tolerance and withdrawal in zebrafish (Danio rerio)

PubMed Central

Tran, Steven; Chatterjee, Diptendu; Gerlai, Robert

2014-01-01

The zebrafish is emerging as a popular animal model for alcohol (ethanol or EtOH) addiction due to its simplicity and practical advantages. Two phenomena associated with ethanol addiction are the development of tolerance and withdrawal. Using a multi-level approach in the current study, we characterize ethanol tolerance and withdrawal in zebrafish. We first investigate the temporal trajectory of ethanol concentration in the zebrafish brain in response to an acute exposure and during withdrawal. We report that ethanol concentrations approach a steady state within 60 minutes of exposure to 0.50% and 1.00% v/v ethanol and rapidly decline and return to zero within 60 minutes following withdrawal from chronic ethanol exposure (0.50% v/v). We characterize the changes associated with ethanol tolerance and withdrawal in zebrafish by focusing on 3 domains relevant to ethanol addiction: motor patterns, physiological responses (i.e. cortisol levels), and neurochemical alterations. The use of multiple domains of investigation allowed an in-depth analysis of ethanol induced changes in zebrafish. PMID:24598276

Tolerance assays: measuring the unknown.

PubMed

Newell, Kenneth A; Larsen, Christian P

2006-06-15

Distinguishing transplant recipients who will benefit from a reduction in, or even the withdrawal of, immunosuppression from those who require intensive, lifelong immunosuppression will be dependent on developing strategies for immune monitoring. Currently, no assays have been shown to accurately predict the development or presence of donor-specific tolerance in humans after transplantation. In this overview we describe and discuss those assays that we believe may be useful for identifying tolerant transplant recipients. Validation of "tolerance" assays will be critical for the safe development of tolerance regimens in humans.

Developmental Hypoxia Has Negligible Effects on Long-Term Hypoxia Tolerance and Aerobic Metabolism of Atlantic Salmon (Salmo salar).

PubMed

Wood, Andrew T; Clark, Timothy D; Andrewartha, Sarah J; Elliott, Nicholas G; Frappell, Peter B

Exposure to developmental hypoxia can have long-term impacts on the physiological performance of fish because of irreversible plasticity. Wild and captive-reared Atlantic salmon (Salmo salar) can be exposed to hypoxic conditions during development and continue to experience fluctuating oxygen levels as juveniles and adults. Here, we examine whether developmental hypoxia impacts subsequent hypoxia tolerance and aerobic performance of Atlantic salmon. Individuals at 8°C were exposed to 50% (hypoxia) or 100% (normoxia) dissolved oxygen (DO) saturation (as percent of air saturation) from fertilization for ∼100 d (800 degree days) and then raised in normoxic conditions for a further 15 mo. At 18 mo after fertilization, aerobic scope was calculated in normoxia (100% DO) and acute (18 h) hypoxia (50% DO) from the difference between the minimum and maximum oxygen consumption rates ([Formula: see text] and [Formula: see text], respectively) at 10°C. Hypoxia tolerance was determined as the DO at which loss of equilibrium (LOE) occurred in a constantly decreasing DO environment. There was no difference in [Formula: see text], [Formula: see text], or aerobic scope between fish raised in hypoxia or normoxia. There was some evidence that hypoxia tolerance was lower (higher DO at LOE) in hypoxia-raised fish compared with those raised in normoxia, but the magnitude of the effect was small (12.52% DO vs. 11.73% DO at LOE). Acute hypoxia significantly reduced aerobic scope by reducing [Formula: see text], while [Formula: see text] remained unchanged. Interestingly, acute hypoxia uncovered individual-level relationships between DO at LOE and [Formula: see text], [Formula: see text], and aerobic scope. We discuss our findings in the context of developmental trajectories and the role of aerobic performance in hypoxia tolerance.

Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs.

PubMed

Russell, Karen E; Olsen, Eva H N; Raymer, Robin A; Merricks, Elizabeth P; Bellinger, Dwight A; Read, Marjorie S; Rup, Bonita J; Keith, James C; McCarthy, Kyle P; Schaub, Robert G; Nichols, Timothy C

2003-12-15

Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P <.001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P =.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B.

Accident tolerant fuel cladding development: Promise, status, and challenges

NASA Astrophysics Data System (ADS)

Terrani, Kurt A.

2018-04-01

The motivation for transitioning away from zirconium-based fuel cladding in light water reactors to significantly more oxidation-resistant materials, thereby enhancing safety margins during severe accidents, is laid out. A review of the development status for three accident tolerant fuel cladding technologies, namely coated zirconium-based cladding, ferritic alumina-forming alloy cladding, and silicon carbide fiber-reinforced silicon carbide matrix composite cladding, is offered. Technical challenges and data gaps for each of these cladding technologies are highlighted. Full development towards commercial deployment of these technologies is identified as a high priority for the nuclear industry.

Efficacy and tolerability of EPs 7630 in children and adolescents with acute bronchitis - a randomized, double-blind, placebo-controlled multicenter trial with a herbal drug preparation from Pelargonium sidoides roots.

PubMed

Kamin, W; Maydannik, V; Malek, F A; Kieser, M

2010-03-01

The study aim was to demonstrate the efficacy and to investigate the tolerability of EPs 7630, a herbal drug preparation from Pelargonium sidoides roots, in the treatment of patients (1 - 18 years) with acute bronchitis outside the strict indication for antibiotics. A total of 200 patients were randomized to receive either active drug containing EPs 7630 (1 - 6 years: 3 x 10 drops/d; > 6 - 12 years: 3 x 20 drops/d; > 12 - 18 years: 3 x 30 drops/d) or placebo for 7 consecutive days. change in the total score of bronchitis-specific symptoms (BSS) from Day 0 to Day 7. Main secondary outcome measures: treatment outcome, patients' satisfaction with treatment, onset of effect, bed rest. From baseline to Day 7, the mean BSS score improved significantly more for EPs 7630 compared with placebo (3.4 +/- 1.8 vs. 1.2 +/- 1.8 points, p < 0.0001). On Day 7, treatment outcome was significantly better (p < 0.0001), satisfaction with treatment more pronounced (77.6% vs. 25.8%, p < 0.0001), onset of effect faster, and time of bed rest shorter as compared with placebo. Tolerability was similarly good in both groups. All adverse events were assessed as non-serious. EPs 7630 was shown to be efficacious and safe in the treatment of acute bronchitis in children and adolescents outside the strict indication for antibiotics with patients treated with EPs 7630 perceiving a more favorable course of the disease and a good tolerability as compared with placebo.

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.…

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…

[Efficacy of ivabradine in combination therapy for complicated acute coronary syndrome in patients with type 2 diabetes mellitus].

PubMed

Kondrat'ev, A I; Dolgikh, V T; Stotskiĭ, A O

2010-01-01

To study the effect of ivabradine (coraxan, Servier) as part of combination therapy on the clinical manifestations of acute left ventricular failure (ALVF) in Braunwald class II-IIIB unstable angina in patients with type 2 diabetes mellitus (T2DM). Thirty-six T2DM patients (mean age 56 + 4.3 years) with a diagnosis of acute coronary syndrome were examined. Eighteen healthy individuals were examined as an age- and gender-matched control group. Metabolic, hemodynamic, and electrophysiological parameters were studied in all the patients on hospital stay days I and S. Ivabradine used in combination therapy for unstable angina caused reductions in the clinical manifestations of ALVF, heart rate, the number of myocardial ischemic episodes. In the ivabradine-treated patients, left ventricular ejection fraction showed a significant trend for increase. No adverse reactions were recorded. Ivabradine therapy demonstrated antiischemic and antianginal efficiencies and a good tolerability, without leading to the development of tolerance and without being followed by the development of the withdrawal syndrome.

Reduced β-Cell Secretory Capacity in Pancreatic-Insufficient, but Not Pancreatic-Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance.

PubMed

Sheikh, Saba; Gudipaty, Lalitha; De Leon, Diva D; Hadjiliadis, Denis; Kubrak, Christina; Rosenfeld, Nora K; Nyirjesy, Sarah C; Peleckis, Amy J; Malik, Saloni; Stefanovski, Darko; Cuchel, Marina; Rubenstein, Ronald C; Kelly, Andrea; Rickels, Michael R

2017-01-01

Patients with pancreatic-insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined β-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed-meal tolerance tests (MMTTs), respectively, in pancreatic-sufficient cystic fibrosis (PS-CF), PI-CF, and normal control subjects, all with normal glucose tolerance, in order to identify early pathophysiologic defects. Acute islet cell secretory responses were determined under fasting, 230 mg/dL, and 340 mg/dL hyperglycemia clamp conditions. PI-CF subjects had lower acute insulin, C-peptide, and glucagon responses compared with PS-CF and normal control subjects, indicating reduced β-cell secretory capacity and α-cell function. Fasting proinsulin-to-C-peptide and proinsulin secretory ratios during glucose potentiation were higher in PI-CF, suggesting impaired proinsulin processing. In the first 30 min of the MMTT, insulin secretion was lower in PI-CF compared with PS-CF and normal control subjects, and glucagon-like peptide 1 and gastric inhibitory polypeptide were lower compared with PS-CF, and after 180 min, glucose was higher in PI-CF compared with normal control subjects. These findings indicate that despite "normal" glucose tolerance, adolescents and adults with PI-CF have impairments in functional islet mass and associated early-phase insulin secretion, which with decreased incretin responses likely leads to the early development of postprandial hyperglycemia in CF. © 2017 by the American Diabetes Association.

Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression.

PubMed

Serebrovska, Tetiana V; Portnychenko, Alla G; Drevytska, Tetiana I; Portnichenko, Vladimir I; Xi, Lei; Egorov, Egor; Gavalko, Anna V; Naskalova, Svitlana; Chizhova, Valentina; Shatylo, Valeriy B

2017-09-01

The present study aimed at examining beneficial effects of intermittent hypoxia training (IHT) under prediabetic conditions. We investigate the effects of three-week IHT on blood glucose level, tolerance to acute hypoxia, and leukocyte mRNA expression of hypoxia inducible factor 1α (HIF-1α) and its target genes, i.e. insulin receptor, facilitated glucose transporter-solute carrier family-2, and potassium voltage-gated channel subfamily J. Seven healthy and 11 prediabetic men and women (44-70 years of age) were examined before, next day and one month after three-week IHT (3 sessions per week, each session consisting 4 cycles of 5-min 12% O 2 and 5-min room air breathing). We found that IHT afforded beneficial effects on glucose homeostasis in patients with prediabetes reducing fasting glucose and during standard oral glucose tolerance test. The most pronounced positive effects were observed at one month after IHT termination. IHT also significantly increased the tolerance to acute hypoxia (i.e. SaO 2 level at 20th min of breathing with 12% O 2 ) and improved functional parameters of respiratory and cardiovascular systems. IHT stimulated HIF-1α mRNA expression in blood leukocytes in healthy and prediabetic subjects, but in prediabetes patients the maximum increase was lagged. The greatest changes in mRNA expression of HIF-1α target genes occurred a month after IHT and coincided with the largest decrease in blood glucose levels. The higher expression of HIF-1α was positively associated with higher tolerance to hypoxia and better glucose homeostasis. In conclusion, our results suggest that IHT may be useful for preventing the development of type 2 diabetes. Impact statement The present study investigated the beneficial effects of intermittent hypoxia training (IHT) in humans under prediabetic conditions. We found that three-week moderate IHT induced higher HIF-1α mRNA expressions as well as its target genes, which were positively correlated with higher tolerance

Determination of the tolerable upper intake level of leucine in acute dietary studies in young men.

PubMed

Elango, Rajavel; Chapman, Karen; Rafii, Mahroukh; Ball, Ronald O; Pencharz, Paul B

2012-10-01

Leucine has been suggested to improve athletic performance. Therefore, the branched-chain amino acids (BCAAs), especially leucine, are popular as dietary supplements in strength-training athletes; however, the intake of leucine in excess of requirements raises concerns regarding adverse effects. Currently, the tolerable upper intake level (UL) for leucine is unknown. The objective of the current study was to determine the UL for leucine in adult men under acute dietary conditions. Five healthy adults (20-35 y) each received graded stepwise increases in leucine intakes of 50, 150, 250, 500, 750, 1000, and 1250 mg · kg⁻¹ · d⁻¹, which corresponded to the Estimated Average Requirement (EAR) and the EAR ×3, ×5, ×10, ×15, ×20, and ×25 in a total of 29 studies. The UL of leucine was identified by the measurement of plasma and urinary biochemical variables and changes in leucine oxidation by using l-[1-¹³C]-leucine. A significant increase in blood ammonia concentrations above normal values, plasma leucine concentrations, and urinary leucine excretion were observed with leucine intakes >500 mg · kg⁻¹ · d⁻¹. The oxidation of l-[1-¹³C]-leucine expressed as label tracer oxidation in breath (F¹³CO₂), leucine oxidation, and α-ketoisocaproic acid (KIC) oxidation led to different results: a plateau in F¹³CO₂ observed after 500 mg · kg⁻¹ · d⁻¹, no clear plateau observed in leucine oxidation, and KIC oxidation appearing to plateau after 750 mg · kg⁻¹ · d⁻¹. On the basis of plasma and urinary variables, the UL for leucine in healthy adult men can be suggested at 500 mg · kg⁻¹ · d⁻¹ or ~35 g/d as a cautious estimate under acute dietary conditions.

The Development of a Machine Learning Inpatient Acute Kidney Injury Prediction Model.

PubMed

Koyner, Jay L; Carey, Kyle A; Edelson, Dana P; Churpek, Matthew M

2018-07-01

To develop an acute kidney injury risk prediction model using electronic health record data for longitudinal use in hospitalized patients. Observational cohort study. Tertiary, urban, academic medical center from November 2008 to January 2016. All adult inpatients without pre-existing renal failure at admission, defined as first serum creatinine greater than or equal to 3.0 mg/dL, International Classification of Diseases, 9th Edition, code for chronic kidney disease stage 4 or higher or having received renal replacement therapy within 48 hours of first serum creatinine measurement. None. Demographics, vital signs, diagnostics, and interventions were used in a Gradient Boosting Machine algorithm to predict serum creatinine-based Kidney Disease Improving Global Outcomes stage 2 acute kidney injury, with 60% of the data used for derivation and 40% for validation. Area under the receiver operator characteristic curve (AUC) was calculated in the validation cohort, and subgroup analyses were conducted across admission serum creatinine, acute kidney injury severity, and hospital location. Among the 121,158 included patients, 17,482 (14.4%) developed any Kidney Disease Improving Global Outcomes acute kidney injury, with 4,251 (3.5%) developing stage 2. The AUC (95% CI) was 0.90 (0.90-0.90) for predicting stage 2 acute kidney injury within 24 hours and 0.87 (0.87-0.87) within 48 hours. The AUC was 0.96 (0.96-0.96) for receipt of renal replacement therapy (n = 821) in the next 48 hours. Accuracy was similar across hospital settings (ICU, wards, and emergency department) and admitting serum creatinine groupings. At a probability threshold of greater than or equal to 0.022, the algorithm had a sensitivity of 84% and a specificity of 85% for stage 2 acute kidney injury and predicted the development of stage 2 a median of 41 hours (interquartile range, 12-141 hr) prior to the development of stage 2 acute kidney injury. Readily available electronic health record data can be

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

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.

Development of Communicative Tolerance among Teachers of Primary and Senior Level of the General Education School

ERIC Educational Resources Information Center

Povarenkov, Yury P.; Baranova, Nataly A.; Sidorova, Anna D.; Mitiukov, Nicholas W.

2018-01-01

The article is devoted to the study of the influence of the level of development of communicative tolerance on the effectiveness of the teaching and educational activity of primary and senior schoolteachers. In the article the concepts of psychophysiological and communicative tolerance are separated. The psychological content of communicative…

Heme Oxygenase-1 Induction and Organic Nitrate Therapy: Beneficial Effects on Endothelial Dysfunction, Nitrate Tolerance, and Vascular Oxidative Stress

PubMed Central

Daiber, Andreas; Oelze, Matthias; Wenzel, Philip; Bollmann, Franziska; Pautz, Andrea; Kleinert, Hartmut

2012-01-01

Organic nitrates are a group of very effective anti-ischemic drugs. They are used for the treatment of patients with stable angina, acute myocardial infarction, and chronic congestive heart failure. A major therapeutic limitation inherent to organic nitrates is the development of tolerance, which occurs during chronic treatment with these agents, and this phenomenon is largely based on induction of oxidative stress with subsequent endothelial dysfunction. We therefore speculated that induction of heme oxygenase-1 (HO-1) could be an efficient strategy to overcome nitrate tolerance and the associated side effects. Indeed, we found that hemin cotreatment prevented the development of nitrate tolerance and vascular oxidative stress in response to chronic nitroglycerin therapy. Vice versa, pentaerithrityl tetranitrate (PETN), a nitrate that was previously reported to be devoid of adverse side effects, displayed tolerance and oxidative stress when the HO-1 pathway was blocked pharmacologically or genetically by using HO-1+/– mice. Recently, we identified activation of Nrf2 and HuR as a principle mechanism of HO-1 induction by PETN. With the present paper, we present and discuss our recent and previous findings on the role of HO-1 for the prevention of nitroglycerin-induced nitrate tolerance and for the beneficial effects of PETN therapy. PMID:22506100

Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic leukemia.

PubMed

Albayrak, Meryem; Konyssova, Uljan; Kaya, Zuhre; Gursel, Turkiz; Guntekin, Sezen; Percin, E Ferda; Kocak, Ulker

2011-11-01

Thiopurine methyltransferase (TPMT) enzyme is involved in the metabolism of 6-mercaptopurine (6-MP), a key component of acute lymphoblastic leukemia (ALL) treatment protocols in children. The aims of this study were to investigate the frequency of common genetic polymorphisms associated with low TPMT activity and correlations of polymorphic variants with 6-MP tolerance in a group of Turkish children with ALL. Genotyping for G238C, A719G, and G460A mutations were performed by using NanoChip Technology. Adverse reactions during the first 6 months of maintenance therapy with oral 6-MP and methotrexate were retrospectively analyzed from patient's files. Five (8.6%) of 58 children with ALL had a polymorphic TPMT allele: 4 (3.4%) were heterozygous for TPMT*3A (G460A and A719G), and one (0.9%) was heterozygous for TPMT*3C (A719G). No cases with TPMT*3B (G460A) or TPMT*2 (G238C) variants were identified. Children with TPMT*3A and *3C had significantly lower leukocyte and neutrophil counts and percentage of target 6-MP dosage, and longer periods with ≥grade 2 infections, ≥grade 2 liver toxicity, and chemotherapy interruptions than the children with wild-type TPMT during the first 24 weeks of maintenance therapy. The frequency and distribution of common TPMT polymorphisms in Turkish children with ALL is similar to other Caucasian populations. Polymorphic variants were associated with excessive 6-MP toxicity supporting the suggestion that TPMT genotyping should be performed before institution of 6-MP therapy.

Mechanisms of Oral Tolerance.

PubMed

Tordesillas, Leticia; Berin, M Cecilia

2018-02-27

Oral tolerance is a state of systemic unresponsiveness that is the default response to food antigens in the gastrointestinal tract, although immune tolerance can also be induced by other routes, such as the skin or inhalation. Antigen can be acquired directly by intestinal phagocytes, or pass through enterocytes or goblet cell-associated passages prior to capture by dendritic cells (DCs) in the lamina propria. Mucin from goblet cells acts on DCs to render them more tolerogenic. A subset of regulatory DCs expressing CD103 is responsible for delivery of antigen to the draining lymph node and induction of Tregs. These DCs also imprint gastrointestinal homing capacity, allowing the recently primed Tregs to home back to the lamina propria where they interact with macrophages that produce IL-10 and expand. Tregs induced by dietary antigen include Foxp3 + Tregs and Foxp3 - Tregs. In addition to Tregs, T cell anergy can also contribute to oral tolerance. The microbiota plays a key role in the development of oral tolerance, through regulation of macrophages and innate lymphoid cells that contribute to the regulatory phenotype of gastrointestinal dendritic cells. Absence of microbiota is associated with a susceptibility to food allergy, while presence of Clostridia strains can suppress development of food allergy through enhancement of Tregs and intestinal barrier function. It is not clear if feeding of antigens can also induce true immune tolerance after a memory immune response has been generated, but mechanistic studies of oral immunotherapy trials demonstrate shared pathways in oral tolerance and oral immunotherapy, with a role for Tregs and anergy. An important role for IgA and IgG antibodies in development of immune tolerance is also supported by studies of oral tolerance in humans. The elucidation of key pathways in oral tolerance could identify new strategies to increase efficacy of immunotherapy treatments for food allergy.

Impaired cardiac ischemic tolerance in spontaneously hypertensive rats is attenuated by adaptation to chronic and acute stress.

PubMed

Ravingerová, T; Bernátová, I; Matejíková, J; Ledvényiová, V; Nemčeková, M; Pecháňová, O; Tribulová, N; Slezák, J

2011-01-01

Chronic hypertension may have a negative impact on the myocardial response to ischemia. On the other hand, intrinsic ischemic tolerance may persist even in the pathologically altered hearts of hypertensive animals, and may be modified by short- or long-term adaptation to different stressful conditions. The effects of long-term limitation of living space (ie, crowding stress [CS]) and brief ischemia-induced stress on cardiac response to ischemia/reperfusion (I/R) injury are not yet fully characterized in hypertensive subjects. The present study was designed to test the influence of chronic and acute stress on the myocardial response to I/R in spontaneously hypertensive rats (SHR) compared with their effects in normotensive counterparts. In both groups, chronic, eight-week CS was induced by caging five rats per cage in cages designed for two rats (200 cm(2)/rat), while controls (C) were housed four to a cage in cages designed for six animals (480 cm(2)/rat). Acute stress was evoked by one cycle of I/R (5 min each, ischemic preconditioning) before sustained I/R in isolated Langendorff-perfused hearts of normotensive and SHR rats. At baseline conditions, the effects of CS were manifested only as a further increase in blood pressure in SHR, and by marked limitation of coronary perfusion in normotensive animals, while no changes in heart mechanical function were observed in any of the groups. Postischemic recovery of contractile function, severity of ventricular arrhythmias and lethal injury (infarction size) were worsened in the hypertrophied hearts of C-SHR compared with normotensive C. However, myo-cardial stunning and reperfusion-induced ventricular arrhythmias were attenuated by CS in SHR, which was different from deterioration of I/R injury in the hearts of normotensive animals. In contrast, ischemic preconditioning conferred an effective protection against I/R in both groups, although the extent of anti-infarct and anti-arrhythmic effects was lower in SHR. Both

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. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Assessment of biochemical mechanisms of tolerance to chlorpyrifos in ancient and contemporary Daphnia pulicaria genotypes.

PubMed

Simpson, Adam M; Jeyasingh, Punidan D; Belden, Jason B

2017-12-01

The evolution of tolerance to environmental contaminants in non-target taxa has been largely studied by comparing extant populations experiencing contrasting exposure. Previous research has demonstrated that "resurrected" genotypes from a population of Daphnia pulicaria express temporal variation in sensitivity to the insecticide chlorpyrifos. Ancient genotypes (1301-1646AD.) were on average more sensitive to this chemical compared to the contemporary genotypes (1967-1977AD.). To determine the physiological mechanisms of tolerance, a series of biochemical assays was performed on three ancient and three contemporary genotypes; these six genotypes exhibited the most sensitive and most tolerant phenotypes within the population, respectively. Metabolic tolerance mechanisms were evaluated using acute toxicity testing, while target-site tolerance was assessed via in vitro acetylcholinesterase (AChE) assays. Acute toxicity tests were conducted using i) the toxic metabolite chlorpyrifos-oxon (CPF-oxon) and ii) CPF-oxon co-applied with piperonyl butoxide (PBO), a known Phase-I metabolic inhibitor. Both series of toxicity tests reduced the mean variation in sensitivity between tolerant and sensitive genotypes. Exposure to CPF-O reduced the disparity from a 4.7-fold to 1.6-fold difference in sensitivity. The addition of PBO further reduced the variation to a 1.2-fold difference in sensitivity. In vitro acetylcholinesterase assays yielded no significant differences in constitutive activity or target-site sensitivity. These findings suggest that pathways involving Phase-I detoxification and/or bioactivation of chlorpyrifos play a significant role in dictating the microevolutionary trajectories of tolerance in this population. Copyright © 2017 Elsevier B.V. All rights reserved.

Long-term and acute effects of temperature and oxygen on metabolism, food intake, growth and heat tolerance in a freshwater gastropod.

PubMed

Hoefnagel, K Natan; Verberk, Wilco C E P

2017-08-01

Temperature affects the physiology and life-history of ectothermic animals, often increasing metabolic rate and decreasing body size. Oxygen limitation has been put forward as a mechanism to explain thermal responses of body size and the ability to survive stress. However the time-scales involved in growth performance and heat tolerance differ radically. In order to increase our understanding of oxygen and temperature effects on body size and heat tolerance and the time scale involved, we reared Lymnaea stagnalis under six combinations of temperature and oxygen tension from hatching up to an age of 300 days and recorded shell length during this whole period. At the end of this period, we determined scope for growth by measuring food intake rate, assimilation efficiency, respiration rate and ammonium excretion rate at two different temperatures. We also measured the snails' ability to survive heat stress (CTmax), both at normoxia and hypoxia. We found that scope for growth and long term growth performance were much more affected by interactions of chronic oxygen and temperature conditions during rearing than by acute conditions during testing. Furthermore, our study shows that individual variation in growth performance can be traced back to individual differences in rates of food and oxygen consumption. Developmental acclimation also gave rise to differences in CTmax, but these were relatively small and were only expressed when CTmax was tested under hypoxia. The large effects of rearing oxygen conditions on growth and other physiological rates compared to modest effects of test oxygen conditions on CTmax suggest that small effects of hypoxia on the short term (e.g. heat tolerance) may nevertheless have large repercussions on the long term (e.g. growth and reproduction), even in a pulmonate snail that can compensate for hypoxia to some extent by aerial respiration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chronic intermittent ethanol exposure in early adolescent and adult male rats: effects on tolerance, social behavior, and ethanol intake.

PubMed

Broadwater, Margaret; Varlinskaya, Elena I; Spear, Linda P

2011-08-01

Given the prevalence of alcohol use in adolescence, it is important to understand the consequences of chronic ethanol exposure during this critical period in development. The purpose of this study was to assess possible age-related differences in susceptibility to tolerance development to ethanol-induced sedation and withdrawal-related anxiety, as well as voluntary ethanol intake after chronic exposure to relatively high doses of ethanol during adolescence or adulthood. Juvenile/adolescent and adult male Sprague-Dawley rats were assigned to one of five 10-day exposure conditions: chronic ethanol (4 g/kg every 48 hours), chronic saline (equivalent volume every 24 hours), chronic saline/acutely challenged with ethanol (4 g/kg on day 10), nonmanipulated/acutely challenged with ethanol (4 g/kg on day 10), or nonmanipulated. For assessment of tolerance development, duration of the loss of righting reflex (LORR) and blood ethanol concentrations (BECs) upon regaining of righting reflex (RORR) were tested on the first and last ethanol exposure days in the chronic ethanol group, with both saline and nonmanipulated animals likewise challenged on the last exposure day. Withdrawal-induced anxiety was indexed in a social interaction test 24 hours after the last ethanol exposure, with ethanol-naïve chronic saline and nonmanipulated animals serving as controls. Voluntary intake was assessed 48 hours after the chronic exposure period in chronic ethanol, chronic saline and nonmanipulated animals using an 8-day 2 bottle choice, limited-access ethanol intake procedure. In general, adolescent animals showed shorter durations of LORR and higher BECs upon RORR than adults on the first and last ethanol exposure days, regardless of chronic exposure condition. Adults, but not adolescents, developed chronic tolerance to the sedative effects of ethanol, tolerance that appeared to be metabolic in nature. Social deficits were observed after chronic ethanol in both adolescents and adults

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate.

PubMed

Yap, B S; McCredie, K B; Benjamin, R S; Bodey, G P; Freireich, E J

1978-09-16

Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m(2) methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m(2). Seven days later intravenous methotrexate, 120 mg/m(2) was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m(2) with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m(2) (median 200 mg/m(2)). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m(2) caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.

Effect of Shenmai injection on preventing the development of nitroglycerin-induced tolerance in rats.

PubMed

Zhou, Qian; Sun, Yan; Tan, Wangxiao; Liu, Xiao; Qian, Yuchen; Ma, Xianghui; Wang, Ting; Wang, Xiaoying; Gao, Xiumei

2017-01-01

Long-term nitroglycerin (NTG) therapy causes tolerance to its effects attributing to increased oxidative stress and endothelial dysfunction. Shenmai injection (SMI), which is clinically used to treat cardiovascular diseases, consists of two herbal medicines, Ginseng Rubra and Ophiopogonjaponicas, and is reported to have antioxidant effects. The present study was designed to investigate the potential preventive effects of Shenmai injection on development of nitroglycerin-induced tolerance. The present study involves both in vivo and in vitro experiments to investigate nitroglycerin-induced tolerance. We examined the effect of Shenmai injection on the cardiovascular oxidative stress by measuring the serum levels of malondialdehyde (MDA) and superoxide dismutase (SOD). Endothelial dysfunction was determined by an endothelium-dependent vasorelaxation method in aortic rings and NOS activity. Inhibition of the cGMP/cGK-I signalling pathway was determined from released serum levels of cGMP and the protein expression levels of sGC, cGK-I, PDE1A and P-VASP by western blot. Here, we showed that SMI ameliorated the decrease in AV Peak Vel, the attenuation in the vasodilation response to nitroglycerin and endothelial dysfunction. SMI also reduced the cardiovascular oxidative stress by reducing the release of MDA and increasing the activity of SOD. Shenmai injection further ameliorated inhibition of the cGMP/cGK-I signalling pathway triggered by nitroglycerin-induced tolerance through up-regulating the protein expression of sGC, cGK-I, and P-VASP and down- regulating the proteins expression of PDE1A. In vitro studies showed that Shenmai injection could recover the attenuated vasodilation response to nitroglycerin following incubation (of aortic rings) with nitroglycerin via activating the enzymes of sGC and cGK-I. Therefore, we conclude that Shenmai injection could prevent NTG nitroglycerin-induced tolerance at least in part by decreasing the cardiovascular oxidative stress

Effect of Shenmai injection on preventing the development of nitroglycerin-induced tolerance in rats

PubMed Central

Zhou, Qian; Sun, Yan; Tan, Wangxiao; Liu, Xiao; Qian, Yuchen; Ma, Xianghui; Wang, Ting; Wang, Xiaoying; Gao, Xiumei

2017-01-01

Long-term nitroglycerin (NTG) therapy causes tolerance to its effects attributing to increased oxidative stress and endothelial dysfunction. Shenmai injection (SMI), which is clinically used to treat cardiovascular diseases, consists of two herbal medicines, Ginseng Rubra and Ophiopogonjaponicas, and is reported to have antioxidant effects. The present study was designed to investigate the potential preventive effects of Shenmai injection on development of nitroglycerin-induced tolerance. The present study involves both in vivo and in vitro experiments to investigate nitroglycerin-induced tolerance. We examined the effect of Shenmai injection on the cardiovascular oxidative stress by measuring the serum levels of malondialdehyde (MDA) and superoxide dismutase (SOD). Endothelial dysfunction was determined by an endothelium-dependent vasorelaxation method in aortic rings and NOS activity. Inhibition of the cGMP/cGK-I signalling pathway was determined from released serum levels of cGMP and the protein expression levels of sGC, cGK-I, PDE1A and P-VASP by western blot. Here, we showed that SMI ameliorated the decrease in AV Peak Vel, the attenuation in the vasodilation response to nitroglycerin and endothelial dysfunction. SMI also reduced the cardiovascular oxidative stress by reducing the release of MDA and increasing the activity of SOD. Shenmai injection further ameliorated inhibition of the cGMP/cGK-I signalling pathway triggered by nitroglycerin-induced tolerance through up-regulating the protein expression of sGC, cGK-I, and P-VASP and down- regulating the proteins expression of PDE1A. In vitro studies showed that Shenmai injection could recover the attenuated vasodilation response to nitroglycerin following incubation (of aortic rings) with nitroglycerin via activating the enzymes of sGC and cGK-I. Therefore, we conclude that Shenmai injection could prevent NTG nitroglycerin-induced tolerance at least in part by decreasing the cardiovascular oxidative stress

Effect of Acarbose on Long-Term Prognosis in Acute Coronary Syndromes Patients with Newly Diagnosed Impaired Glucose Tolerance.

PubMed

Yun, Peng; Du, Ai-ming; Chen, Xue-jun; Liu, Jing-cheng; Xiao, Hu

2016-01-01

To investigate the effect of acarbose therapy on the long-term prognosis of patients with acute coronary syndromes (ACS) complicating newly diagnosed impaired glucose tolerance (IGT). 135 patients hospitalized for ACS who had been newly diagnosed with IGT were randomly assigned to acarbose group (150 mg/day, n = 67) or control group (no acarbose, n = 68). All cases in each group were given the same elementary treatment. Mean follow-up was 2.3 years. The incidence of major adverse cardiovascular event (MACE) and carotid intima-middle thickness (CIMT) were statistically analyzed. During the mean follow-up of 2.3 years, the risk of recurrent MACE in acarbose group was decreased significantly compared with that in control group (26.67% versus 46.88%, P < 0.05); at the same time, thickening of the CIMT was significantly slower than the control group ((1.28 ± 0.42) mm versus (1.51 ± 0.64) mm, P < 0.05). Acarbose can effectively reduce the risk of MACE in ACS patients with newly diagnosed IGT, simultaneously retarding the progression of carotid intima-media thickness.

Drought Tolerance during Reproductive Development is Important for Increasing wheat yield Potential under Climate change in Europe.

PubMed

Senapati, Nimai; Stratonovitch, Pierre; Paul, Matthew J; Semenov, Mikhail A

2018-06-12

Drought stress during reproductive development could drastically reduce grain number and wheat yield, but quantitative evaluation of such effect is unknown under climate change. The objectives of this study were to a) evaluate potential yield benefits of drought tolerance during reproductive development for wheat ideotypes under climate change in Europe, and b) identify potential cultivar parameters for improvement. We used the Sirius wheat model to optimise drought tolerant (DT) and drought sensitive (DS) wheat ideotypes under future 2050 climate scenario at 13 contrasting sites, representing major wheat growing regions in Europe. Averaged over the sites, DT ideotypes achieved 13.4% greater yield compared to DS, with the double yield stability for DT. However, the performances of the ideotypes were site dependent. Mean yield of DT was 28-37% greater compared to DS in southern Europe. In contrast, no yield difference (≤ 1%) between ideotypes was found in north-western Europe. An intermediate yield benefit of 10-23% was found due to drought tolerance in central and eastern Europe. We conclude that tolerance to drought stress during reproductive development is important for high yield potentials and greater yield stability of wheat under climate change in Europe.

The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective.

PubMed

Abdollahi, Hakime; Ghaemi-Jandabi, Masoumeh; Azizi, Hossein; Semnanian, Saeed

2016-09-01

Long-term exposure to opioid agonists results in tolerance to their analgesic effects, so the effectiveness of opioid agonists in the management of pain becomes limited. The locus coeruleus (LC) nucleus has been involved in the development of tolerance to opiates. Orexin type-1 receptors (OX1Rs) are highly expressed in LC nucleus. Orexin plays a noteworthy role in the occurrence of morphine tolerance. The purpose of the present study is to investigate the role of orexin type-1 receptors in the development of morphine tolerance in LC neurons. In this study, adult male Wistar rats weighing 250-300g were utilized. Induction of morphine tolerance was obtained by single injection of morphine per day for 6 successive days. An orexin type-1 receptor antagonist (SB-334867) was injected into the lateral ventricle instantly prior to morphine injection. On day 7, the effect of morphine on the electrical activity of LC neurons was studied using in vivo extracellular single unit recording. The results demonstrate that morphine injection for 6 consecutive days led to the development of morphine-induced tolerance in LC neurons. In other words, there was a significant decrease in LC neuronal responsiveness to morphine injection. Inhibitory responses of LC neurons to intraperitoneally applied morphine can be observed with the treatment of the SB-334867 prior to morphine injection. This study showed that OX1R blockade by SB-334867 prevents the development of morphine tolerance in LC neurons. We hope that further studies will lead to considerable progress in understanding the molecular adaptations that contribute to morphine tolerance. Copyright © 2016 Elsevier B.V. All rights reserved.

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. Copyright © 2010 Elsevier Inc. All rights reserved.

Upper thermal tolerances of early life stages of freshwater mussels

USGS Publications Warehouse

Pandolfo, Tamara J.; Cope, W. Gregory; Arellano, Consuelo; Bringolf, Robert B.; Barnhart, M. Christopher; Hammer, E

2010-01-01

Freshwater mussels (order Unioniformes) fulfill an essential role in benthic aquatic communities, but also are among the most sensitive and rapidly declining faunal groups in North America. Rising water temperatures, caused by global climate change, industrial discharges, drought, or land development, could further challenge imperiled unionid communities. The aim of our study was to determine the upper thermal tolerances of the larval (glochidia) and juvenile life stages of freshwater mussels. Glochidia of 8 species of mussels were tested: Lampsilis siliquoidea, Potamilus alatus, Ligumia recta, Ellipsaria lineolata,Lasmigona complanata, Megalonaias nervosa, Alasmidonta varicosa, and Villosa delumbis. Seven of these species also were tested as juveniles. Survival trends were monitored while mussels held at 3 acclimation temperatures (17, 22, and 27°C) were exposed to a range of common and extreme water temperatures (20–42°C) in standard acute laboratory tests. The average median lethal temperature (LT50) among species in 24-h tests with glochidia was 31.6°C and ranged from 21.4 to 42.7°C. The mean LT50 in 96-h juvenile tests was 34.7°C and ranged from 32.5 to 38.8°C. Based on comparisons of LT50s, thermal tolerances differed among species for glochidia, but not for juveniles. Acclimation temperature did not affect thermal tolerance for either life stage. Our results indicate that freshwater mussels already might be living close to their upper thermal tolerances in some systems and, thus, might be at risk from rising environmental temperatures.

Inducible Tolerance to Agrochemicals Was Paved by Evolutionary Responses to Predators.

PubMed

Jones, Devin K; Hintz, William D; Schuler, Matthew S; Yates, Erika K; Mattes, Brian M; Relyea, Rick A

2017-12-05

Recent research has reported increased tolerance to agrochemicals in target and nontarget organisms following acute physiological changes induced through phenotypic plasticity. Moreover, the most inducible populations are those from more pristine locations, far from agrochemical use. We asked why do populations with no known history of pesticide exposure have the ability to induce adaptive responses to novel agrochemicals? We hypothesized that increased pesticide tolerance results from a generalized stressor response in organisms, and would be induced following sublethal exposure to natural and anthropogenic stressors. We exposed larval wood frogs (Lithobates sylvaticus) to one of seven natural or anthropogenic stressors (predator cue (Anax spp.), 0.5 or 1.0 mg carbaryl/L, road salt (200 or 1000 mg Cl - /L), ethanol-vehicle control, or no-stressor control) and subsequently tested their tolerance to a lethal carbaryl concentration using time-to-death assays. We observed induced carbaryl tolerance in tadpoles exposed to 0.5 mg/L carbaryl and also in tadpoles exposed to predator cues. Our results suggest that the ability to induce pesticide tolerance likely arose through evolved antipredator responses. Given that antipredator responses are widespread among species, many animals might possess inducible pesticide tolerance, buffering them from agrochemical exposure.

Tolerance and cross-tolerance to head twitch behavior elicited by phenethylamine- and tryptamine-derived hallucinogens in mice.

PubMed

Smith, Douglas A; Bailey, Jessica M; Williams, Diarria; Fantegrossi, William E

2014-12-01

The serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor is a potential therapeutic target to a host of neuropsychiatric conditions, but agonist actions at this site are linked to abuse-related hallucinogenic effects that may limit therapeutic efficacy of chronic drug administration. Tolerance to some effects of hallucinogens has been observed in humans and laboratory animals, but the understanding of tolerance and cross-tolerance between distinct structural classes of hallucinogens is limited. Here, we used the drug-elicited head twitch response (HTR) in mice to assess the development of tolerance and cross-tolerance with two phenethylamine-derived [DOI (2,5-dimethoxy-4-iodoamphetamine) and 2C-T-7 (2,5-dimethoxy-4-propylthiophenethylamine)] and two tryptamine-derived [DPT (N,N-dipropyltryptamine) and DIPT (N,N-diisopropyltryptamine)] drugs with agonist affinity for 5-HT2A receptors. Tolerance developed to HTR elicited by daily DOI or 2C-T-7, but not to HTR elicited by DPT or DIPT. DOI-elicited tolerance was not surmountable with dose, and a similar insurmountable cross-tolerance was evident when DOI-tolerant mice were tested with various doses of 2C-T-7 or DPT. These studies suggest that the use of phenethylamine-derived hallucinogens as therapeutic agents may be limited not only by their abuse potential, but also by the rapid development of tolerance that would likely be maintained even if a patient were switched to a different 5-HT2A agonist medication from a distinct structural class. However, these experiments also imply that tryptamine-derived hallucinogens might have a reduced potential for tolerance development, compared with phenethylamine-derived 5-HT2A agonists, and might therefore be more suitable for chronic administration in a therapeutic context. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Tolerance and Cross-Tolerance to Head Twitch Behavior Elicited by Phenethylamine- and Tryptamine-Derived Hallucinogens in Mice

PubMed Central

Smith, Douglas A.; Bailey, Jessica M.; Williams, Diarria

2014-01-01

The serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor is a potential therapeutic target to a host of neuropsychiatric conditions, but agonist actions at this site are linked to abuse-related hallucinogenic effects that may limit therapeutic efficacy of chronic drug administration. Tolerance to some effects of hallucinogens has been observed in humans and laboratory animals, but the understanding of tolerance and cross-tolerance between distinct structural classes of hallucinogens is limited. Here, we used the drug-elicited head twitch response (HTR) in mice to assess the development of tolerance and cross-tolerance with two phenethylamine-derived [DOI (2,5-dimethoxy-4-iodoamphetamine) and 2C-T-7 (2,5-dimethoxy-4-propylthiophenethylamine)] and two tryptamine-derived [DPT (N,N-dipropyltryptamine) and DIPT (N,N-diisopropyltryptamine)] drugs with agonist affinity for 5-HT2A receptors. Tolerance developed to HTR elicited by daily DOI or 2C-T-7, but not to HTR elicited by DPT or DIPT. DOI-elicited tolerance was not surmountable with dose, and a similar insurmountable cross-tolerance was evident when DOI-tolerant mice were tested with various doses of 2C-T-7 or DPT. These studies suggest that the use of phenethylamine-derived hallucinogens as therapeutic agents may be limited not only by their abuse potential, but also by the rapid development of tolerance that would likely be maintained even if a patient were switched to a different 5-HT2A agonist medication from a distinct structural class. However, these experiments also imply that tryptamine-derived hallucinogens might have a reduced potential for tolerance development, compared with phenethylamine-derived 5-HT2A agonists, and might therefore be more suitable for chronic administration in a therapeutic context. PMID:25271256

Repeated bouts of exhaustive exercise increase circulating cell free nuclear and mitochondrial DNA without development of tolerance in healthy men

PubMed Central

Stawski, Robert; Walczak, Konrad; Kosielski, Piotr; Meissner, Pawel; Budlewski, Tomasz; Padula, Gianluca; Nowak, Dariusz

2017-01-01

Objective Acute single strenuous exercise increases circulating cell free DNA (cf DNA). We tested whether three repeated bouts of exhaustive exercise induced the cf DNA response without development of tolerance in healthy men. Methods Eleven average-trained men (age 34.0±5.2 years, body mass index 26.2±3.1 kg/m2, maximal oxygen consumption—VO2max 49.6±4.5 ml/kg*min) performed three treadmill exercise tests to exhaustion at speed corresponding to 70% VO2max separated by 72 hours of resting. Blood was collected before and after each bout of exercise for determination of cell free nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) by real-time PCR, selected markers of muscle damage, and blood cell count. Results Each bout induced the increase (p<0.05) in plasma cf n-DNA: from 3.4±1.4 to 38.5±27.5, from 4.1±3.3 to 48.5±26.2, and 3.1±1.6 to 53.8±39.9 ng/mL after the first, second, and third exercise, respectively. In a congruent way, cf mt-DNA rose significantly after the second (from 229±216 to 450±228*103 GE/mL) and third bout of exercise (from 173±120 to 462±314*103 GE/mL). Pre-exercise cf mt-DNA decreased (p<0.05) by 2-times (from 355±219 before the first bout to 173±120*103 GE/mL before the third bout) over the study period and were accompanied by significant increase in white blood cells, platelets, creatine kinase, creatinine and lactate after each bout. However, the exercise induced percentage increment of cf n-DNA was always many times higher than corresponding increments of the afore-mentioned markers at any occasion. Conclusions Repeated bouts of exhaustive exercise induced remarkable increase in circulating cf n-DNA without signs of tolerance development. Baseline cf mt-DNA decreased in response to series of strenuous exercise. Since percentage increments of cf n-DNA in response to exercise were many times higher than those observed for other markers, measurement of circulating cf n-DNA could be a sensitive tool for monitoring acute

Interception of the development of self tolerance in fetal lambs.

PubMed

McCullagh, P

1989-08-01

Investigation of the nature of immunological self tolerance has usually relied upon experimental protocols in which the tolerant state is interrupted in mature animals with the production of autoimmune disease. While such research has improved the understanding of those processes operative in overt autoimmunity, it has not been informative in relation to events associated with the establishment of self tolerance. Any description of this state which is to be based on observation will necessitate the use of experimental systems that permit observation of animals during the development of self tolerance. The present experiment entailed intervention approximately one third of the way through the gestation period of fetal lambs. An earlier experiment had established that 54-day fetal lambs would accept allografts of adult skin. This indicated that the capacity to discriminate between self and non-self had not been acquired at that age. Fetuses at this stage of gestation were submitted to either partial or total removal of the thyroid gland. The excised tissue was then implanted in nude mice for periods of 5 to 9 weeks. It was subsequently replaced subcutaneously, either in the original donor or in another fetus at a comparable stage of gestation. At postmortem examination, several weeks later, self implants in lambs from which the thyroid gland had been completely removed displayed autoimmune thyroiditis of varying degrees of severity. However, self implants in partially thyroidectomized animals were uniformly free from autoimmune manifestations. This implied that these reactions had not been directed against contaminating murine tissues in the implants replaced in completely thyroidectomized lambs. All allogeneic implants were subject to vey heavy lymphocytic infiltration, usually with accompanying necrosis consistent with allograft rejection. This was taken as an indication that hypothyroid fetal lambs had become immunocompetent by the time of thyroid reimplantation

Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation.

PubMed

Gallon, Lorenzo; Mathew, James M; Bontha, Sai Vineela; Dumur, Catherine I; Dalal, Pranav; Nadimpalli, Lakshmi; Maluf, Daniel G; Shetty, Aneesha A; Ildstad, Suzanne T; Leventhal, Joseph R; Mas, Valeria R

2018-02-01

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways. Copyright © 2018 by the

Drosophila CYP6g1 and its human homolog CYP3A4 confer tolerance to methylmercury during development

PubMed Central

Rand, Matthew D.; Lowe, Jessica A.; Mahapatra, Cecon T.

2012-01-01

Methylmercury (MeHg) is a persistent environmental toxicant that is commonly encountered through dietary fish and seafood. While the fetal nervous system is a well-known primary target for MeHg toxicity, the risks of MeHg exposures that are commonly experienced today through diet and environmental exposure remain uncertain. Despite knowledge of numerous cellular processes that are affected by MeHg, the mechanisms that ultimately influence tolerance or susceptibility to MeHg in the developing fetus are not well understood. Using transcriptomic analyses of developing brains of MeHg tolerant and susceptible strains of Drosophila, we previously identified members of the cytochrome p450 (CYP) family of monooxygenases/oxidoreductases as candidate MeHg tolerance genes. While CYP genes encode Phase I enzymes best known for xenobiotic metabolism in the liver, several classes of CYPs are required for synthesis or degradation of essential endobiotics, such as hormones and fatty acids, that are critical to normal development. We now demonstrate that variation in expression CYP genes can strongly influence MeHg tolerance in the developing fly. Importantly, modulating expression of a single CYP, CYP6g1, specifically in neurons or the fat body (liver equivalent) is sufficient to rescue development in the presence of MeHg. We also demonstrate a conserved function for CYP3A4, a human homolog of CYP6g1, in conferring MeHg tolerance to flies. Finally, we show that pharmacological induction of CYPs with caffeine parallels an increase in tolerance to MeHg in developing flies. These findings establish a previously unidentified role for CYPs in MeHg toxicity and point to a potentially conserved role of CYP genes to influence susceptibility to MeHg toxicity across species. PMID:22699155

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.

Acute and sub-acute oral toxicity of Dracaena cinnabari resin methanol extract in rats.

PubMed

Al-Afifi, Nashwan Abdullah; Alabsi, Aied Mohammed; Bakri, Marina Mohd; Ramanathan, Anand

2018-02-05

Dracaena cinnabari (DC) is a perennial tree that located on the Southern coast of Yemen native to the Socotra Island. This tree produces a deep red resin known as the Dragon's blood, the Twobrother's Blood or Damm Alakhwain. The current study performed to evaluate the safety of the DC resin methanol extract after a single or 28 consecutive daily oral administrations. In assessing the safety of DC resin methanol extract, acute and sub-acute oral toxicity tests performed following OECD guidelines 423 and 407, respectively, with slight modifications. In acute oral toxicity test, DC resin methanol extract administered to female Sprague Dawley rats by oral gavage at a single dose of 300 and 2000 mg/kg body weight. Rats observed for toxic signs for 14 days. In sub-acute oral toxicity test, DC resin methanol extract administered to the rats by oral gavage at 500, 1000, and 1500 mg/kg body weight daily up to 28 days to male and female Spradgue Dawley rats. The control and high dose in satellite groups were also maintained and handled as the previous groups to determine the late onset toxicity of DC resin methanol extract. At the end of each test, hematological and biochemical analysis of the collected blood were performed as well as gross and microscopic pathology. In acute oral toxicity, no treatment-related death or toxic signs were observed. It revealed that the DC resin methanol extract could be well tolerated up to the dose 2000 mg/kg body weight and could be classified as Category 5. The sub-acute test observations indicated that there are no treatment-related changes up to the high dose level compared to the control. Food consumption, body weight, organ weight, hematological parameters, biochemical parameters and histopathological examination (liver, kidney, heart, spleen and lung) revealed no abnormalities. Water intake was significantly higher in the DC resin methanol extract treated groups compared to the control. This study demonstrates tolerability of DC

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

...] Draft Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for... ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment.'' The purpose of... antimicrobial drugs for the treatment of acute bacterial skin and skin structure infections (ABSSSI), impetigo...

Impact of intravenous nitroglycerin in the management of acute decompensated heart failure.

PubMed

den Uil, Corstiaan A; Brugts, Jasper J

2015-02-01

Intravenous nitroglycerin is a well-known, but underused, treatment for acute decompensated heart failure. Nitroglycerin has a rapid onset of action and short half-life and there is a clear dose-response curve on both global hemodynamics and peripheral circulation. IV nitroglycerin reduces LV and RV filling pressures and afterload. In the case of acute decompensated heart failure, there is a typical decreased bioavailability of nitric oxide (NO), which needs to be supplemented by exogenous nitrates. Additionally, there is benefit on clinical endpoints, such as fast optimization of arterial oxygenation, lower rates of mechanical ventilation, and improved survival. Drawbacks of therapy include not only side effects such as headache, resistance, and development of tolerability to nitrates but also free radical production. However, nitrates in combination with diuretics remain the cornerstone of acute decompensated heart failure treatment. We propose a more aggressive use of nitrates and a more limited use of inotropes (due to ischemic demand and pro-arrhythmogenic characteristics) in normo- or hypertensive patients with acute heart failure.

Early Pregnancy Cravings, Dietary Intake, and Development of Abnormal Glucose Tolerance.

PubMed

Farland, Leslie V; Rifas-Shiman, Sheryl L; Gillman, Matthew W

2015-12-01

Little is known about the relationships between pregnancy cravings, maternal diet, and development of abnormal glucose tolerance. We examined relationships of pregnancy cravings with dietary intake and risk of developing isolated hyperglycemia (IH), impaired glucose tolerance (IGT), or gestational diabetes (GDM) later in pregnancy. Among 2,022 mothers in Project Viva, a prospective birth cohort recruited from medical practices in eastern Massachusetts between 1999 and 2002, we assessed type of pregnancy craving based on self-report at mean gestation of 10.9 weeks. The outcomes were cross-sectional dietary intake from a food frequency questionnaire and incident IH, IGT, or GDM determined by glucose tolerance screening at 26 to 28 weeks. We used linear regression to analyze the cross-sectional relationships between pregnancy cravings and dietary intake and multinomial logistic regression to analyze the prospective relationships among pregnancy cravings and development of IH, IGT, or GDM. During the first trimester, 443 (22%) women craved sweets, 225 (11%) craved salty foods, 261 (13%) craved savory foods, and 100 (4.9%) craved starchy foods. Sweet cravings were associated with increased intake of sucrose (1.9 g/day; 95% CI 0.1 to 3.7), total fat (1.5 g/day; 95% CI 0.1 to 2.9), and saturated fat (0.8 g/day; 95% CI 0.2 to 1.4); salty cravings were associated with increased fiber (0.7 servings/day; 95% CI -0.1 to 1.6); savory cravings were associated with increased n-3 fatty acids (0.10 g/day; 95% CI 0.02 to 0.17); and starchy cravings were associated with increased carbohydrates (8.0 g/day; 95% CI 0.3 to 15.7) and decreased total fat (-2.6 g/day; 95% CI -5.2 to -0.1). Salty cravings were associated with lower risk of GDM (adjusted odds ratio 0.34, 95% CI 0.12-0.97). New cravings in the first trimester of pregnancy were associated with dietary intake. Craving salty foods may predict reduced risk of developing GDM, whereas craving sweet food does not appear to alter one

Analgesic tolerance to morphine is regulated by PPARγ

PubMed Central

de Guglielmo, Giordano; Kallupi, Marsida; Scuppa, Giulia; Stopponi, Serena; Demopulos, Gregory; Gaitanaris, George; Ciccocioppo, Roberto

2014-01-01

Background and Purpose Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice. Experimental Approach We monitored analgesia on alternate days using the tail immersion test. Key Results Daily administration of morphine (30 mg·kg−1, bid) resulted in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg·kg−1, bid) significantly attenuated the development and expression of tolerance. However, pretreatment with GW-9662 (5 mg·kg−1, bid), a selective PPARγ antagonist, completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg·kg−1, bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance. Conclusions and Implications Overall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse. PMID:25048682

Acute sirolimus overdose: a multicenter case series.

PubMed

Ceschi, Alessandro; Heistermann, Elja; Gros, Sonja; Reichert, Cornelia; Kupferschmidt, Hugo; Banner, Nicholas R; Krähenbühl, Stephan; Taegtmeyer, Anne B

2015-01-01

There are few data relating to sirolimus overdose in the medical literature. Our objectives were to describe all cases of overdose with sirolimus reported to Swiss, German and Austrian Poisons Centres between 2002-2013. An observational case-series analysis was performed to determine circumstances, magnitude, management and outcome of sirolimus overdose. Five cases of acute sirolimus overdose were reported--three in young children and two in adults. Four were accidental and one was with suicidal intent. Two patients developed symptoms probably related to sirolimus overdose: mild elevation of alkaline phosphatase, fever and gastroenteritis in a 2.5-year-old male who ingested 3 mg, and mild changes in total cholesterol in an 18-year-old female after ingestion of 103 mg. None of these events were life-threatening. Serial blood concentration measurements were performed starting 24 h after ingestion of 103 mg in a single case, and these followed a similar pharmacokinetic time-course to measurements taken after dosing in the therapeutic range. Acute sirolimus overdose occurred accidentally in the majority of cases. Even large overdoses appeared to be well-tolerated, however children might be at greater risk of developing complications. Further study of sirolimus overdose is needed.

Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat

PubMed Central

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

2014-01-01

Background Sex differences in cannabinoid effects have been reported in rodents, with adult females typically being more sensitive than adult males. The present study compared the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) in adult, gonadally intact female vs. male rats. Methods Cumulative dose-effect curves were obtained for THC (1.0–18 mg/kg i.p.) on warm water tail withdrawal and paw pressure tests. Vehicle or the sex-specific ED80 dose for THC was administered twice daily for 9 days; THC dose-effect curves were then re-determined. Results On the pre-chronic test day, THC was significantly more potent in females than males in producing antinociception on the tail withdrawal and paw pressure tests. After 9 days of twice-daily THC treatment (5.4 mg/kg/injection in females, 7.6 mg/kg/injection in males), THC potency on both tests decreased more in females than males. On the tail withdrawal test, chronic THC produced 4.2- vs. 2.8-fold increases in ED50 values in females vs. males, respectively. On the paw pressure test, chronic THC produced 4.4- vs. 2.9-fold increases in ED50 values in females vs. males, respectively. Chronic THC treatment did not significantly disrupt estrous cycling in females. Conclusions These results demonstrate that – even when sex differences in acute THC potency are controlled for – females develop more antinociceptive tolerance to THC than males. Given the importance of drug tolerance in the development of drug dependence, these results suggest that females may be more vulnerable than males to developing dependence after chronic cannabinoid exposure. PMID:25131716

Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate-Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress.

PubMed

Daiber, Andreas; Münzel, Thomas

2015-10-10

Organic nitrates, such as nitroglycerin (GTN), isosorbide-5-mononitrate and isosorbide dinitrate, and pentaerithrityl tetranitrate (PETN), when given acutely, have potent vasodilator effects improving symptoms in patients with acute and chronic congestive heart failure, stable coronary artery disease, acute coronary syndromes, or arterial hypertension. The mechanisms underlying vasodilation include the release of •NO or a related compound in response to intracellular bioactivation (for GTN, the mitochondrial aldehyde dehydrogenase [ALDH-2]) and activation of the enzyme, soluble guanylyl cyclase. Increasing cyclic guanosine-3',-5'-monophosphate (cGMP) levels lead to an activation of the cGMP-dependent kinase I, thereby causing the relaxation of the vascular smooth muscle by decreasing intracellular calcium concentrations. The hemodynamic and anti-ischemic effects of organic nitrates are rapidly lost upon long-term (low-dose) administration due to the rapid development of tolerance and endothelial dysfunction, which is in most cases linked to increased intracellular oxidative stress. Enzymatic sources of reactive oxygen species under nitrate therapy include mitochondria, NADPH oxidases, and an uncoupled •NO synthase. Acute high-dose challenges with organic nitrates cause a similar loss of potency (tachyphylaxis), but with distinct pathomechanism. The differences among organic nitrates are highlighted regarding their potency to induce oxidative stress and subsequent tolerance and endothelial dysfunction. We also address pleiotropic effects of organic nitrates, for example, their capacity to stimulate antioxidant pathways like those demonstrated for PETN, all of which may prevent adverse effects in response to long-term therapy. Based on these considerations, we will discuss and present some preclinical data on how the nitrate of the future should be designed.

Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate-Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress

PubMed Central

2015-01-01

Abstract Organic nitrates, such as nitroglycerin (GTN), isosorbide-5-mononitrate and isosorbide dinitrate, and pentaerithrityl tetranitrate (PETN), when given acutely, have potent vasodilator effects improving symptoms in patients with acute and chronic congestive heart failure, stable coronary artery disease, acute coronary syndromes, or arterial hypertension. The mechanisms underlying vasodilation include the release of •NO or a related compound in response to intracellular bioactivation (for GTN, the mitochondrial aldehyde dehydrogenase [ALDH-2]) and activation of the enzyme, soluble guanylyl cyclase. Increasing cyclic guanosine-3′,-5′-monophosphate (cGMP) levels lead to an activation of the cGMP-dependent kinase I, thereby causing the relaxation of the vascular smooth muscle by decreasing intracellular calcium concentrations. The hemodynamic and anti-ischemic effects of organic nitrates are rapidly lost upon long-term (low-dose) administration due to the rapid development of tolerance and endothelial dysfunction, which is in most cases linked to increased intracellular oxidative stress. Enzymatic sources of reactive oxygen species under nitrate therapy include mitochondria, NADPH oxidases, and an uncoupled •NO synthase. Acute high-dose challenges with organic nitrates cause a similar loss of potency (tachyphylaxis), but with distinct pathomechanism. The differences among organic nitrates are highlighted regarding their potency to induce oxidative stress and subsequent tolerance and endothelial dysfunction. We also address pleiotropic effects of organic nitrates, for example, their capacity to stimulate antioxidant pathways like those demonstrated for PETN, all of which may prevent adverse effects in response to long-term therapy. Based on these considerations, we will discuss and present some preclinical data on how the nitrate of the future should be designed. Antioxid. Redox Signal. 23, 899–942. PMID:26261901

Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection

PubMed Central

See Hoe, Louise E.; Schilling, Jan M.; Tarbit, Emiri; Kiessling, Can J.; Busija, Anna R.; Niesman, Ingrid R.; Du Toit, Eugene; Ashton, Kevin J.; Roth, David M.; Headrick, John P.; Patel, Hemal H.

2014-01-01

Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function and protective stress signaling. However, the importance of membrane cholesterol content to cardiovascular function and myocardial responses to ischemia-reperfusion (I/R) and cardioprotective stimuli are unclear. We assessed the effects of graded cholesterol depletion with methyl-β-cyclodextrin (MβCD) and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3) on cardiac function, I/R tolerance, and opioid receptor (OR)-mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02–1.0 mM MβCD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25-min ischemia/45-min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically [sustained ligand-activated preconditioning (SLP)] were assessed. MβCD concentration dependently reduced normoxic contractile function and postischemic outcomes in association with graded (10–30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with ≥20 μM MβCD, whereas SLP was more robust and only inhibited with ≥200 μM MβCD. Deletion of Cav-3 also reduced, whereas Cav-3 OE improved, myocardial I/R tolerance. Protection via SLP remained equally effective in Cav-3 KO mice and was additive with innate protection arising with Cav-3 OE. These data reveal the membrane cholesterol dependence of normoxic myocardial and coronary function, I/R tolerance, and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3, whereas cardiac I/R tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression. PMID:25063791

Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry roundtable.

PubMed

Fisher, Marc; Albers, Gregory W; Donnan, Geoffrey A; Furlan, Anthony J; Grotta, James C; Kidwell, Chelsea S; Sacco, Ralph L; Wechsler, Lawrence R

2005-08-01

Previous Stroke Therapy Academic Industry Roundtable (STAIR) meetings focused on preclinical evidence of drug efficacy and enhancing acute stroke trial design and performance. A fourth (STAIR-IV) was held to discuss relevant issues related to acute stroke drug development and regulatory approval. The STAIR-IV meeting had 3 main focus areas. The first topic was novel approaches to statistical design of acute stroke trials and appropriate outcome measures. The second focus was the need for better cooperation among participants in stroke therapy development that may be addressed through a national consortium of stroke trial centers in the United States and elsewhere. Lastly, regulatory issues related to the approval of novel mono and multiple acute stroke therapies were discussed. The development of additional acute stroke therapies represents a large unmet need with many remaining challenges and also opportunities to incorporate novel approaches to clinical trial design that will lead to regulatory approval. The STAIR-IV meeting explored new concepts of trial methodology and data analysis, initiatives for implementing a US clinical trialist consortium, and pertinent regulatory issues to expedite approval of novel therapies.

Phased Development of Accident Tolerant Fue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bragg-Sitton, Shannon M.; Carmack, W. Jon

2016-09-01

The United States Department of Energy (U.S. DOE) Advanced Fuels Campaign (AFC) has adopted a three-phase approach for the development and eventual commercialization of enhanced, accident tolerant fuel (ATF) for light water reactors (LWRs). Extending from 2012 to 2016, AFC is currently coming to the end of Phase 1 research that has entailed Feasibility Assessment and Prioritization for a large number of proposed fuel systems (fuel and cladding) that could provide improved performance under accident conditions. Phase 1 activities will culminate with a prioritization of concepts for both near-term and long-term development based on the available experimental data and modelingmore » predictions. This process will provide guidance to DOE on what concepts should be prioritized for investment in Phase 2 Development/Qualification activities based on technical performance improvements and probability of meeting the aggressive schedule to insert a lead fuel rod (LFR) in a commercial power reactor by 2022. While Phase 1 activities include small-scale fabrication work, materials characterization, and limited irradiation of samples, Phase 2 will require development teams to expand to industrial fabrication methods, conduct irradiation tests under more prototypic reactor conditions (i.e. in contact with reactor primary coolant at LWR conditions and in-pile transient testing), conduct additional characterization and post-irradiation examination, and develop a fuel performance code for the candidate ATF. Phase 2 will culminate in the insertion of an LFR (or lead fuel assembly) in a commercial power reactor. The Phase 3 Commercialization work will extend past 2022. Following post-irradiation examination of LFRs, partial-core reloads will be demonstrated. The commercialization phase will further entail the establishment of commercial fabrication capabilities and the transition of LWR cores to the new fuel. The three development phases described roughly correspond to the

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Hong-Bin; Chen, Hu-Cheng; Chen, Kai

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. Here, 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 clockmore » 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.« less

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

DOE PAGES

Liu, Hong-Bin; Chen, Hu-Cheng; Chen, Kai; ...

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. Here, 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 clockmore » 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.« less

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)

Morphine tolerance as a function of ratio schedule: response requirement or unit price?

PubMed

Hughes, Christine E; Sigmon, Stacey C; Pitts, Raymond C; Dykstra, Linda A

2005-05-01

Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, l-methadone, and cocaine dose-dependently decreased overall response rates in each of the components. When a rate decreasing dose of morphine was administered daily, tolerance, as measured by an increase in the dose that reduced response rates to 50% of control (i.e., the ED50 value), developed in each of the components; however, the degree of tolerance was smallest in the fixed-ratio 90 component (i.e., the ED50 value increased the least). When the l-methadone dose-effect curve was redetermined during the chronic morphine phase, the degree of cross-tolerance conferred to l-methadone was similar across components, suggesting that behavioral variables may not influence the degree of cross-tolerance between opioids. During the chronic phase, the cocaine dose-effect curve shifted to the right for 2 pigeons and to the left for 1 pigeon, which is consistent with predictions based on the lack of pharmacological similarity between morphine and cocaine. When the morphine, l-methadone, and cocaine dose-effect curves were redetermined after chronic morphine administration ended, the morphine and l-methadone ED50s replicated those obtained prior to chronic morphine administration. The morphine data suggest that the fixed-ratio value (i.e., the absolute output) determines the degree of tolerance and not the unit price.

Engineering antigen-specific immunological tolerance.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kontos, Stephan; Grimm, Alizee J.; Hubbell, Jeffrey A.

2015-05-01

Unwanted immunity develops in response to many protein drugs, in autoimmunity, in allergy, and in transplantation. Approaches to induce immunological tolerance aim to either prevent these responses or reverse them after they have already taken place. We present here recent developments in approaches, based on engineered peptides, proteins and biomaterials, that harness mechanisms of peripheral tolerance both prophylactically and therapeutically to induce antigenspecific immunological tolerance. These mechanisms are based on responses of B and T lymphocytes to other cells in their immune environment that result in cellular deletion or ignorance to particular antigens, or in development of active immune regulatorymore » responses. Several of these approaches are moving toward clinical development, and some are already in early stages of clinical testing.« less

Effect of Acarbose on Long-Term Prognosis in Acute Coronary Syndromes Patients with Newly Diagnosed Impaired Glucose Tolerance

PubMed Central

Yun, Peng; Du, Ai-ming; Chen, Xue-jun; Liu, Jing-cheng; Xiao, Hu

2016-01-01

Objective. To investigate the effect of acarbose therapy on the long-term prognosis of patients with acute coronary syndromes (ACS) complicating newly diagnosed impaired glucose tolerance (IGT). Methodology. 135 patients hospitalized for ACS who had been newly diagnosed with IGT were randomly assigned to acarbose group (150 mg/day, n = 67) or control group (no acarbose, n = 68). All cases in each group were given the same elementary treatment. Mean follow-up was 2.3 years. The incidence of major adverse cardiovascular event (MACE) and carotid intima-middle thickness (CIMT) were statistically analyzed. Results. During the mean follow-up of 2.3 years, the risk of recurrent MACE in acarbose group was decreased significantly compared with that in control group (26.67% versus 46.88%, P < 0.05); at the same time, thickening of the CIMT was significantly slower than the control group ((1.28 ± 0.42) mm versus (1.51 ± 0.64) mm, P < 0.05). Conclusions. Acarbose can effectively reduce the risk of MACE in ACS patients with newly diagnosed IGT, simultaneously retarding the progression of carotid intima-media thickness. PMID:26770983

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

QTLs for tolerance of drought and breeding for tolerance of abiotic and biotic stress: an integrated approach.

PubMed

Dixit, Shalabh; Huang, B Emma; Sta Cruz, Ma Teresa; Maturan, Paul T; Ontoy, Jhon Christian E; Kumar, Arvind

2014-01-01

The coupling of biotic and abiotic stresses leads to high yield losses in rainfed rice (Oryza sativa L.) growing areas. While several studies target these stresses independently, breeding strategies to combat multiple stresses seldom exist. This study reports an integrated strategy that combines QTL mapping and phenotypic selection to develop rice lines with high grain yield (GY) under drought stress and non-stress conditions, and tolerance of rice blast. A blast-tolerant BC2F3-derived population was developed from the cross of tropical japonica cultivar Moroberekan (blast- and drought-tolerant) and high-yielding indica variety Swarna (blast- and drought-susceptible) through phenotypic selection for blast tolerance at the BC2F2 generation. The population was studied for segregation distortion patterns and QTLs for GY under drought were identified along with study of epistatic interactions for the trait. Segregation distortion, in favour of Moroberekan, was observed at 50 of the 59 loci. Majority of these marker loci co-localized with known QTLs for blast tolerance or NBS-LRR disease resistance genes. Despite the presence of segregation distortion, high variation for DTF, PH and GY was observed and several QTLs were identified under drought stress and non-stress conditions for the three traits. Epistatic interactions were also detected for GY which explained a large proportion of phenotypic variance observed in the population. This strategy allowed us to identify QTLs for GY along with rapid development of high-yielding purelines tolerant to blast and drought with considerably reduced efforts. Apart from this, it also allowed us to study the effects of the selection cycle for blast tolerance. The developed lines were screened at IRRI and in the target environment, and drought and blast tolerant lines with high yield were identified. With tolerance to two major stresses and high yield potential, these lines may provide yield stability in rainfed rice areas.

Chronic tolerance to ethanol-induced sedation: implication for age-related differences in locomotor sensitization.

PubMed

Quoilin, Caroline; Didone, Vincent; Tirelli, Ezio; Quertemont, Etienne

2013-06-01

The adolescent brain has been suggested to be particularly sensitive to ethanol-induced neuroadaptations, which in turn could increase the risk of youths for alcohol abuse and dependence. Sensitization to the locomotor stimulant effects of ethanol has often been used as an animal model of ethanol-induced neuroadaptations. Previously, we showed that young mice were more sensitive than adults to the locomotor sensitization induced by high ethanol doses. However, this effect could be due to age-related differences in chronic tolerance to the sedative effects of ethanol. The aim of the present study is to assess chronic tolerance to the sedative effects of ethanol in weaning 21-day-old (P21), adolescent 35-day-old (P35) and adult 63-day-old (P63) female Swiss mice. After a daily injection of saline or 4 g/kg ethanol during 6 consecutive days, all P21, P35 and P63 mice were injected with 4 g/kg ethanol and submitted to the loss of righting reflex procedure. Our results confirm that the sensitivity to the acute sedative effects of ethanol gradually increases with age. Although this schedule of ethanol injections induces significant age-related differences in ethanol sensitization, it did not reveal significant differences between P21, P35 and P63 mice in the development of a chronic ethanol tolerance to its sedative effects. The present results show that age-related differences in the development of ethanol sensitization cannot be explained by differences in chronic ethanol tolerance to its sedative effects. More broadly, they do not support the idea that ethanol-induced sensitization is a by-product of chronic ethanol tolerance. Copyright © 2013 Elsevier Inc. All rights reserved.

Influence of clonidine induced sympathicolysis on anaemia tolerance in anaesthetized pigs.

PubMed

Lauscher, Patrick; Kertscho, Harry; Krömker, Malte; Haberichter, Barbara; Zacharowski, Kai; Rosenberger, Peter; Meier, Jens

2016-10-12

Clonidine effectively decreases perioperative mortality by reducing sympathetic tone. However, application of clonidine might also restrict anaemia tolerance due to impairment of compensatory mechanisms. Therefore, the influence of clonidine induced, short-term sympathicolysis on anaemia tolerance was assessed in anaesthetized pigs. We measured the effect of clonidine on anaemia tolerance and of the potential for macrohemodynamic alterations to constrain the acute anaemia compensatory mechanisms. After governmental approval, 14 anaesthetized pigs of either gender (Deutsche Landrasse, weight (mean ± SD) 24.1 ± 2.4 kg) were randomly assigned to intravenous saline or clonidine treatment (bolus: 20 μg · kg -1 , continuous infusion: 15 μg · kg -1  · h -1 ). Thereafter, the animals were hemodiluted by exchange of whole blood for 6 % hydroxyethyl starch (MW 130.000/0.4) until the individual critical haemoglobin concentration (Hb crit ) was reached. Primary outcome parameters were Hb crit and the exchangeable blood volume (EBV) until Hb crit was reached. Hb crit did not differ between both groups (values are median [interquartile range]: saline: 2.2 (2.0-2.5) g · dL -1 vs. clonidine: 2.1 (2.1-2.4) g · dL -1 ; n.s.). Furthermore, there was no difference in exchangeable blood volume (EBV) between both groups (saline: 88 (76-106) mL · kg -1 vs. clonidine: 92 (85-95) mL · kg -1 ; n.s.). Anaemia tolerance was not affected by clonidine induced sympathicolysis. Consequently, perioperative clonidine administration probably has not to be omitted in view of acute anaemia.

The growth threshold conjecture: a theoretical framework for understanding T-cell tolerance.

PubMed

Arias, Clemente F; Herrero, Miguel A; Cuesta, José A; Acosta, Francisco J; Fernández-Arias, Cristina

2015-07-01

Adaptive immune responses depend on the capacity of T cells to target specific antigens. As similar antigens can be expressed by pathogens and host cells, the question naturally arises of how can T cells discriminate friends from foes. In this work, we suggest that T cells tolerate cells whose proliferation rates remain below a permitted threshold. Our proposal relies on well-established facts about T-cell dynamics during acute infections: T-cell populations are elastic (they expand and contract) and they display inertia (contraction is delayed relative to antigen removal). By modelling inertia and elasticity, we show that tolerance to slow-growing populations can emerge as a population-scale feature of T cells. This result suggests a theoretical framework to understand immune tolerance that goes beyond the self versus non-self dichotomy. It also accounts for currently unexplained observations, such as the paradoxical tolerance to slow-growing pathogens or the presence of self-reactive T cells in the organism.

Expression responses of five cold tolerant related genes to two temperature dropping treatments in sea cucumber Apostichopus japonicus

NASA Astrophysics Data System (ADS)

Li, Chengze; Chang, Yaqing; Pang, Zhenguo; Ding, Jun; Ji, Nanjing

2015-03-01

Environmental conditions, including ambient temperature, play important roles in survival, growth development, and reproduction of the Japanese sea cucumber, Apostichopus japonicus. Low temperatures result in slowed growth and skin ulceration disease. In a previous study, we investigated the effect of low temperature on gene expression profiles in A. japonicus by suppression subtractive hybridization (SSH). Genes encoding Ferritin, Lysozyme, Hsp70, gp96, and AjToll were selected from a subtracted cDNA library of A. japonicus under acute cold stress. The transcriptional expression profiles of these genes were investigated in different tissues (coelomocyte, respiratory tree, intestine, longitudinal muscle) after exposure to acute and mild temperature dropping treatments. The results show that (1) the five cold-tolerance-related genes were found in all four tissues and the highest mRNA levels were observed in coelomocyte and respiratory tree; (2) under the temperature dropping treatments, three types of transcriptional regulation patterns were observed: primary suppression followed by up-regulation at -2°C, suppressed expression throughout the two treatments, and more rarely an initial stimulation followed by suppression; and (3) gene expression suppression was more severe under acute temperature dropping than under mild temperature dropping treatment. The five cold-tolerance-related genes that were distributed mainly in coelomocyte and respiratory tissues were generally down-regulated by low temperature stress but an inverse up-regulation event was found at the extreme temperature (-2°C).

Negative Affect Mediates the Relation Between Trait Urgency and Behavioral Distress Tolerance

PubMed Central

Borges, Allison M.; Dahne, Jennifer; Lim, Aaron C.; MacPherson, Laura

2017-01-01

Distress tolerance is associated with a range of psychopathology and risk-taking behavior. Current research suggests that the behavioral ability to persist at goal-directed behavior when distressed may be malleable. However, little is known about the contributing factors that underlie individual differences in distress tolerance. Trait urgency, or the tendency to act impulsively in the context of acute changes in affect, may predict distress tolerance because the prepotent response to avoid or remove an aversive state may undermine persistence. To date, most research has examined the role of negative urgency, a valenced subfactor of urgency, in relation to distress tolerance. However, the broad trait of urgency may be associated with a greater change in affect that precedes the inability to tolerate distress. The current study examined whether greater changes in negative affect was indeed a mediator in the relationship between trait urgency and behavioral distress tolerance. The effects of both positive and negative urgency on affect change were examined to investigate the potential contribution of the broader urgency trait. The results suggest that a greater change in negative affect over the course of a stressor mediated the association between both subfactors of urgency and distress tolerance. These findings suggest that trait urgency, regardless of valence, may be associated with experiencing greater changes in affect that ultimately undermine the ability to tolerate distress. These findings also highlight important components of distress tolerance that could inform behavioral interventions. PMID:28080084

Negative affect mediates the relation between trait urgency and behavioral distress tolerance.

PubMed

Borges, Allison M; Dahne, Jennifer; Lim, Aaron C; MacPherson, Laura

2017-06-01

Distress tolerance is associated with a range of psychopathology and risk-taking behavior. Current research suggests that the behavioral ability to persist at goal-directed behavior when distressed may be malleable. However, little is known about the contributing factors that underlie individual differences in distress tolerance. Trait urgency, or the tendency to act impulsively in the context of acute changes in affect, may predict distress tolerance because the prepotent response to avoid or remove an aversive state may undermine persistence. To date, most research has examined the role of negative urgency, a valenced subfactor of urgency, in relation to distress tolerance. However, the broad trait of urgency may be associated with a greater change in affect that precedes the inability to tolerate distress. The current study examined whether greater changes in negative affect was indeed a mediator in the relationship between trait urgency and behavioral distress tolerance. The effects of both positive and negative urgency on affect change were examined to investigate the potential contribution of the broader urgency trait. The results suggest that a greater change in negative affect over the course of a stressor mediated the association between both subfactors of urgency and distress tolerance. These findings suggest that trait urgency, regardless of valence, may be associated with experiencing greater changes in affect that ultimately undermine the ability to tolerate distress. These findings also highlight important components of distress tolerance that could inform behavioral interventions. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 objectivemore » 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

Acute anal toxicity after whole pelvic radiotherapy in patients with asymptomatic haemorrhoids: identification of dosimetric and patient factors.

PubMed

Jang, H; Baek, J G; Yoo, S-J

2015-06-01

Patients with asymptomatic haemorrhoids are known to be less tolerant of radiation doses lower than known tolerance doses. In the present study, the authors sought to identify the risk factors of acute haemorrhoid aggravation after whole pelvic radiotherapy (WPRT). The records of 33 patients with cervical, rectal or prostate cancer with asymptomatic haemorrhoids, which were confirmed by colonoscopy before the start of radiotherapy (RT), were reviewed. Acute anal symptoms, such as anal pain and bleeding, were observed up to 1 month after RT completion. Dosimetric and patient factors were analysed, and subgroup analyses were performed. The median induction dose for acute anal symptoms was 34.1 Gy (range, 28.8-50.4 Gy). Post-operative treatment intent showed more acute anal toxicity of patient factors (p = 0.04). In subgroup analysis, post-operative treatment intent and concurrent chemoradiotherapy were found to be related to acute anal symptoms (p < 0.01). Of the dosimetric factors, V10 tended to be related to acute anal symptoms (p = 0.08). This study indicates that asymptomatic haemorrhoid may deteriorate after low-dose radiation and that patient factors, such as treatment intent and concurrent chemotherapy, probably influence anal toxicity. In patients with asymptomatic haemorrhoids, WPRT requires careful dosimetry and clinical attention. The tolerance of anal canal tends to be ignored in patients with pelvic cancer who are undergoing WPRT. However, patients with asymptomatic haemorrhoids may be troubled by low radiation doses, and further studies are required.

Urine biomarkers informative of human kidney allograft rejection and tolerance.

PubMed

Nissaisorakarn, Voravech; Lee, John Richard; Lubetzky, Michelle; Suthanthiran, Manikkam

2018-05-01

We developed urinary cell messenger RNA (mRNA) profiling to monitor in vivo status of human kidney allografts based on our conceptualization that the kidney allograft may function as an in vivo flow cell sorter allowing access of graft infiltrating cells to the glomerular ultrafiltrate and that interrogation of urinary cells is informative of allograft status. For the profiling urinary cells, we developed a two-step preamplification enhanced real-time quantitative PCR (RT-QPCR) assays with a customized amplicon; preamplification compensating for the low RNA yield from urine and the customized amplicon facilitating absolute quantification of mRNA and overcoming the inherent limitations of relative quantification widely used in RT-QPCR assays. Herein, we review our discovery and validation of urinary cell mRNAs as noninvasive biomarkers prognostic and diagnostic of acute cellular rejection (ACR) in kidney allografts. We summarize our results reflecting the utility of urinary cell mRNA profiling for predicting reversal of ACR with anti-rejection therapy; differential diagnosis of kidney allograft dysfunction; and noninvasive diagnosis and prognosis of BK virus nephropathy. Messenger RNA profiles associated with human kidney allograft tolerance are also summarized in this review. Altogether, data supporting the idea that urinary cell mRNA profiles are informative of kidney allograft status and tolerance are reviewed in this report. Copyright © 2018. Published by Elsevier Inc.

SMAD4 is Involved in the Development of Endotoxin Tolerance in Microglia.

PubMed

Liu, Xiaorong; Qin, Yongwei; Dai, Aihua; Zhang, Yu; Xue, Huaqing; Ni, Haidan; Han, Lijian; Zhu, Liang; Yuan, Debin; Tao, Tao; Cao, Maohong

2016-07-01

Initial exposure of macrophages to LPS induces hyporesponsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Smad4 plays important roles in the induction of LPS tolerance. However, the function of Smad4 in microglia remains unknown. Here we show that expression of Smad4 was highly up-regulated in LPS-tolerized mouse cerebral cortex. Smad4 was mostly colocalized with microglia, rarely with neurons. Using a microglia cell line, BV2, we find that LPS activates endogenous Smad4, inducing its migration into the nucleus and increasing its expression. Smad4 significantly suppressed TLR-triggered production of proinflammatory cytokines (IL-6), increased anti-inflammatory cytokine in LPS-tolerized microglia. Moreover, IL-6 concentrations in culture supernatants after second LPS challenge are higher in SMAD4 small interfering RNA (siRNA) BV2 cells than control siRNA BV2 cells, indicating failure to induce tolerance in absence of Smad4 signaling. In our study, we conclude that both in vivo and in vitro, Smad4 signaling is required for maximal induction of endotoxin tolerance.

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

USDA-ARS?s Scientific Manuscript database

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 ...

Acute lymphoblastic leukemia: a comprehensive review and 2017 update

PubMed Central

Terwilliger, T; Abdul-Hay, M

2017-01-01

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone. The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. In adults, 75% of cases develop from precursors of the B-cell lineage, with the remainder of cases consisting of malignant T-cell precursors. Traditionally, risk stratification has been based on clinical factors such age, white blood cell count and response to chemotherapy; however, the identification of recurrent genetic alterations has helped refine individual prognosis and guide management. Despite advances in management, the backbone of therapy remains multi-agent chemotherapy with vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of ALL. PMID:28665419

Oral sumatriptan in acute migraine.

PubMed

Goadsby, P J; Zagami, A S; Donnan, G A; Symington, G; Anthony, M; Bladin, P F; Lance, J W

1991-09-28

The efficacy in acute migraine of oral sumatriptan was assessed in a double-blind, randomised, placebo-controlled, crossover study of 61 patients (mean age 39 [SD 10] years). 41 completed treatment of four attacks, two with sumatriptan 100 mg and two with placebo. The response rate (reduction in headache from moderate or severe to mild or absent at 2 h) was 51% (45/89) with sumatriptan and 10% (9/93) with placebo (p less than 0.01); rescue medication was needed at 2 h in 41% and 88%, respectively. Of 28 patients headache-free at 24 h, 11 (39%) had recurrent headache within 24 h. There were no substantial side-effects. Thus, sumatriptan is an effective well-tolerated treatment for acute migraine attacks.

Acute Pancreatitis: Etiology, Pathology, Diagnosis, and Treatment.

PubMed

Majidi, Shirin; Golembioski, Adam; Wilson, Stephen L; Thompson, Errington C

2017-11-01

Acute pancreatitis is a fascinating disease. In the United States, the two most common etiologies of acute pancreatitis are gallstones and excessive alcohol consumption. The diagnosis of acute pancreatitis is made with a combination of history, physical examination, computed tomography scan, and laboratory evaluation. Differentiating patients who will have a benign course of their pancreatitis from patients who will have severe pancreatitis is challenging to the clinician. C-reactive protein, pro-calcitonin, and the Bedside Index for Severity of Acute Pancreatitis appeared to be the best tools for the early and accurate diagnosis of severe pancreatitis. Early laparoscopic cholecystectomy is indicated for patients with mild gallstone pancreatitis. For patients who are going to have a prolonged hospitalization, enteral nutrition is preferred. Total parenteral nutrition should be reserved for patients who cannot tolerate enteral nutrition. Prophylactic antibiotics are not indicated for patients with pancreatic necrosis. Surgical intervention for infected pancreatic necrosis should be delayed as long as possible to improve patient outcomes.

Physiological tolerances of juvenile robust redhorse, Moxostoma robustum: Conservation implications for an imperiled species

USGS Publications Warehouse

Walsh, S.J.; Haney, D.C.; Timmerman, C.M.; Dorazio, R.M.

1998-01-01

The robust redhorse, Moxostoma robustum (Teleostei: Catostomidae), is an imperiled sucker native to large rivers of the Atlantic slope of the southeastern United States. Juvenile M. robustum were tested for tolerances to temperature, salinity, pH, and hypoxia in order to evaluate basic early life-history requirements. Static (acute) tests resulted in estimates of mean lower temperature tolerances (5.3-19.4 ??C) that varied with prior thermal acclimation and indicated no apparent difference in tolerance among fish 30, 60, and 90 days old. Fish acclimated to 20 ??C and 30 ??C had significantly different mean critical thermal maxima (34.9 ??C and 37.2 ??C, respectively) and exhibited pronounced increased opercular ventilation rates with elevated temperatures. Fish exposed to acute and chronic increases in salinity showed unusual patterns of mortality above the isosmotic point (9 ppt) that reflected possible differences in body mass and prior acclimation conditions (i.e., water ionic composition); small fish and those held in soft water were the least tolerant of increased salinity. Abrupt exposure to extreme pH values resulted in greater than 50% mortality at pH values below 4.3 and above 9.5 within a 96-hour period. Fish exposed to progressive hypoxia utilized aquatic surface respiration at a mean oxygen concentration of 0.72-0.80 mg O2 l-1 (20 ??C and 30 ??C acclimated fish, respectively), and lost equilibrium at 0.54-.57 mg O2 l-1. Juvenile M. robustum are moderately tolerant of a wide range of ambient physicochemical parameters, but further research is needed to determine how both abiotic and biotic factors have contributed to population decline and extirpation of this species.

Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs.

PubMed

Hofer-Inteeworn, Natalie; Panciera, David L; Monroe, William E; Saker, Korinn E; Davies, Rebecca Hegstad; Refsal, Kent R; Kemnitz, Joseph W

2012-04-01

To determine the effects of hypothyroidism on insulin sensitivity, glucose tolerance, and concentrations of hormones counter-regulatory to insulin in dogs. 8 anestrous mixed-breed bitches with experimentally induced hypothyroidism and 8 euthyroid control dogs. The insulin-modified frequently sampled IV glucose tolerance test and minimal model analysis were used to determine basal plasma insulin and glucose concentrations, acute insulin response to glucose, insulin sensitivity, glucose effectiveness, and disposition index. Growth hormone response was assessed by stimulation and suppression tests. Additionally, basal serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations and urine cortisol-to-creatinine concentration ratios were measured and dual energy x-ray absorptiometry was performed to evaluate body composition. Insulin sensitivity was lower in the hypothyroid group than in the euthyroid group, whereas acute insulin response to glucose was higher. Glucose effectiveness and disposition index were not different between groups. Basal serum GH and IGF-1 concentrations as well as abdominal fat content were high in hypothyroid dogs, but urine cortisol-to-creatinine concentration ratios were unchanged. Hypothyroidism appeared to negatively affect glucose homeostasis by inducing insulin resistance, but overall glucose tolerance was maintained by increased insulin secretion in hypothyroid dogs. Possible factors affecting insulin sensitivity are high serum GH and IGF-1 concentrations and an increase in abdominal fat. In dogs with diseases involving impaired insulin secretion such as diabetes mellitus, concurrent hypothyroidism can have important clinical implications.

A systematic review on the role of anticonvulsants in the treatment of acute bipolar depression.

PubMed

Reinares, María; Rosa, Adriane R; Franco, Carolina; Goikolea, José Manuel; Fountoulakis, Kostas; Siamouli, Melina; Gonda, Xenia; Frangou, Sophia; Vieta, Eduard

2013-03-01

Despite the high morbidity and mortality associated with bipolar depression, the optimal treatment for this phase is still a matter of debate. The aim of the current review was to provide updated evidence about the efficacy and tolerability of anticonvulsants in the treatment of acute bipolar depression. A comprehensive review of randomized controlled trials (RCTs) evaluating the use of anticonvulsants for the treatment of acute bipolar depression up to June 2011 was conducted by means of the PubMed-Medline database. Eligibility criteria included active comparator-controlled or placebo-controlled randomized studies involving monotherapy or combination therapy. A total of 18 RCTs fulfilled the inclusion criteria. Studies supported the efficacy of divalproex as monotherapy in acute bipolar depression but small sample size was a common methodological limitation. Findings were inconclusive for lamotrigine and carbamazepine although overall lamotrigine may have a beneficial but modest effect. Negative results were found for levetiracetam and gabapentin but the evidence base on these agents is scant. All anticonvulsants were generally well tolerated. No double-blind RCTs were found for the use of other anticonvulsants such as oxcarbazepine, licarbazepine, zonisamide, retigabine, pregabalin, tiagabine, felbamate and vigabatrine in the acute treatment of bipolar depression. To sum up, taking into consideration the efficacy and tolerability profiles of anticonvulsants, current evidence supports the use of divalproex and lamotrigine in the treatment of acute bipolar depression. However, available data for most other anticonvulsants are inconclusive and further RCTs with larger sample sizes are needed before drawing firm conclusions.

Development of low-loading, carbon monoxide tolerant PEM fuel cell electrodes

NASA Astrophysics Data System (ADS)

Haug, Andrew Thomas

This work discusses the problems of, and potential solutions to, high catalyst cost of and carbon monoxide (CO) poisoning of the proton-exchange membrane fuel cell (PEMFC). As this is a comprehensive work, background on fuel cells and specifically PEMFCs is first presented. A discussion of the current status of PEMFCs is presented showing ongoing work for stationary, transportation, portable and military applications. This leads into two of the more significant problems preventing widespread commercialization of PEMFC technology: poisoning of the catalyst by CO and the cost of the catalyst. A thorough examination of CO poisoning of the PEMFC anode is presented from how CO comes to be present in the feed stream of the PEMFC anode to how it then poisons the PEMFC anode. The first work presented here describes the development of a novel CO tolerant anode (the Ruthenium filter). It shows that by placing a layer of carbon-supported Ruthenium catalyst between the Pt catalyst and the anode flow field to form a filter, tolerance to CO will be increased relative to a Pt:Ru alloy when oxygen is added to the anode fuel stream. Secondly, after an introduction to catalyst preparation techniques used today and a brief discussion of catalyst-cost in PEMFCs, it is shown how sputter-deposition technology may be used to create more kinetically active PEMFC catalyst electrodes versus standard ink-based techniques. The technologies of the Ru filter and sputter-deposition are then combined to create a low-loading, CO tolerant anode for the PEMFC. In the final work, the effect of the airbleed on CO oxidation is then modeled. In the concluding chapter, it is shown how the work presented can lead the PEMFC closer to large-scale commercialization. The Appendix A provides a detailed method by which PEMFC MEAs were manufactured using catalyst inks. This method served as the basis for all original works presented. Appendix B--F provide further background and information on the mathematical

Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine

PubMed Central

Garzón, Javier; de la Torre-Madrid, Elena; Rodríguez-Muñoz, María; Vicente-Sánchez, Ana; Sánchez-Blázquez, Pilar

2009-01-01

Background Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs) are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated. Results Intracerebroventricular (icv) administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs) and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than 2 weeks, and it also

Tolerance and Cross-Tolerance following Toll-Like Receptor (TLR)-4 and -9 Activation Are Mediated by IRAK-M and Modulated by IL-7 in Murine Splenocytes

PubMed Central

Julian, Mark W.; Strange, Heather R.; Ballinger, Megan N.; Hotchkiss, Richard S.; Papenfuss, Tracey L.; Crouser, Elliott D.

2015-01-01

Objective Immune suppression during critical illness predisposes to serious infections. We sought to determine the mechanisms regulating tolerance and cross-tolerance to common pro-inflammatory danger signals in a model that recapitulates the intact in vivo immune response. Materials and Methods Flt3-expanded splenocytes obtained from wild-type or matching IRAK-M knockout (IRAK-M-/-), C57BL/6, male mice (8–10 weeks old) were treated repeatedly or alternately with either LPS or CpGA DNA, agonists of Toll-like receptor (TLR)-4 and -9, respectively, over successive 24-hour periods. Supernatants were collected following each 24-hour period with cytokine release (ELISA) and splenocyte IRAK-M expression (Western blot) determined. Tolerance and cross-tolerance were assessed in the absence or presence of programmed death receptor (PD)-1 blocking antibody or IL-7 pre-treatment. Main Results Splenocytes notably exhibited both tolerance and cross-tolerance to subsequent treatments with either LPS or CpGA DNA. The character of tolerance and cross-tolerance in this model was distinct following initial LPS or CpGA treatment in that TNFα and IFNγ release (not IL-10) were suppressed following LPS; whereas, initial CpGA treatment suppressed TNFα, IFNγ and IL-10 release in response to subsequent stimulation (LPS or CpGA). Tolerance and cross-tolerance were unrelated to IL-10 release or PD-1 but were attenuated in IRAK-M-/- splenocytes. IL-7 significantly suppressed IRAK-M expression and restored TNFα and IFNγ production without influencing IL-10 release. Conclusions In summary, acute immune tolerance and cross-tolerance in response to LPS or CpGA were distinct in that LPS selectively suppressed pro-inflammatory cytokine responses; whereas, CpGA suppressed both pro- and anti-inflammatory responses. The induction of tolerance and cross-tolerance in response to common danger signals was mechanistically unrelated to IL-10 or PD-1 but was directly influenced by IRAK-M expression

Tolerance to insect defoliation: biocenotic aspects

Treesearch

Andrey A. Pleshanov; Victor I. Voronin; Elena S. Khlimankova; Valentina I. Epova

1991-01-01

Woody plant resistance to insect damage is of great importance in forest protection, and tree tolerance is an important element of this resistance. The compensating mechanisms responsible for tolerance are nonspecific as a rule and develop after damage has been caused by phytophagous animals or other unfavorable effects. Beyond that, plant tolerance depends on duration...

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matyas, Josef; Vienna, John D.; Peeler, David

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.

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.

Effects of Transcranial Direct Current Stimulation (tDCS) on Pain Distress Tolerance: A Preliminary Study.

PubMed

Mariano, Timothy Y; van't Wout, Mascha; Jacobson, Benjamin L; Garnaat, Sarah L; Kirschner, Jason L; Rasmussen, Steven A; Greenberg, Benjamin D

2015-08-01

Pain remains a critical medical challenge. Current treatments target nociception without addressing affective symptoms. Medically intractable pain is sometimes treated with cingulotomy or deep brain stimulation to increase tolerance of pain-related distress. Transcranial direct current stimulation (tDCS) may noninvasively modulate cortical areas related to sensation and pain representations. The present study aimed to test the hypothesis that cathodal ("inhibitory") stimulation targeting left dorsal anterior cingulate cortex (dACC) would increase tolerance to distress from acute painful stimuli vs anodal stimulation. Forty healthy volunteers received both anodal and cathodal stimulation. During stimulation, we measured pain distress tolerance with three tasks: pressure algometer, cold pressor, and breath holding. We measured pain intensity with a visual-analog scale before and after each task. Mixed ANOVA revealed that mean cold pressor tolerance tended to be higher with cathodal vs anodal stimulation (P = 0.055) for participants self-completing the task. Pressure algometer (P = 0.81) and breath holding tolerance (P = 0.19) did not significantly differ. The pressure algometer exhibited a statistically significant order effect irrespective of stimulation polarity (all P < 0.008). Pain intensity ratings increased acutely after cold pressor and pressure algometer tasks (both P < 0.01), but not after breath holding (P = 0.099). Cold pressor pain ratings tended to rise less after cathodal vs anodal tDCS (P = 0.072). Although our primary results were nonsignificant, there is a preliminary suggestion that cathodal tDCS targeting left dACC may increase pain distress tolerance to cold pressor. Pressure algometer results are consistent with task-related sensitization. Future studies are needed to refine this novel approach for pain neuromodulation. Wiley Periodicals, Inc.

Role of Maternal Dietary Peanut Exposure in Development of Food Allergy and Oral Tolerance.

PubMed

Järvinen, Kirsi M; Westfall, Jennifer; De Jesus, Magdia; Mantis, Nicholas J; Carroll, Jessica A; Metzger, Dennis W; Sampson, Hugh A; Berin, M Cecilia

2015-01-01

The impact of maternal ingestion of peanut during pregnancy and lactation on an offspring's risk for peanut allergy is under debate. To investigate the influence of maternal dietary peanut exposure and breast milk on an offspring's allergy risk. Preconceptionally peanut-exposed C3H/HeJ females were either fed or not fed peanut during pregnancy and lactation. The offsprings' responses to peanut sensitization or oral tolerance induction by feeding antigen prior to immunization were assessed. We also assessed the impact of immune murine milk on tolerance induction pre- or post-weaning. For antigen uptake studies, mice were gavaged with fluorescent peanut in the presence or absence of immune murine milk; Peyer's patches were harvested for immunostaining. Preconceptional peanut exposure resulted in the production of varying levels of maternal antibodies in serum (and breast milk), which were transferred to the offspring. Despite this, maternal peanut exposure either preconceptionally or during pregnancy and lactation, when compared to no maternal exposure, had no impact on peanut allergy. When offspring were fed peanut directly, dose-dependent tolerance induction, unaltered by maternal feeding of peanut, was seen. Although peanut uptake into the gut-associated lymphoid tissues was enhanced by immune milk as compared to naïve milk, tolerance induction was not affected by the co-administration of immune milk either pre- or post-weaning. Maternal peanut exposure during pregnancy and lactation has no impact on the development of peanut allergy in the offspring. Tolerance to peanut can be induced early, even pre-weaning, by giving moderate amounts of peanut directly to the infant, and this is neither enhanced nor impaired by concurrent exposure to immune milk.

Differential expression of benzodiazepine anticonvulsant cross-tolerance according to time following flurazepam or diazepam treatment.

PubMed

Rosenberg, H C

1995-01-01

In previous studies in which the anti-pentylenetetrazol (PTZ) effect of benzodiazepines was used to measure tolerance, the results depended on the benzodiazepine used for chronic treatment as well as the benzodiazepine given acutely to test for tolerance. In this study, the time course of tolerance reversal was studied in rats given two treatments known to cause anticonvulsant tolerance, 1-week flurazepam (FZP), and 3-week diazepam (DZP). Neither treatment altered convulsive threshold for IV PTZ, but both treatments decreased the convulsive threshold for bicuculline. Withdrawing DZP, but not FZP, treatment resulted in a loss of body weight. Twelve hours after 1-week FZP treatment, all benzodiazepines were significantly less effective, showing tolerance. Forty-eight hours after the 1-week FZP treatment, tolerance was still observed with DZP, FZP, and zolpidem, but was no longer present with clonazepam or bretazenil. After the 3-week DZP treatment, rats were tolerant to all benzodiazepines tested at 12 h of withdrawal, but had lost tolerance to all the drugs except bretazenil by 48 h. The results suggest differences in the way these benzodiazepines interact with their receptors, allowing differential expression of tolerance, and that chronic DZP and FZP treatments affected interactions of the benzodiazepines with their receptors, but not in the same fashion.

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. Crown Copyright © 2012. Published by Elsevier Masson SAS. All rights reserved.

Casemix classification payment for sub-acute and non-acute inpatient care, Thailand.

PubMed

Khiaocharoen, Orathai; Pannarunothai, Supasit; Zungsontiporn, Chairoj; Riewpaiboon, Wachara

2010-07-01

There is a need to develop other casemix classifications, apart from DRG for sub-acute and non-acute inpatient care payment mechanism in Thailand. To develop a casemix classification for sub-acute and non-acute inpatient service. The study began with developing a classification system, analyzing cost, assigning payment weights, and ended with testing the validity of this new casemix system. Coefficient of variation, reduction in variance, linear regression, and split-half cross-validation were employed. The casemix for sub-acute and non-acute inpatient services contained 98 groups. Two percent of them had a coefficient of variation of the cost of higher than 1.5. The reduction in variance of cost after the classification was 32%. Two classification variables (physical function and the rehabilitation impairment categories) were key determinants of the cost (adjusted R2 = 0.749, p = .001). Validity results of split-half cross-validation of sub-acute and non-acute inpatient service were high. The present study indicated that the casemix for sub-acute and non-acute inpatient services closely predicted the hospital resource use and should be further developed for payment of the inpatients sub-acute and non-acute phase.

[Psychotherapy impact on effectiveness of in-hospital physical rehabilitation in patients with acute coronary syndrome].

PubMed

Sumin, A N; Khaĭredinova, O P; Sumina, L Iu; Variushkina, E V; Doronin, D V; Galimzianov, D M; Masin, A N; Gol'dberg, G A

2000-01-01

Of 103 patients with acute coronary syndrome (mean age 51.6 +/- 0.9 years) 47 patients participated in 5 group psychotherapeutic sessions added to conversional rehabilitation program. Psychotherapy included progressive muscular relaxation, neurolinguistic programming, eriksonian hypnosis, therapeutic metaphora. Psychotherapy decreased the hear rate, number of ventricular extrasystoles, stimulated tonicity of the parasympathetic nervous system. Compared to the controls, the test patients developed higher exercise tolerance and lower reactivity of the central hemodynamics in all the exercise tests.

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

Development of Cold Spray Coatings for Accident-Tolerant Fuel Cladding in Light Water Reactors

NASA Astrophysics Data System (ADS)

Maier, Benjamin; Yeom, Hwasung; Johnson, Greg; Dabney, Tyler; Walters, Jorie; Romero, Javier; Shah, Hemant; Xu, Peng; Sridharan, Kumar

2018-02-01

The cold spray coating process has been developed at the University of Wisconsin-Madison for the deposition of oxidation-resistant coatings on zirconium alloy light water reactor fuel cladding with the goal of improving accident tolerance during loss of coolant scenarios. Coatings of metallic (Cr), alloy (FeCrAl), and ceramic (Ti2AlC) materials were successfully deposited on zirconium alloy flats and cladding tube sections by optimizing the powder size, gas preheat temperature, pressure and composition, and other process parameters. The coatings were dense and exhibited excellent adhesion to the substrate. Evaluation of the samples after high-temperature oxidation tests at temperatures up to 1300°C showed that the cold spray coatings significantly mitigate oxidation kinetics because of the formation of thin passive oxide layers on the surface. The results of the study indicate that the cold spray coating process is a viable near-term option for developing accident-tolerant zirconium alloy fuel cladding.

Levetiracetam-induced acute psychosis in a child

PubMed Central

Zaki, Syed Ahmed; Gupta, Saurabh

2014-01-01

Levetiracetam is well-tolerated and commonly used as a broad spectrum antiepileptic in both partial and generalized seizures. Few cases of levetiracetam-induced psychosis in children are reported in the literature. The present case of levetiracetam-induced acute psychosis highlights the adverse effect of this drug and also emphasizes the need for close monitoring of children on levetiracetam. PMID:24987186

Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

PubMed Central

Lilius, T O; Jokinen, V; Neuvonen, M S; Niemi, M; Kalso, E A; Rauhala, P V

2015-01-01

Background and Purpose The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. Experimental Approach Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. Key Results In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. Conclusions and Implications The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID:25297798

Acute otitis media guidelines in selected developed and developing countries: uniformity and diversity.

PubMed

Ovnat Tamir, Sharon; Shemesh, Shay; Oron, Yahav; Marom, Tal

2017-05-01

Acute otitis media (AOM) is a common childhood disease, with an enormous economic and healthcare-related burden. Guidelines and consensus papers for AOM diagnosis and management were published in many countries. Our objective was to study the differences and similarities between these protocols in developing and developed countries. The keywords: 'acute otitis media' AND 'children' AND ['treatment' or 'management'] AND ['guideline' or 'consensus'] were used in various electronic databases between 1 January 1989 through 31 December 2015. Overall, 99 sources from 62 countries were retrieved: 53 from 22 developed countries, and 46 from 40 developing countries. Representative guidelines from America (the USA, Argentina), Europe (Italy, Moldova), Africa (South Africa, Tanzania, Ethiopia), Asia (Japan, Afghanistan, Sri Lanka),and Oceania (South Australia, Fiji) were compared. Paediatric societies publish guidelines in most developed countries; in developing countries, the Ministry of Health usually initiates guideline formulation. Most guidelines use the same diagnostic criteria and offer watchful waiting in mild-moderate scenarios. Amoxicillin is the suggested first-line antibiotic, whereas options for second-line and third-line therapies vary. Duration of therapy varies and is usually age dependent: 5-7 days for children <2 years and 10 days for children >2 years in developed countries, while duration and age groups vary greatly in developing countries. Reduction of AOM risk factors is encouraged in developed countries, but rarely in developing countries. Guidelines for AOM from developing and developed countries are similar in many aspects, with variation in specific recommendations, due to local epidemiology and healthcare accessibility. Formulation of regional guidelines may help reduce AOM burden. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Early investigational antibiotics for the treatment of acute exacerbations of chronic bronchitis.

PubMed

Falagas, Matthew E; Georgiou, Maria

2017-03-01

Acute exacerbations in patients with chronic bronchitis are a leading cause of hospitalizations and death. Bacteria contribute significantly to such exacerbations. The aim of this review was to explore the potential role of investigational antibiotics in the treatment of these episodes. Areas covered: The available literature in PubMed database, in websites related to investigational drugs and in websites of the producing companies has been searched. The in vitro activity against pathogens involved in acute exacerbations of chronic bronchitis and the pharmacokinetic profile of antibiotics currently under development were taken into consideration for inclusion in the review. Expert opinion: Several novel antimicrobial agents have completed preclinical and Phase I studies and were well-tolerated. Further investigation is mandatory in order to evaluate their future in treatment of chronic bronchitis exacerbations and discover potential advantages compared to already approved antimicrobials.

Semi-elemental formula or polymeric formula: is there a better choice for enteral nutrition in acute pancreatitis? Randomized comparative study.

PubMed

Tiengou, Laurent-Eric; Gloro, Romain; Pouzoulet, Julien; Bouhier, Karine; Read, Marie-Hélène; Arnaud-Battandier, Franck; Plaze, Jean-Marie; Blaizot, Xavier; Dao, Thông; Piquet, Marie-Astrid

2006-01-01

Jejunal nutrition is recommended during acute pancreatitis. The use of semi-elemental formulas presents several theoretical advantages over polymeric formulas, but their clinical value has been poorly documented. Our aim was to evaluate in patients with acute pancreatitis the effect of enteral nutrition by a semi-elemental formula compared with a polymeric formula. A randomized prospective pilot study, stratified according to severity, was performed in 30 consecutive patients with acute pancreatitis requiring jejunal nutrition. The semi-elemental group received 35 kcal/kg/d of Peptamen (n = 15), and the polymeric group received the same quantity of Sondalis-Iso (n = 15). Tolerance was evaluated after 7 days of enteral nutrition (D7) on visual analog scale (VAS), stool frequency, and 24-hour steatorrhea/creatorrhea. Outcome was evaluated by weight loss, length of hospital stay, and infection rate. Results were calculated as mean +/- SEM, t-test, or chi2. Patients of the 2 groups were comparable in terms of age, gender, and severity. Tolerance was good in both groups (semi-elemental vs polymeric: VAS, 7.4 +/- 0.6 vs 7.1 +/- 0.6, not significant (NS); number of stools per 24 hours, 1.7 +/- 0.4 vs 1.8 +/- 0.4, NS). Steatorrhea and creatorrhea were lower than normal in both groups. In semi-elemental group, the length of hospital stay was shorter (23 +/- 2 vs 27 +/- 1, p = .006) and weight loss was less marked (1 +/- 1 vs 2 +/- 0, p = .01). One patient in semi-elemental group and 3 patients in polymeric group developed an infection (NS). Semi-elemental and polymeric nutrition are very well tolerated in patients with acute pancreatitis. Nutrition with a semi-elemental formula supports the hypothesis of a more favorable clinical course than nutrition with a polymeric formula, but this conclusion needs to be established in larger adequately powered clinical trials.

Clinical course of ulcerative colitis patients who develop acute pancreatitis.

PubMed

Kim, Jong Wook; Hwang, Sung Wook; Park, Sang Hyoung; Song, Tae Jun; Kim, Myung-Hwan; Lee, Ho-Su; Ye, Byong Duk; Yang, Dong-Hoon; Kim, Kyung-Jo; Byeon, Jeong-Sik; Myung, Seung-Jae; Yang, Suk-Kyun

2017-05-21

To investigate the clinical course of ulcerative colitis (UC) patients who develop acute pancreatitis. We analyzed 3307 UC patients from the inflammatory bowel disease registry at Asan Medical Center from June 1989 to May 2015. The clinical course of UC patients who developed acute pancreatitis was compared with that of non-pancreatitis UC patients. Among 51 patients who developed acute pancreatitis, 13 (0.40%) had autoimmune, 10 (0.30%) had aminosalicylate-induced, and 13 (1.73%) had thiopurine-induced pancreatitis. All 13 patients with autoimmune pancreatitis (AIP) had type 2 AIP. Two (15.4%) patients had pre-existing AIP, and three (23.1%) patients developed AIP and UC simultaneously. Compared to non-pancreatitis patients, AIP patients had UC diagnosed at a significantly younger age (median, 22.9 years vs 36.4 years; P = 0.001). AIP and aminosalicylate-induced pancreatitis patients had more extensive UC compared to non-pancreatitis patients. All patients with pancreatitis recovered uneventfully, and there were no recurrences. Biologics were used more frequently in aminosalicylate- and thiopurine-induced pancreatitis patients compared to non-pancreatitis patients [adjusted OR (95%CI), 5.16 (1.42-18.67) and 6.90 (1.83-25.98), respectively]. Biologic utilization rate was similar among AIP and non-pancreatitis patients [OR (95%CI), 0.84 (0.11-6.66)]. Colectomy rates for autoimmune, aminosalicylate-induced, and thiopurine-induced pancreatitis, and for non-pancreatitis patients were 15.4% (2/13), 20% (2/10), 15.4% (2/13), and 7.3% (239/3256), respectively; the rates were not significantly different after adjusting for baseline disease extent. Pancreatitis patients show a non-significant increase in colectomy, after adjusting for baseline disease extent.

Potential for the development of tolerance by Aspergillus amstelodami, A. repens and A. ruber after repeated exposure to potassium sorbate.

PubMed

Viñas, I; Morlans, I; Sanchis, V

1990-01-01

Three strains of A. amstelodami, A. repens and A. ruber were exposed to various levels of potassium sorbate, and the MICs were determined. Selected strains of the molds were then repeatedly exposed to subinhibitory levels of the compound to determine whether increased tolerance might develop. The MIC of sorbate (pH 5.5 or 6.5) for 3 species of Aspergillus was 0.07%. Increasing levels of sorbate resulted in increasing growth suppression of the molds. The 3 Aspergillus species were tested for increased tolerance to potassium sorbate, and none was found. They developed a slight increase in tolerance dependent upon pH and the mold strain by subculturing at low levels of sorbate.

Noninvasive Mechanical Ventilation in Acute Ventilatory Failure: Rationale and Current Applications.

PubMed

Esquinas, Antonio M; Benhamou, Maly Oron; Glossop, Alastair J; Mina, Bushra

2017-12-01

Noninvasive ventilation plays a pivotal role in acute ventilator failure and has been shown, in certain disease processes such as acute exacerbation of chronic obstructive pulmonary disease, to prevent and shorten the duration of invasive mechanical ventilation, reducing the risks and complications associated with it. The application of noninvasive ventilation is relatively simple and well tolerated by patients and in the right setting can change the course of their illness. Copyright © 2017 Elsevier Inc. All rights reserved.

Outcome of Acute Pancreatic and Peripancreatic Collections Occurring in Patients With Acute Pancreatitis.

PubMed

Manrai, Manish; Kochhar, Rakesh; Gupta, Vikas; Yadav, Thakur Deen; Dhaka, Narendra; Kalra, Naveen; Sinha, Saroj K; Khandelwal, Niranjan

2018-02-01

To study the outcome of acute collections occurring in patients with acute pancreatitis BACKGROUND:: There are limited data on natural history of acute collections arising after acute pancreatitis (AP). Consecutive patients of AP admitted between July 2011 and December 2012 were evaluated by imaging for development of acute collections as defined by revised Atlanta classification. Imaging was repeated at 1 and 3 months. Spontaneous resolution, evolution, and need for intervention were assessed. Of the 189 patients, 151 patients (79.9%) had acute collections with severe disease and delayed hospitalization being predictors of acute collections. Thirty-six patients had acute interstitial edematous pancreatitis, 8 of whom developed acute peripancreatic fluid collections, of which 1 evolved into pseudocyst. Among the 153 patients with acute necrotizing pancreatitis, 143 (93.4%) developed acute necrotic collection (ANC). Twenty-three of 143 ANC patients died, 21 had resolved collections, whereas 84 developed walled-off necrosis (WON), with necrosis >30% (P = 0.010) and Computed Tomographic Severity Index score ≥7 (P = 0.048) predicting development of WON. Of the 84 patients with WON, 8 expired, 53 patients required an intervention, and 23 were managed conservatively. Independent predictors of any intervention among all patients were Computed Tomographic Severity Index score ≥7 (P < 0.001) and interval between onset of pain to hospitalization >7 days (P = 0.04). Patients with severe AP and delayed hospitalization more often develop acute collections. Pancreatic pseudocysts are a rarity in acute interstitial pancreatitis. A majority of patients with necrotising pancreatitis will develop ANC, more than half of whom will develop WON. Delay in hospitalization and higher baseline necrosis score predict need for intervention.

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 Docket FDA-2008-N-0041; Formerly 2008N-0004] Guidance for Industry on Acute Bacterial Otitis Media... entitled ``Acute Bacterial Otitis Media: Developing Drugs for Treatment.'' This guidance addresses FDA's... an indication for the treatment of acute bacterial otitis media (ABOM). This guidance finalizes the...

An assay for evoked locomotor behavior in Drosophila reveals a role for integrins in ethanol sensitivity and rapid ethanol tolerance.

PubMed

Bhandari, Poonam; Kendler, Kenneth S; Bettinger, Jill C; Davies, Andrew G; Grotewiel, Mike

2009-10-01

Ethanol induces similar behavioral responses in mammals and the fruit fly, Drosophila melanogaster. By coupling assays for ethanol-related behavior to the genetic tools available in flies, a number of genes have been identified that influence physiological responses to ethanol. To enhance the utility of the Drosophila model for investigating genes involved in ethanol-related behavior, we explored the value of an assay that measures the sedative effects of ethanol on negative geotaxis, an evoked locomotor response. We established eRING (ethanol Rapid Iterative Negative Geotaxis) as an assay for quantitating the sedative effects of ethanol on negative geotaxis (i.e., startle-induced climbing). We validated the assay by assessing acute sensitivity to ethanol and rapid ethanol tolerance in several different control strains and in flies with mutations known to disrupt these behaviors. We also used eRING in a candidate screen to identify mutants with altered ethanol-related behaviors. Negative geotaxis measured in eRING assays was dose-dependently impaired by ethanol exposure. Flies developed tolerance to the intoxicating effects of ethanol when tested during a second exposure. Ethanol sensitivity and rapid ethanol tolerance varied across 4 control strains, but internal ethanol concentrations were indistinguishable in the 4 strains during a first and second challenge with ethanol. Ethanol sensitivity and rapid ethanol tolerance, respectively, were altered in flies with mutations in amnesiac and hangover, genes known to influence these traits. Additionally, mutations in the beta integrin gene myospheroid and the alpha integrin gene scab increased the initial sensitivity to ethanol and enhanced the development of rapid ethanol tolerance without altering internal ethanol concentrations. The eRING assay is suitable for investigating genetic mechanisms that influence ethanol sensitivity and rapid ethanol tolerance. Ethanol sensitivity and rapid ethanol tolerance depend on the

More oxygen during development enhanced flight performance but not thermal tolerance of Drosophila melanogaster

PubMed Central

Shiehzadegan, Shayan; Le Vinh Thuy, Jacqueline; Szabla, Natalia; Angilletta, Michael J.

2017-01-01

High temperatures can stress animals by raising the oxygen demand above the oxygen supply. Consequently, animals under hypoxia could be more sensitive to heating than those exposed to normoxia. Although support for this model has been limited to aquatic animals, oxygen supply might limit the heat tolerance of terrestrial animals during energetically demanding activities. We evaluated this model by studying the flight performance and heat tolerance of flies (Drosophila melanogaster) acclimated and tested at different concentrations of oxygen (12%, 21%, and 31%). We expected that flies raised at hypoxia would develop into adults that were more likely to fly under hypoxia than would flies raised at normoxia or hyperoxia. We also expected flies to benefit from greater oxygen supply during testing. These effects should have been most pronounced at high temperatures, which impair locomotor performance. Contrary to our expectations, we found little evidence that flies raised at hypoxia flew better when tested at hypoxia or tolerated extreme heat better than did flies raised at normoxia or hyperoxia. Instead, flies raised at higher oxygen levels performed better at all body temperatures and oxygen concentrations. Moreover, oxygen supply during testing had the greatest effect on flight performance at low temperature, rather than high temperature. Our results poorly support the hypothesis that oxygen supply limits performance at high temperatures, but do support the idea that hyperoxia during development improves performance of flies later in life. PMID:28542380

More oxygen during development enhanced flight performance but not thermal tolerance of Drosophila melanogaster.

PubMed

Shiehzadegan, Shayan; Le Vinh Thuy, Jacqueline; Szabla, Natalia; Angilletta, Michael J; VandenBrooks, John M

2017-01-01

High temperatures can stress animals by raising the oxygen demand above the oxygen supply. Consequently, animals under hypoxia could be more sensitive to heating than those exposed to normoxia. Although support for this model has been limited to aquatic animals, oxygen supply might limit the heat tolerance of terrestrial animals during energetically demanding activities. We evaluated this model by studying the flight performance and heat tolerance of flies (Drosophila melanogaster) acclimated and tested at different concentrations of oxygen (12%, 21%, and 31%). We expected that flies raised at hypoxia would develop into adults that were more likely to fly under hypoxia than would flies raised at normoxia or hyperoxia. We also expected flies to benefit from greater oxygen supply during testing. These effects should have been most pronounced at high temperatures, which impair locomotor performance. Contrary to our expectations, we found little evidence that flies raised at hypoxia flew better when tested at hypoxia or tolerated extreme heat better than did flies raised at normoxia or hyperoxia. Instead, flies raised at higher oxygen levels performed better at all body temperatures and oxygen concentrations. Moreover, oxygen supply during testing had the greatest effect on flight performance at low temperature, rather than high temperature. Our results poorly support the hypothesis that oxygen supply limits performance at high temperatures, but do support the idea that hyperoxia during development improves performance of flies later in life.

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. Copyright © 2013. Published by Elsevier Masson SAS.

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…

BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF ACUTE CHLORPYRIFOS IN RATS: TOLERANCE TO PROLONGED INHIBITION OF CHOLINESTERASE

EPA Science Inventory

Chlorpyrifos (CPF), a commercially prevalent organophosphate (OP) pesticide, inhibits blood and brain cholinesterase for up to 10 weeks after acute s.c. injection in rats. his prolonged inhibition suggested that acute CPF may affect muscarinic receptors and behavior as does repea...

Corneal Confocal Microscopy Detects Corneal Nerve Damage in Patients Admitted With Acute Ischemic Stroke.

PubMed

Khan, Adnan; Akhtar, Naveed; Kamran, Saadat; Ponirakis, Georgios; Petropoulos, Ioannis N; Tunio, Nahel A; Dargham, Soha R; Imam, Yahia; Sartaj, Faheem; Parray, Aijaz; Bourke, Paula; Khan, Rabia; Santos, Mark; Joseph, Sujatha; Shuaib, Ashfaq; Malik, Rayaz A

2017-11-01

Corneal confocal microscopy can identify corneal nerve damage in patients with peripheral and central neurodegeneration. However, the use of corneal confocal microscopy in patients presenting with acute ischemic stroke is unknown. One hundred thirty patients (57 without diabetes mellitus [normal glucose tolerance], 32 with impaired glucose tolerance, and 41 with type 2 diabetes mellitus) admitted with acute ischemic stroke, and 28 age-matched healthy control participants underwent corneal confocal microscopy to quantify corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length. There was a significant reduction in corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length in stroke patients with normal glucose tolerance ( P <0.001, P <0.001, P <0.001), impaired glucose tolerance ( P =0.004, P <0.001, P =0.002), and type 2 diabetes mellitus ( P <0.001, P <0.001, P <0.001) compared with controls. HbA1c and triglycerides correlated with corneal nerve fiber density ( r =-0.187, P =0.03; r =-0.229 P =0.01), corneal nerve fiber length ( r =-0.228, P =0.009; r =-0.285; P =0.001), and corneal nerve branch density ( r =-0.187, P =0.033; r =-0.229, P =0.01). Multiple linear regression showed no independent associations between corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length and relevant risk factors for stroke. Corneal confocal microscopy is a rapid noninvasive ophthalmic imaging technique that identifies corneal nerve fiber loss in patients with acute ischemic stroke. © 2017 American Heart Association, Inc.

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. © 2012 New York Academy of Sciences.

Transcriptomic Insights into Phenological Development and Cold Tolerance of Wheat Grown in the Field1[OPEN

PubMed Central

Li, Qiang; Byrns, Brook; Badawi, Mohamed A.; Diallo, Abdoulaye Banire; Danyluk, Jean; Sarhan, Fathey; Zou, Jitao

2018-01-01

Cold acclimation and winter survival in cereal species is determined by complicated environmentally regulated gene expression. However, studies investigating these complex cold responses are mostly conducted in controlled environments that only consider the responses to single environmental variables. In this study, we have comprehensively profiled global transcriptional responses in crowns of field-grown spring and winter wheat (Triticum aestivum) genotypes and their near-isogenic lines with the VRN-A1 alleles swapped. This in-depth analysis revealed multiple signaling, interactive pathways that influence cold tolerance and phenological development to optimize plant growth and development in preparation for a wide range of over-winter stresses. Investigation of genetic differences at the VRN-A1 locus revealed that a vernalization requirement maintained a higher level of cold response pathways while VRN-A1 genetically promoted floral development. Our results also demonstrated the influence of genetic background on the expression of cold and flowering pathways. The link between delayed shoot apex development and the induction of cold tolerance was reflected by the gradual up-regulation of abscisic acid-dependent and C-REPEAT-BINDING FACTOR pathways. This was accompanied by the down-regulation of key genes involved in meristem development as the autumn progressed. The chromosome location of differentially expressed genes between the winter and spring wheat genetic backgrounds showed a striking pattern of biased gene expression on chromosomes 6A and 6D, indicating a transcriptional regulation at the genome level. This finding adds to the complexity of the genetic cascades and gene interactions that determine the evolutionary patterns of both phenological development and cold tolerance traits in wheat. PMID:29259104

Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure.

PubMed

Berry, C; Brett, M; Stevenson, K; McMurray, J J V; Norrie, J

2008-03-01

To investigate the nature and importance of blood glucose abnormalities in an unselected heart failure (HF) population. Cohort study. Urban University hospital. All index emergency HF admissions to one University hospital during the year 2000 were studied. 454 consecutive index admissions had blood chemistry, diabetic status and follow-up information recorded. 390 (86%) patients had an echocardiogram, of whom 117 (30%) had preserved left ventricular systolic function and 110 (24%) had diabetes. Sixty (13%) patients had abnormal glucose tolerance (8.0-10.99 mmol/l), and 284 (63%) patients had a normal admission blood glucose (<8 mmol/l). 51 (11.2%) patients died in hospital. After adjustment for other prognostic attributes, abnormal glucose tolerance (Cox hazard ratio HR, 95% CI: 5.920, 1.03 to 34.00; p = 0.046) but not diabetes (HR 3.46, 0.75 to 16.02; p = 0.112) predicted in-hospital mortality. During follow-up (median 812 (range 632-978) days), 104 (36.6%), 30 (50.0%) and 55 (50%) patients with a normal admission blood glucose concentration, abnormal glucose tolerance and diabetes, respectively, died (log rank test p = 0.0037, adjusted p = 0.075). Compared with patients with normal admission blood glucose, abnormal glucose tolerance (adjusted HR: 1.41 (0.92 to 2.16); p = 0.12) and diabetes (adjusted HR: 2.02 (1.41 to 2.88); p = 0.0001) predicted mortality. Considering glucose on admission as a continuous covariate, a 2 mmol/l increase was associated with a HR of 1.08 (1.03 to 1.13), p = 0.0010, which after adjustment for the above covariates became 1.08 (1.03 to 1.13), p = 0.0023. Admission blood glucose concentration and diabetes are prognostically important in HF and could help target some patients for more intensive therapy.

Modulation between high- and low-frequency transcutaneous electric nerve stimulation delays the development of analgesic tolerance in arthritic rats.

PubMed

Desantana, Josimari M; Santana-Filho, Valter J; Sluka, Kathleen A

2008-04-01

To investigate whether repeated administration of modulating frequency transcutaneous electric nerve stimulation (TENS) prevents development of analgesic tolerance. Knee joint inflammation (3% carrageenan and kaolin) was induced in rats. Either mixed or alternating frequency was administered daily (20min) for 2 weeks to the inflamed knee under light halothane anesthesia (1%-2%). Laboratory. Adult male Sprague-Dawley rats (N=36). Mixed- (4Hz and 100Hz) or alternating- (4Hz on 1 day; 100Hz on the next day) frequency TENS at sensory intensity and 100micros pulse duration. Paw and joint withdrawal thresholds to mechanical stimuli were assessed before induction of inflammation, and before and after daily application of TENS. The reduced paw and joint withdrawal thresholds that occur 24 hours after the induction of inflammation were significantly reversed by the first administration of TENS when compared with sham treatment or to the condition before TENS treatment, which was observed through day 9. By the tenth day, repeated daily administration of either mixed- or alternating-frequency TENS did not reverse the decreased paw and joint withdrawal thresholds. These data suggest that repeated administration of modulating frequency TENS leads to a development of opioid tolerance. However, this tolerance effect is delayed by approximately 5 days compared with administration of low- or high-frequency TENS independently. Clinically, we can infer that a treatment schedule of repeated daily TENS administration will result in a tolerance effect. Moreover, modulating low and high frequency TENS seems to produce a better analgesic effect and tolerance is slower to develop.

Prostate Hypofractionated Radiation Therapy With Injection of Hyaluronic Acid: Acute Toxicities in a Phase 2 Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chapet, Olivier, E-mail: olivier.chapet@chu-lyon.fr; EMR3738, Université Lyon 1, Lyon; Decullier, Evelyne

Purpose: Hypofractionated radiation therapy (RT) in prostate cancer can be developed only if the risk of rectal toxicity is controlled. In a multicenter phase 2 trial, hypofractionated irradiation was combined with an injection of hyaluronic acid (HA) to preserve the rectal wall. Tolerance of the injection and acute toxicity rates are reported. Methods and Materials: The study was designed to assess late grade 2 toxicity rates. The results described here correspond to the secondary objectives. Acute toxicity was defined as occurring during RT or within 3 months after RT and graded according to the Common Terminology Criteria for Adverse Eventsmore » version 4.0. HA tolerance was evaluated with a visual analog scale during the injection and 30 minutes after injection and then by use of the Common Terminology Criteria at each visit. Results: From 2010 to 2012, 36 patients with low-risk to intermediate-risk prostate cancer were included. The HA injection induced a mean pain score of 4.6/10 ± 2.3. Thirty minutes after the injection, 2 patients still reported pain (2/10 and 3/10), which persisted after the intervention. Thirty-three patients experienced at least 1 acute genitourinary toxicity and 20 patients at least 1 acute gastrointestinal toxicity. Grade 2 toxicities were reported for 19 patients with urinary obstruction, frequency, or both and for 1 patient with proctitis. No grade 3 or 4 toxicities were reported. At the 3-month visit, 4 patients described grade 2 obstruction or frequency, and no patients had any grade 2 gastrointestinal toxicities. Conclusions: The injection of HA makes it possible to deliver hypofractionated irradiation over 4 weeks with a dose per fraction of > 3 Gy, with limited acute rectal toxicity.« less

Characterization of the Antinociceptive Effects of the Individual Isomers of Methadone Following Acute and Chronic Administration

PubMed Central

Morgan, Richard W.; Nicholson, Katherine L.

2011-01-01

Methadone is a long-acting opioid used in the treatment of various pain states and substitution therapy in heroin addiction. Extensive behavioral characterization has been carried out utilizing the racemate, but limited investigation has been performed with the individual isomers. While the l-isomer is a potent opioid agonist, the d-isomer has weak μ opioid activity and has also been shown to possess N-methyl-d-aspartate (NMDA) antagonist properties in vitro. The acute antinociceptive effects of the isomers were evaluated in rats using a warm water tail withdrawal procedure at two stimulus intensities (50° and 55° C). Increasing dose ratios of d- to l-methadone were administered chronically to determine the ability of the d-isomer to modulate antinociceptive tolerance to the l-isomer. Acutely, both l- (0.1-5.6 mg/kg, sc) and d- (3.0-56.0 mg/kg, sc) methadone produced antinociception though the efficacy of the d-isomer was limited at 55° C. These effects were dose-dependently blocked by naltrexone (0.01-1.0 mg/kg, sc). Administered chronically, d-methadone (1.7-10 mg/kg, sc) dose-dependently blocked tolerance development to the l-isomer (1.7 mg/kg, sc). These findings support the antinociceptive effects of the isomers being opioid receptor mediated with the l-isomer functioning as a full efficacy agonist whereas the d-isomer appears to have lower efficacy. The ability of nonracemic doses of the d-isomer to prevent tolerance development to the l-isomer may be attributed to partial μ agonist activity however NMDA antagonist activity cannot be discounted. PMID:21836464

Acute analgesic effects of nicotine and tobacco in humans: a meta-analysis.

PubMed

Ditre, Joseph W; Heckman, Bryan W; Zale, Emily L; Kosiba, Jesse D; Maisto, Stephen A

2016-07-01

Although animal models have consistently demonstrated acute pain inhibitory effects of nicotine and tobacco, human experimental studies have yielded mixed results. The main goal of this meta-analysis was to quantify the effects of nicotine/tobacco administration on human experimental pain threshold and tolerance ratings. A search of PubMed and PsycINFO online databases identified 13 eligible articles, including k = 21 tests of pain tolerance (N = 393) and k = 15 tests of pain threshold (N = 339). Meta-analytic integration for both threshold and tolerance outcomes revealed that nicotine administered through tobacco smoke and other delivery systems (eg, patch, nasal spray) produced acute analgesic effects that may be characterized as small to medium in magnitude (Hedges g = 0.35, 95% confidence interval = 0.21-0.50). Publication bias-corrected estimates remained significant and indicated that these effects may be closer to small. Sex composition was observed to be a significant moderator, such that pain threshold effects were more robust among samples that included more men than women. These results help to clarify a mixed literature and may ultimately help to inform the treatment of both pain and nicotine dependence. Pain and tobacco smoking are both highly prevalent and comorbid conditions. Current smoking has been associated with more severe chronic pain and physical impairment. Acute nicotine-induced analgesia could make smoking more rewarding and harder to give up. Future research should use dynamic measures of experimental pain reactivity and further explore biopsychosocial mechanisms of action.

Acute but not chronic activation of brain glucagon-like peptide-1 receptors enhances glucose-stimulated insulin secretion in mice.

PubMed

Tudurí, E; Beiroa, D; Porteiro, B; López, M; Diéguez, C; Nogueiras, R

2015-08-01

To investigate the role of brain glucagon-like peptide-1 (GLP-1) in pancreatic β-cell function. To determine the role of brain GLP-1 receptor (GLP-1R) on β-cell function, we administered intracerebroventricular (i.c.v.) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), in both an acute and a chronic setting. We observed that acute i.c.v. GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired glucose excursion after a glucose load. Sustained activation of central nervous system GLP-1R, however, did not produce any effect on either GSIS or glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with i.c.v. GLP-1 resulted in no differences compared with controls. In addition, in mice fed a high-fat diet we observed that acute i.c.v. GLP-1 infusion improved glucose tolerance without changes in GSIS, while chronic GLP-1R activation had no effect on glucose homeostasis. Our results indicate that, under non-clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents. © 2015 John Wiley & Sons Ltd.

Advanced information processing system - Status report. [for fault tolerant and damage tolerant data processing for aerospace vehicles

NASA Technical Reports Server (NTRS)

Brock, L. D.; Lala, J.

1986-01-01

The Advanced Information Processing System (AIPS) is designed to provide a fault tolerant and damage tolerant data processing architecture for a broad range of aerospace vehicles. The AIPS architecture also has attributes to enhance system effectiveness such as graceful degradation, growth and change tolerance, integrability, etc. Two key building blocks being developed by the AIPS program are a fault and damage tolerant processor and communication network. A proof-of-concept system is now being built and will be tested to demonstrate the validity and performance of the AIPS concepts.

Acute Esophageal Necrosis: “Black Esophagus”

PubMed Central

Weigel, Tracey L.

2007-01-01

Acute esophageal necrosis (AEN) is an uncommon event. We report a case of an 84-year-old female with a giant paraesophageal hernia who presented with coffee ground emesis and on esophagogastroduodenoscopy (EGD) demonstrated findings consistent with acute esophageal necrosis and a giant paraesophageal hernia with normal-appearing gastric mucosa. She was managed conservatively with bowel rest, parenteral nutrition, and continuous intravenous proton pump inhibitor (PPI). After significant improvement in the gross appearance of her esophageal mucosa, surgery was performed to reduce her giant paraesophageal hernia. The patient's postoperative course was uneventful, and she was discharged home on postoperative day 6, tolerating a normal diet. The percutaneous endoscopic gastrostomy (PEG) tube was removed in clinic 2 months postoperatively. PMID:17651583

Clinical course of ulcerative colitis patients who develop acute pancreatitis

PubMed Central

Kim, Jong Wook; Hwang, Sung Wook; Park, Sang Hyoung; Song, Tae Jun; Kim, Myung-Hwan; Lee, Ho-Su; Ye, Byong Duk; Yang, Dong-Hoon; Kim, Kyung-Jo; Byeon, Jeong-Sik; Myung, Seung-Jae; Yang, Suk-Kyun

2017-01-01

AIM To investigate the clinical course of ulcerative colitis (UC) patients who develop acute pancreatitis. METHODS We analyzed 3307 UC patients from the inflammatory bowel disease registry at Asan Medical Center from June 1989 to May 2015. The clinical course of UC patients who developed acute pancreatitis was compared with that of non-pancreatitis UC patients. RESULTS Among 51 patients who developed acute pancreatitis, 13 (0.40%) had autoimmune, 10 (0.30%) had aminosalicylate-induced, and 13 (1.73%) had thiopurine-induced pancreatitis. All 13 patients with autoimmune pancreatitis (AIP) had type 2 AIP. Two (15.4%) patients had pre-existing AIP, and three (23.1%) patients developed AIP and UC simultaneously. Compared to non-pancreatitis patients, AIP patients had UC diagnosed at a significantly younger age (median, 22.9 years vs 36.4 years; P = 0.001). AIP and aminosalicylate-induced pancreatitis patients had more extensive UC compared to non-pancreatitis patients. All patients with pancreatitis recovered uneventfully, and there were no recurrences. Biologics were used more frequently in aminosalicylate- and thiopurine-induced pancreatitis patients compared to non-pancreatitis patients [adjusted OR (95%CI), 5.16 (1.42-18.67) and 6.90 (1.83-25.98), respectively]. Biologic utilization rate was similar among AIP and non-pancreatitis patients [OR (95%CI), 0.84 (0.11-6.66)]. Colectomy rates for autoimmune, aminosalicylate-induced, and thiopurine-induced pancreatitis, and for non-pancreatitis patients were 15.4% (2/13), 20% (2/10), 15.4% (2/13), and 7.3% (239/3256), respectively; the rates were not significantly different after adjusting for baseline disease extent. CONCLUSION Pancreatitis patients show a non-significant increase in colectomy, after adjusting for baseline disease extent. PMID:28596686

Skin surface cooling improves orthostatic tolerance following prolonged head-down bed rest

PubMed Central

Keller, David M.; Low, David A.; Davis, Scott L.; Hastings, Jeff

2011-01-01

Prolonged exposure to microgravity, as well as its ground-based analog, head-down bed rest (HDBR), reduces orthostatic tolerance in humans. While skin surface cooling improves orthostatic tolerance, it remains unknown whether this could be an effective countermeasure to preserve orthostatic tolerance following HDBR. We therefore tested the hypothesis that skin surface cooling improves orthostatic tolerance after prolonged HDBR. Eight subjects (six men and two women) participated in the investigation. Orthostatic tolerance was determined using a progressive lower-body negative pressure (LBNP) tolerance test before HDBR during normothermic conditions and on day 16 or day 18 of 6° HDBR during normothermic and skin surface cooling conditions (randomized order post-HDBR). The thermal conditions were achieved by perfusing water (normothermia ∼34°C and skin surface cooling ∼12–15°C) through a tube-lined suit worn by each subject. Tolerance tests were performed after ∼30 min of the respective thermal stimulus. A cumulative stress index (CSI; mmHg LBNP·min) was determined for each LBNP protocol by summing the product of the applied negative pressure and the duration of LBNP at each stage. HDBR reduced normothermic orthostatic tolerance as indexed by a reduction in the CSI from 1,037 ± 96 mmHg·min to 574 ± 63 mmHg·min (P < 0.05). After HDBR, skin surface cooling increased orthostatic tolerance (797 ± 77 mmHg·min) compared with normothermia (P < 0.05). While the reduction in orthostatic tolerance following prolonged HDBR was not completely reversed by acute skin surface cooling, the identified improvements may serve as an important and effective countermeasure for individuals exposed to microgravity, as well as immobilized and bed-stricken individuals. PMID:21454746

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

PubMed Central

Sherlock, LaGuinn P.; Formby, Craig

2017-01-01

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

Effect of dehydration on the development of collaterals in acute middle cerebral artery occlusion.

PubMed

Chang, S-W; Huang, Y-C; Lin, L-C; Yang, J-T; Weng, H-H; Tsai, Y-H; Lee, T-H

2016-03-01

Recent large series studies have demonstrated that dehydration is common amongst stroke subjects and is associated with poor outcome. However, the effects of hydration status on the development of collaterals have never been discussed. In this study, the hypothesis that hydration status is an important factor for developing collaterals after acute middle cerebral artery (MCA) infarction was tested. Eighty-seven patients with acute infarction due to occlusion of the MCA were enrolled. Two collateral markers, posterior cerebral artery (PCA) laterality and fluid-attenuated inversion recovery hyperintense vessels (HVs) were assessed from magnetic resonance imaging. Dehydration status was defined by a nitrogen to creatinine ratio ≧ of 15. The associations between dehydration status and the development of collaterals were estimated. Sixty-one of 87 patients (70.1%) were identified as dehydrated. The development of PCA laterality and HVs shows a significant difference between dehydrated and euhydrated patients. A serum nitrogen to creatinine ratio <15, diastolic blood pressure and the presence of a dense MCA on computed tomography were significantly associated with the development of PCA laterality. A serum nitrogen to creatinine ratio <15, the initial National Institutes of Health Stroke Scale score, the presence of a dense MCA and calcifications of the internal carotid artery on computed tomography were significantly associated with the development of HVs. Dehydration remained an independent negative predictor for the development of PCA laterality and HVs in the multivariate analysis. Hydration status is associated with the development of collateral flow after acute MCA occlusion. This preliminary study provides an imaging clue that hydration status and early hydration therapy could be important for acute stroke management. © 2016 EAN.

Anti-IFNγ and peptide-tolerization therapies inhibit acute lung injury induced by crossreactive influenza-A (IAV)-specific memory T-cells

PubMed Central

Wlodarczyk, Myriam F.; Kraft, Anke R.; Chen, Hong D.; Kenney, Laurie L.; Selin, Liisa K.

2013-01-01

Viral infections have variable outcomes with severe disease occurring in only few individuals. We hypothesized that this variable outcome could correlate with the nature of responses made to previous microbes. To test this, mice were infected initially with IAV and in memory-phase challenged with LCMV, which we show here to have relatively minor cross-reactivity with IAV. The outcome in genetically identical mice varied from mild pneumonitis to severe acute lung injury with extensive pneumonia and bronchiolization, similar to that observed in patients that died of the 1918 H1N1 pandemic. Lesion expression did not correlate with virus titers. Instead, disease severity directly correlated with and was predicted by the frequency of IAV-PB1703- and -PA224-specific responses, which crossreacted with LCMV-GP34 and -GP276, respectively. Eradication or functional ablation of these pathogenic memory T-cell populations, using mutant-viral strains, peptide-based tolerization strategies, or short-term anti-IFNγ treatment inhibited severe lesions such as bronchiolization from occurring. Heterologous immunity can shape outcome of infections and likely individual responses to vaccination, and can be manipulated to treat or prevent severe pathology. PMID:23408839

Modulation Between High- and Low-Frequency Transcutaneous Electric Nerve Stimulation Delays the Development of Analgesic Tolerance in Arthritic Rats

PubMed Central

DeSantana, Josimari M.; Santana-Filho, Valter J.; Sluka, Kathleen A.

2009-01-01

Objective To investigate whether repeated administration of modulating frequency transcutaneous electric nerve stimulation (TENS) prevents development of analgesic tolerance. Design Knee joint inflammation (3% carrageenan and kaolin) was induced in rats. Either mixed or alternating frequency was administered daily (20min) for 2 weeks to the inflamed knee under light halothane anesthesia (1%–2%). Setting Laboratory. Animals Adult male Sprague-Dawley rats (N=36). Intervention Mixed- (4Hz and 100Hz) or alternating- (4Hz on 1 day; 100Hz on the next day) frequency TENS at sensory intensity and 100μs pulse duration. Main Outcome Measures Paw and joint withdrawal thresholds to mechanical stimuli were assessed before induction of inflammation, and before and after daily application of TENS. Results The reduced paw and joint withdrawal thresholds that occur 24 hours after the induction of inflammation were significantly reversed by the first administration of TENS when compared with sham treatment or to the condition before TENS treatment, which was observed through day 9. By the tenth day, repeated daily administration of either mixed- or alternating-frequency TENS did not reverse the decreased paw and joint withdrawal thresholds. Conclusions These data suggest that repeated administration of modulating frequency TENS leads to a development of opioid tolerance. However, this tolerance effect is delayed by approximately 5 days compared with administration of low- or high-frequency TENS independently. Clinically, we can infer that a treatment schedule of repeated daily TENS administration will result in a tolerance effect. Moreover, modulating low and high frequency TENS seems to produce a better analgesic effect and tolerance is slower to develop. PMID:18374009

Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System

PubMed Central

Wu, Bechien U.; Batech, Michael; Quezada, Michael; Lew, Daniel; Fujikawa, Kelly; Kung, Jonathan; Jamil, Laith H.; Chen, Wansu; Afghani, Elham; Reicher, Sonya; Buxbaum, James; Pandol, Stephen J.

2017-01-01

OBJECTIVES Acute pancreatitis has a highly variable course. Currently there is no widely accepted method to measure disease activity in patients hospitalized for acute pancreatitis. We aimed to develop a clinical activity index that incorporates routine clinical parameters to assist in the measurement, study, and management of acute pancreatitis. METHODS We used the UCLA/RAND appropriateness method to identify items for inclusion in the disease activity instrument. We conducted a systematic literature review followed by two sets of iterative modified Delphi meetings including a panel of international experts between November 2014 and November 2015. The final instrument was then applied to patient data obtained from five separate study cohorts across Southern California to assess profiles of disease activity. RESULTS From a list of 35 items comprising 6 domains, we identified 5 parameters for inclusion in the final weighted clinical activity scoring system: organ failure, systemic inflammatory response syndrome, abdominal pain, requirement for opiates and ability to tolerate oral intake. We applied the weighted scoring system across the 5 study cohorts comprising 3,123 patients. We identified several distinct patterns of disease activity: (i) overall there was an elevated score at baseline relative to discharge across all study cohorts, (ii) there were distinct patterns of disease activity related to duration of illness as well as (iii) early and persistent elevation of disease activity among patients with severe acute pancreatitis defined as persistent organ failure. CONCLUSIONS We present the development and initial validation of a clinical activity score for real-time assessment of disease activity in patients with acute pancreatitis. PMID:28462914

Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System.

PubMed

Wu, Bechien U; Batech, Michael; Quezada, Michael; Lew, Daniel; Fujikawa, Kelly; Kung, Jonathan; Jamil, Laith H; Chen, Wansu; Afghani, Elham; Reicher, Sonya; Buxbaum, James; Pandol, Stephen J

2017-07-01

Acute pancreatitis has a highly variable course. Currently there is no widely accepted method to measure disease activity in patients hospitalized for acute pancreatitis. We aimed to develop a clinical activity index that incorporates routine clinical parameters to assist in the measurement, study, and management of acute pancreatitis. We used the UCLA/RAND appropriateness method to identify items for inclusion in the disease activity instrument. We conducted a systematic literature review followed by two sets of iterative modified Delphi meetings including a panel of international experts between November 2014 and November 2015. The final instrument was then applied to patient data obtained from five separate study cohorts across Southern California to assess profiles of disease activity. From a list of 35 items comprising 6 domains, we identified 5 parameters for inclusion in the final weighted clinical activity scoring system: organ failure, systemic inflammatory response syndrome, abdominal pain, requirement for opiates and ability to tolerate oral intake. We applied the weighted scoring system across the 5 study cohorts comprising 3,123 patients. We identified several distinct patterns of disease activity: (i) overall there was an elevated score at baseline relative to discharge across all study cohorts, (ii) there were distinct patterns of disease activity related to duration of illness as well as (iii) early and persistent elevation of disease activity among patients with severe acute pancreatitis defined as persistent organ failure. We present the development and initial validation of a clinical activity score for real-time assessment of disease activity in patients with acute pancreatitis.

Effect of the disease severity on the risk of developing new-onset diabetes after acute pancreatitis.

PubMed

Tu, Jianfeng; Yang, Yue; Zhang, Jingzhu; Yang, Qi; Lu, Guotao; Li, Baiqiang; Tong, Zhihui; Ke, Lu; Li, Weiqin; Li, Jieshou

2018-06-01

Endocrine pancreatic insufficiency secondary to acute pancreatitis (AP) drew increasing attention in the recent years. The aim of the present study was to assess the impact of pancreatic necrosis and organ failure on the risk of developing new-onset diabetes after AP.The follow-up study was conducted for patients recovered from AP in the treatment center of Jinling Hospital. Endocrine function was evaluated by simplified oral glucose tolerance test (OGTT). Pancreatic necrosis was examined by abdominal contrast-enhanced CT (CECT) scan during hospitalization. The data including APACHE II score, Balthazar's score, organ failure (AKI and ARDS) was also collected from the medical record database. All patients were divided into group diabetes mellitus (DM) and group non-DM according to the endocrine function and group pancreatic necrosis (PN) and persistent organ failure (OF), group PN and non-OF, group non-PN and OF, and group non-PN and non-OF according to the occurrence of pancreatic necrosis and persistent organ failure.Around 256 patients were included for the final analysis. 154 patients (60.2%) were diagnosed with DM (include impaired glucose tolerance, IGT), while 102 patients (39.8%) were deemed as normal endocrine function. APACHE II score and Balthazar score of the patients in the group DM were significant higher than those in the non-DM group (F = 6.09, P = .01; F = 10.74, P = .001). The incidence of pancreatic necrosis in group DM and group non-DM was, respectively, 64.7% and 53.0% (χ = 3.506, P = .06). The patients underwent necrosis debridement by percutaneous catheter drainage (PCD) and/or the operative necrosectomy (ON) were more likely to developed new onset DM than the patients without PCD or ON (χ = 2.385, P = .02). The morbidity of new-onset DM after AP gradually increased from group non-PN and non-OF, group non-PN and OF, group PN and non-OF to group PN and OF in order (χ = 4.587, P = .03). The value of

Arabidopsis dynamin-related protein 1E in sphingolipid-enriched plasma membrane domains is associated with the development of freezing tolerance.

PubMed

Minami, Anzu; Tominaga, Yoko; Furuto, Akari; Kondo, Mariko; Kawamura, Yukio; Uemura, Matsuo

2015-08-01

The freezing tolerance of Arabidopsis thaliana is enhanced by cold acclimation, resulting in changes in the compositions and function of the plasma membrane. Here, we show that a dynamin-related protein 1E (DRP1E), which is thought to function in the vesicle trafficking pathway in cells, is related to an increase in freezing tolerance during cold acclimation. DRP1E accumulated in sphingolipid and sterol-enriched plasma membrane domains after cold acclimation. Analysis of drp1e mutants clearly showed that DRP1E is required for full development of freezing tolerance after cold acclimation. DRP1E fused with green fluorescent protein was visible as small foci that overlapped with fluorescent dye-labelled plasma membrane, providing evidence that DRP1E localizes non-uniformly in specific areas of the plasma membrane. These results suggest that DRP1E accumulates in sphingolipid and sterol-enriched plasma membrane domains and plays a role in freezing tolerance development during cold acclimation. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

BIOMARKERS OF OPERATIONAL TOLERANCE IN SOLID ORGAN TRANSPLANTATION

PubMed Central

Heidt, Sebastiaan; Wood, Kathryn J.

2012-01-01

Introduction Long-term immunosuppressive therapy represents a huge burden on transplant recipients, but currently cannot be omitted. Improving long-term transplant outcome by immunosuppressive drug withdrawal may be achieved in patients who have developed (partial) immunological unresponsiveness towards their graft, either spontaneously or through tolerance induction. Reliable biomarkers are essential to define such immunological unresponsiveness and will facilitate controlled immunosuppressive drug weaning as well as provide surrogate end-points for tolerance induction trials. Areas covered Tolerance biomarkers have been defined for both liver and kidney transplantation and can accurately identify operationally tolerant transplant recipients retrospectively. These two tolerance fingerprints are remarkably different, indicating the involvement of distinct mechanisms. Limited data suggest that tolerance biomarkers can be detected in immunosuppressed transplant recipients. Whether these patients can safely have their immunosuppressive drugs withdrawn needs to be established. Expert opinion Mechanistic interpretation of the kidney transplant tolerance biomarker profile dominated by B cell markers remains a challenge in light of experimental evidence suggesting the pivotal involvement of regulatory T cells. Therefore, defining animal models that resemble human transplant tolerance is crucial in understanding the underlying mechanisms. Additionally, to ensure patient safety while monitoring for tolerance, it is essential to develop biomarkers to non-invasively detect early signs of rejection as well. PMID:22988481

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

Acute oral safety study of sodium caseinate glycosylated via maillard reaction with galactose in rats.

PubMed

Anadón, Arturo; Martínez, Maria A; Ares, Irma; Castellano, Victor; Martínez-Larrañaga, Maria R; Corzo-Martínez, Marta; Moreno, F Javier; Villamiel, Mar

2014-03-01

In order to potentially use sodium caseinate (SC) glycated with galactose (Gal) in the food industry as a new functional ingredient with proved technological and biological properties, an evaluation of oral acute toxicity has been carried out. An acute safety study with SC-Gal glycoconjugates in the Wistar rat with a single oral gavage dose of 2,000 mg/kg of body weight was conducted. The SC-Gal glycoconjugates were well tolerated; no adverse effects or mortality was observed during the 2-week observation period. No abnormal signs, behavioral changes, body weight changes, or alterations in food and water consumption occurred. After this period, no changes in hematological and serum chemistry parameters, organ weights, or gross pathology or histopathology were detected. It was concluded that SC-Gal glycoconjugates obtained via the Maillard reaction were well tolerated in rats at an acute oral dose of 2,000 mg/kg of body weight. The SC-Gal glycoconjugates have a low order of acute toxicity, and the oral 50 % lethal dose for male and female rats is in excess of 2,000 mg/kg of body weight.

Acute effect of Ceylon cinnamon extract on postprandial glycemia: alpha-amylase inhibition, starch tolerance test in rats, and randomized crossover clinical trial in healthy volunteers.

PubMed

Beejmohun, Vickram; Peytavy-Izard, Marie; Mignon, Cyril; Muscente-Paque, Delphine; Deplanque, Xavier; Ripoll, Christophe; Chapal, Nicolas

2014-09-23

Postprandial hyperglycemia is a known risk factor for the development of several health disorders including type 2 diabetes, obesity, oxidative stress, and cardiovascular diseases. One encouraging approach for a better control of postprandial glycemia is to reduce carbohydrate digestion. Cinnamon extracts have been known for managing blood glucose. However, their effects on inhibiting digestion of carbohydrate have been poorly analyzed to date. The aim of this study was to investigate the acute effect of a specific Ceylon cinnamon hydro-alcoholic extract (CCE) on carbohydrate digestion and post-meal blood glucose reduction. In vitro enzymatic assays and in vivo starch tolerance tests in rats were designed as preclinical assays. Then, a randomized, double-blind, placebo-controlled, cross-over clinical trial was conducted in 18 healthy female and male volunteers. Following the intake of 1 g of CCE, the subjects ate a standardized meal. Blood samples were collected during the 2 hours following the meal to measure glucose and insulin concentrations. Areas under the curves were calculated and statistical differences between the CCE and placebo groups were analyzed using the Mann Whitney-Wilcoxon test. CCE has demonstrated in the in vitro study that it inhibited pancreatic alpha-amylase activity with an IC50 of 25 μg/mL. In the in vivo study, CCE was shown to acutely reduce the glycemic response to starch in a dose-dependent manner in rats. This effect was significant from the dose of 12.5 mg/kg of body weight. In both, the in vitro and in vivo studies, the hydro-alcoholic extract has shown to be more efficacious than the aqueous extract. In the human clinical trial, 1 g of CCE lowered the area under the curve of glycemia between 0 and 120 min by 14.8% (P = 0.15) and between 0 and 60 min by 21.2% (P < 0.05) compared to the placebo. This effect occurred without stimulating insulin secretion. No adverse effects were reported. These results suggest that Ceylon cinnamon

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

...] Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment... Administration (FDA) is announcing the availability of a guidance for industry entitled ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment.'' The purpose of this guidance is to...

Gene expression changes governing extreme dehydration tolerance in an Antarctic insect

PubMed Central

Teets, Nicholas M.; Peyton, Justin T.; Colinet, Herve; Renault, David; Kelley, Joanna L.; Kawarasaki, Yuta; Lee, Richard E.; Denlinger, David L.

2012-01-01

Among terrestrial organisms, arthropods are especially susceptible to dehydration, given their small body size and high surface area to volume ratio. This challenge is particularly acute for polar arthropods that face near-constant desiccating conditions, as water is frozen and thus unavailable for much of the year. The molecular mechanisms that govern extreme dehydration tolerance in insects remain largely undefined. In this study, we used RNA sequencing to quantify transcriptional mechanisms of extreme dehydration tolerance in the Antarctic midge, Belgica antarctica, the world’s southernmost insect and only insect endemic to Antarctica. Larvae of B. antarctica are remarkably tolerant of dehydration, surviving losses up to 70% of their body water. Gene expression changes in response to dehydration indicated up-regulation of cellular recycling pathways including the ubiquitin-mediated proteasome and autophagy, with concurrent down-regulation of genes involved in general metabolism and ATP production. Metabolomics results revealed shifts in metabolite pools that correlated closely with changes in gene expression, indicating that coordinated changes in gene expression and metabolism are a critical component of the dehydration response. Finally, using comparative genomics, we compared our gene expression results with a transcriptomic dataset for the Arctic collembolan, Megaphorura arctica. Although B. antarctica and M. arctica are adapted to similar environments, our analysis indicated very little overlap in expression profiles between these two arthropods. Whereas several orthologous genes showed similar expression patterns, transcriptional changes were largely species specific, indicating these polar arthropods have developed distinct transcriptional mechanisms to cope with similar desiccating conditions. PMID:23197828

Gene expression changes governing extreme dehydration tolerance in an Antarctic insect.

PubMed

Teets, Nicholas M; Peyton, Justin T; Colinet, Herve; Renault, David; Kelley, Joanna L; Kawarasaki, Yuta; Lee, Richard E; Denlinger, David L

2012-12-11

Among terrestrial organisms, arthropods are especially susceptible to dehydration, given their small body size and high surface area to volume ratio. This challenge is particularly acute for polar arthropods that face near-constant desiccating conditions, as water is frozen and thus unavailable for much of the year. The molecular mechanisms that govern extreme dehydration tolerance in insects remain largely undefined. In this study, we used RNA sequencing to quantify transcriptional mechanisms of extreme dehydration tolerance in the Antarctic midge, Belgica antarctica, the world's southernmost insect and only insect endemic to Antarctica. Larvae of B. antarctica are remarkably tolerant of dehydration, surviving losses up to 70% of their body water. Gene expression changes in response to dehydration indicated up-regulation of cellular recycling pathways including the ubiquitin-mediated proteasome and autophagy, with concurrent down-regulation of genes involved in general metabolism and ATP production. Metabolomics results revealed shifts in metabolite pools that correlated closely with changes in gene expression, indicating that coordinated changes in gene expression and metabolism are a critical component of the dehydration response. Finally, using comparative genomics, we compared our gene expression results with a transcriptomic dataset for the Arctic collembolan, Megaphorura arctica. Although B. antarctica and M. arctica are adapted to similar environments, our analysis indicated very little overlap in expression profiles between these two arthropods. Whereas several orthologous genes showed similar expression patterns, transcriptional changes were largely species specific, indicating these polar arthropods have developed distinct transcriptional mechanisms to cope with similar desiccating conditions.

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

PubMed Central

Larson, John; Drew, Kelly L.; Folkow, Lars P.; Milton, Sarah L.; Park, Thomas J.

2014-01-01

Many vertebrates are challenged by either chronic or acute episodes of low oxygen availability in their natural environments. Brain function is especially vulnerable to the effects of hypoxia and can be irreversibly impaired by even brief periods of low oxygen supply. This review describes recent research on physiological mechanisms that have evolved in certain vertebrate species to cope with brain hypoxia. Four model systems are considered: freshwater turtles that can survive for months trapped in frozen-over lakes, arctic ground squirrels that respire at extremely low rates during winter hibernation, seals and whales that undertake breath-hold dives lasting minutes to hours, and naked mole-rats that live in crowded burrows completely underground for their entire lives. These species exhibit remarkable specializations of brain physiology that adapt them for acute or chronic episodes of hypoxia. These specializations may be reactive in nature, involving modifications to the catastrophic sequelae of oxygen deprivation that occur in non-tolerant species, or preparatory in nature, preventing the activation of those sequelae altogether. Better understanding of the mechanisms used by these hypoxia-tolerant vertebrates will increase appreciation of how nervous systems are adapted for life in specific ecological niches as well as inform advances in therapy for neurological conditions such as stroke and epilepsy. PMID:24671961

Development of acute parotitis after non-invasive ventilation

PubMed Central

Martinez, Eduardo

2017-01-01

A 90-year-old woman underwent laparoscopic exploratory laparotomy for evaluation of suspected mesenteric ischemia. She was promptly extubated postoperatively and transferred to the intensive care unit, where on the first postoperative day she developed hypoxemia necessitating initiation of noninvasive ventilation (NIV) with bilevel positive airway pressure (BiPAP). After 8 hours of BiPAP, she was noted to have swelling, erythema and tenderness in the right preauricular area. Ultrasound evaluation demonstrated an enlarged right parotid gland. With discontinuation of BiPAP and supportive measures, parotitis resolved within 6 days. The mechanism of NIV-induced acute parotitis likely involves transmission of positive pressure to the oral cavity, causing obstruction to salivary flow within the parotid (Stensen) duct. Conditions that increase salivary viscosity and promote salivary stasis, such as advanced age, dehydration, and absence of salivary gland stimulation due to restriction of oral intake, may render patients more susceptible to this complication. As NIV will continue to be a commonly-used modality for the treatment of acute respiratory failure, clinicians should be aware of this phenomenon. PMID:28840025

Functional interaction and cross-tolerance between ethanol and Δ9-THC: possible modulation by mouse cerebellar adenosinergic A1/GABAergic-A receptors.

PubMed

Dar, M Saeed

2014-08-15

We have previously shown a functional motor interaction between ethanol and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) that involved cerebellar adenosinergic A1 and GABAergic A receptor modulation. We now report the development of cross-tolerance between intracerebellar Δ(9)-THC and intraperitoneal ethanol using ataxia as the test response in male CD-1 mice. The drugs [Δ(9)-THC (20 μg), N(6)-cyclohexyladenosine, CHA (12 ng), muscimol (20 ng)] used in the study were directly microinfused stereotaxically via guide cannulas into the cerebellum except ethanol. Δ(9)-THC, infused once daily for 5 days followed 16 h after the last infusion by acute ethanol (2g/kg) and Rotorod evaluation, virtually abolished ethanol ataxia indicating development of cross-tolerance. The cross-tolerance was also observed when the order of ethanol and Δ(9)-THC treatment was reversed, i.e., ethanol injected once daily for 5 days followed 16 h after the last ethanol injection by Δ(9)-THC infusion. The cross-tolerance appeared within 24-48 h, lasted over 72 h and was maximal in 5-day ethanol/Δ(9)-THC-treated animals. Finally, tolerance in chronic ethanol/Δ(9)-THC/-treated animals developed not only to ethanol/Δ(9)-THC-induced ataxia, respectively, but also to the ataxia potentiating effect of CHA and muscimol, indicating modulation by cerebellar adenosinergic A1 and GABAA receptors. A practical implication of these results could be that marijuana smokers may experience little or no negative effects such as ataxia following alcohol consumption. Clinically, such antagonism of ethanol-induced ataxia can be observed in marijuana users thereby encouraging more alcohol consumption and thus may represent a risk factor for the development of alcoholism in this segment of population. Copyright © 2014 Elsevier B.V. All rights reserved.

Does selection on increased cold tolerance in the adult stage confer resistance throughout development?

PubMed

Dierks, A; Kölzow, N; Franke, K; Fischer, K

2012-08-01

Artificial selection is a powerful approach to unravel constraints on genetic adaptation. Although it has been frequently used to reveal genetic trade-offs among different fitness-related traits, only a few studies have targeted genetic correlations across developmental stages. Here, we test whether selection on increased cold tolerance in the adult stage increases cold resistance throughout ontogeny in the butterfly Bicyclus anynana. We used lines selected for decreased chill-coma recovery time and corresponding controls, which had originally been set up from three levels of inbreeding (outbred control, one or two full-sib matings). Four generations after having terminated selection, a response to selection was found in 1-day-old butterflies (the age at which selection took place). Older adults showed a very similar although weaker response. Nevertheless, cold resistance did not increase in either egg, larval or pupal stage in the selection lines but was even lower compared to control lines for eggs and young larvae. These findings suggest a cost of increased adult cold tolerance, presumably reducing resource availability for offspring provisioning and thereby stress tolerance during development, which may substantially affect evolutionary trajectories. © 2012 The Authors. Journal of Evolutionary Biology © 2012 European Society For Evolutionary Biology.

FISH AND AMPHIBIAN TOLERANCE VALUES AND AN ASSEMBLAGE TOLERANCE INDEX FOR STEAMS AND RIVERS IN THE WESTERN USA

EPA Science Inventory

Aquatic species' tolerances to overall human disturbance are key components of biological assessments of aquatic ecosystems. These tolerance classifications enable development of metrics for use in multimetric indexes, such as the index of biotic integrity (IBI). Usually, species...

Acute pain management in patients with persistent pain.

PubMed

Quinlan, Jane; Carter, Kim

2012-06-01

Over the past 20 years, prescriptions of opioids for chronic pain have increased dramatically. This review addresses the difficulties in managing acute pain in this growing group of patients and discusses evidence relating to opioid tolerance and hyperalgesia and new avenues of research in specific painful conditions. There is accumulating evidence surrounding the dangers of high-dose opioids and the risk of overdose and death. Employing nonopioid analgesics and disease-modifying drugs to cover an acute exacerbation of pain will thus limit escalating opioid doses. In specific diseases, the role of oxidative stress and the disruption of calcium homeostasis may provide treatment targets in acute pancreatitis; the identification of psychological stressors may decrease the frequency of acute exacerbations of abdominal pain; modifying the adhesion of sickle cells to inflamed endothelium may reduce vaso-occlusive crises; while vertebroplasty and calcitonin appear to improve pain and functioning after osteoporotic vertebral fractures. Much of the evidence regarding the acute pain management of chronic pain patients is extrapolated from studies of opioid-naïve patients undergoing surgery. More focused research is needed to ascertain whether this model is an appropriate one to follow for such a complex group of patients.

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.

A Phytophthora sojae cytoplasmic effector mediates disease resistance and abiotic stress tolerance in Nicotiana benthamiana.

PubMed

Zhang, Meixiang; Ahmed Rajput, Nasir; Shen, Danyu; Sun, Peng; Zeng, Wentao; Liu, Tingli; Juma Mafurah, Joseph; Dou, Daolong

2015-06-03

Each oomycete pathogen encodes a large number of effectors. Some effectors can be used in crop disease resistance breeding, such as to accelerate R gene cloning and utilisation. Since cytoplasmic effectors may cause acute physiological changes in host cells at very low concentrations, we assume that some of these effectors can serve as functional genes for transgenic plants. Here, we generated transgenic Nicotiana benthamiana plants that express a Phytophthora sojae CRN (crinkling and necrosis) effector, PsCRN115. We showed that its expression did not significantly affect the growth and development of N. benthamiana, but significantly improved disease resistance and tolerance to salt and drought stresses. Furthermore, we found that expression of heat-shock-protein and cytochrome-P450 encoding genes were unregulated in PsCRN115-transgenic N. benthamiana based on digital gene expression profiling analyses, suggesting the increased plant defence may be achieved by upregulation of these stress-related genes in transgenic plants. Thus, PsCRN115 may be used to improve plant tolerance to biotic and abiotic stresses.

Chamber and field evaluations of air pollution tolerances of urban trees

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karnosky, D.F.

1981-04-01

Results are presented for a study of the relative air pollution tolerances of 32 urban-tree cultivars as determined by both chamber fumigations and field exposures. Tolerances to ozone and sulfur dioxide, alone and in combination, were determined using short-term, acute doses administered while the plants were inside a plastic fumigation chamber located inside the Cary Arboretum greenhouses. In a follow-up study still underway, representatives of the same cultivars were outplanted at four locations in the greater New York City area. To date, only oxidant-type injury has been observed on trees in the field plots. Cultivars tolerant to all chamber andmore » field exposures were Acer platanoides Cleveland, Crimson King, Emerald Queen, Jade Glen, and Summershade; Acer rubrum Autumn Flame and Red Sunset; Acer saccharum Green Mountain and Temple's Upright; Fagus sylvatica Rotundifolia; Fraxinus pennsylvanica Summit; and Ginkgo biloba Fastigate and Sentry. Cultivars sensitive to ozone as determined by the chamber and field tests and that may serve as bioindicators of the presence of ozone were Gleditsia triacanthos inermis imperial and Platanus acerifolia Bloodgood.« less

Transcriptomic analysis of submergence-tolerant and sensitive Brachypodium distachyon ecotypes reveals oxidative stress as a major tolerance factor

PubMed Central

Rivera-Contreras, Irma Karla; Zamora-Hernández, Teresa; Huerta-Heredia, Ariana Arlene; Capataz-Tafur, Jacqueline; Barrera-Figueroa, Blanca Estela; Juntawong, Piyada; Peña-Castro, Julián Mario

2016-01-01

When excessive amounts of water accumulate around roots and aerial parts of plants, submergence stress occurs. To find the integrated mechanisms of tolerance, we used ecotypes of the monocot model plant Brachypodium distachyon to screen for genetic material with contrasting submergence tolerance. For this purpose, we used a set of previously studied drought sensitive/tolerant ecotypes and the knowledge that drought tolerance is positively associated with submergence stress. We decided to contrast aerial tissue transcriptomes of the ecotype Bd21 14-day-old plants as sensitive and ecotype Bd2-3 as tolerant after 2 days of stress under a long-day photoperiod. Gene ontology and the grouping of transcripts indicated that tolerant Bd2-3 differentially down-regulated NITRATE REDUCTASE and ALTERNATIVE OXIDASE under stress and constitutively up-regulated HAEMOGLOBIN, when compared with the sensitive ecotype, Bd21. These results suggested the removal of nitric oxide, a gaseous phytohormone and concomitant reactive oxygen species as a relevant tolerance determinant. Other mechanisms more active in tolerant Bd2-3 were the pathogen response, glyoxylate and tricarboxylic acid cycle integration, and acetate metabolism. This data set could be employed to design further studies on the basic science of plant tolerance to submergence stress and its biotechnological application in the development of submergence-tolerant crops. PMID:27282694

Effect of heat acclimation on sitting orthostatic tolerance in the heat after 48 and 96 hour bed rest in men

NASA Technical Reports Server (NTRS)

Greenleaf, J. E.; Matter, M., Jr.

1995-01-01

The purpose of this pilot study was to investigate sitting orthostatic tolerance and determine potentially adverse signs and symptoms that would incapacitate subjects in a hot environment (Gemini reentry cabin temperature profile) after 48 hr and 96 hr of horizontal bed rest (BR), which simulated microgravity deconditioning. Six college men (23-29 yr) were allocated into two groups: heat acclimated (three subjects: No. 1- control, No. 2- 48 hr BR, and No. 3- 96 hr BR) and nonheat acclimated (three subjects: No. 4- control, No. 5- 48 hr BR, and No. 6- 96 hr BR). After BR they sat in an ambient temperature of 57 C (135 F) for 30 min which then was decreased to 49 C (120 F) for up to 480 min. Tolerance time in the heat with seated orthostatic stress was 480 min (subject No. 1) and 180 min (subject No. 4) in the two ambulatory men, but was reduced to 22-150 min in the four bed-rested men irrespective of their heat acclimation status. Although heat acclimation appeared to enhance tolerance and attenuate accompanying physiological responses, as well as ameliorate the frequency and intensity of adverse signs and symptoms at termination of exposure, tolerance was reduced in the bed-rest deconditioned subjects regardless of their acclimation level. Thus, these few collective findings do not indicate an unequivocal positive effect of acute heat acclimation on sitting orthostatic tolerance in acute bed-rest deconditioned subjects.

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing.

PubMed

Lee, Mei-Chong Wendy; Lopez-Diaz, Fernando J; Khan, Shahid Yar; Tariq, Muhammad Akram; Dayn, Yelena; Vaske, Charles Joseph; Radenbaugh, Amie J; Kim, Hyunsung John; Emerson, Beverly M; Pourmand, Nader

2014-11-04

The acute cellular response to stress generates a subpopulation of reversibly stress-tolerant cells under conditions that are lethal to the majority of the population. Stress tolerance is attributed to heterogeneity of gene expression within the population to ensure survival of a minority. We performed whole transcriptome sequencing analyses of metastatic human breast cancer cells subjected to the chemotherapeutic agent paclitaxel at the single-cell and population levels. Here we show that specific transcriptional programs are enacted within untreated, stressed, and drug-tolerant cell groups while generating high heterogeneity between single cells within and between groups. We further demonstrate that drug-tolerant cells contain specific RNA variants residing in genes involved in microtubule organization and stabilization, as well as cell adhesion and cell surface signaling. In addition, the gene expression profile of drug-tolerant cells is similar to that of untreated cells within a few doublings. Thus, single-cell analyses reveal the dynamics of the stress response in terms of cell-specific RNA variants driving heterogeneity, the survival of a minority population through generation of specific RNA variants, and the efficient reconversion of stress-tolerant cells back to normalcy.

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

PubMed Central

Lee, Mei-Chong Wendy; Lopez-Diaz, Fernando J.; Khan, Shahid Yar; Tariq, Muhammad Akram; Dayn, Yelena; Vaske, Charles Joseph; Radenbaugh, Amie J.; Kim, Hyunsung John; Emerson, Beverly M.; Pourmand, Nader

2014-01-01

The acute cellular response to stress generates a subpopulation of reversibly stress-tolerant cells under conditions that are lethal to the majority of the population. Stress tolerance is attributed to heterogeneity of gene expression within the population to ensure survival of a minority. We performed whole transcriptome sequencing analyses of metastatic human breast cancer cells subjected to the chemotherapeutic agent paclitaxel at the single-cell and population levels. Here we show that specific transcriptional programs are enacted within untreated, stressed, and drug-tolerant cell groups while generating high heterogeneity between single cells within and between groups. We further demonstrate that drug-tolerant cells contain specific RNA variants residing in genes involved in microtubule organization and stabilization, as well as cell adhesion and cell surface signaling. In addition, the gene expression profile of drug-tolerant cells is similar to that of untreated cells within a few doublings. Thus, single-cell analyses reveal the dynamics of the stress response in terms of cell-specific RNA variants driving heterogeneity, the survival of a minority population through generation of specific RNA variants, and the efficient reconversion of stress-tolerant cells back to normalcy. PMID:25339441

Biochemical markers of acute limb ischemia, rhabdomyolysis, and impact on limb salvage.

PubMed

Watson, J Devin B; Gifford, Shaun M; Clouse, W Darrin

2014-12-01

Biochemical markers of ischemia reperfusion injury have been of interest to vascular surgeons and researchers for many years. Acute limb ischemia is the quintessential clinical scenario where these markers would seem relevant. The use of biomarkers to preoperatively or perioperatively predict which patients will not tolerate limb-salvage efforts or who will have poor functional outcomes after salvage is of immense interest. Creatinine phosphokinase, myoglobin, lactate, lactate dehydrogenase, potassium, bicarbonate, and neutrophil/leukocyte ratios are a few of the studied biomarkers available. Currently, the most well-studied aspect of ischemia reperfusion injury is rhabdomyolysis leading to acute kidney injury. The last 10 years have seen significant progression and improvement in the treatment of rhabdomyolysis, from minor supportive care to use of continuous renal replacement therapy. Identification of specific biomarkers with predictive outcome characteristics in the setting of ischemia reperfusion injury will help guide therapeutic development and potentially mitigate pathophysiologic changes in acute limb ischemia, including rhabdomyolysis. These may further lead to improvements in short- and long-term surgical outcomes and limb salvage, as well as a better understanding of the timing and selection of intervention. Copyright © 2015 Elsevier Inc. All rights reserved.

Piroxicam in acute musculoskeletal disorders and sports injuries.

PubMed

Heere, L P

1988-05-20

Approximately 20 percent of athletes have an acute or chronic injury related to their sport. In acute musculoskeletal disorders, inflammation is an important component of the symptomatology. Recent clinical studies are showing that nonsteroidal anti-inflammatory drugs (NSAIDs) can significantly reduce inflammation and help speed return to full function. In an international study, the efficacy and toleration of piroxicam were compared with that of indomethacin, naproxen, and aspirin in three multicenter, double-blind, parallel studies involving a total of 1,290 patients with acute sprains and tendinitis. The centers compared piroxicam 40 mg once daily for the first two days followed by 20 mg once daily for the remainder of the studies. This regimen was compared with either indomethacin, 50 mg three times per day for two days and 25 mg three times per day for the remainder of the treatment period; naproxen 500 mg twice daily for two days followed by 250 mg in the morning and 500 mg in the evening thereafter; or aspirin 4 g per day for the duration of the study. Treatment normally lasted 14 days; the minimal duration was seven days, with a maximum of 28 days. Overall assessment of efficacy was excellent or good in more than 80 percent of patients. Statistical differences were seen favoring piroxicam over aspirin (p less than 0.05) regarding reduction in tenderness and resumption of daily activities within 16 days (p less than 0.02). The study comparing piroxicam and naproxen showed a statistically significant difference in favor of piroxicam (p less than 0.025). There was no difference between piroxicam and indomethacin in the number of patients who were able to accomplish normal daily activity within 16 days. Furthermore, although efficacy was comparable among the NSAIDs, piroxicam was significantly better-tolerated than either naproxen or indomethacin. Piroxicam was also better-tolerated than aspirin, but a statistical difference was not reached.

Impact of adolescent alcohol use across the lifespan: Long-lasting tolerance to high-dose alcohol coupled with potentiated spatial memory impairments to moderate-dose alcohol.

PubMed

Matthews, Douglas B; Novier, Adelle; Diaz-Granados, Jaime L; Van Skike, Candice E; Ornelas, Laura; Mittleman, G

2017-06-01

Understanding how alcohol exposure during adolescence affects aging is a critical but understudied area. In the present study, male rats were exposed to either alcohol or saline during adolescence, then tested every 4 months following either an ethanol or saline challenge; animals were tested until postnatal day (PD) 532. It was found that long-lasting tolerance to high-dose ethanol exists through the test period, as measured by loss of righting reflex, while tolerance to lower doses of ethanol is not found. In addition, alcohol exposure during adolescence facilitated spatial memory impairments to acute ethanol challenges later in life. The current work demonstrates that exposure to ethanol during adolescent development can produce long-lasting detrimental impairments. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of perianal ulcer as a result of acute fulminant amoebic colitis.

PubMed

Torigoe, Takayuki; Nakayama, Yoshifumi; Yamaguchi, Koji

2012-09-14

We report a case of acute fulminant amoebic colitis that resulted in the development of a perianal ulcer in a 29-year-old Japanese homosexual man with acquired immunodeficiency syndrome (AIDS). The patient was admitted to our hospital with a persistent perianal abscess that was refractory to antibiotic therapy administered at another hospital. On admission, we observed a giant ulcer in the perianal region. At first, cytomegalovirus colitis was suspected by blood investigations. Ganciclovir therapy was initiated; however, the patient developed necrosis of the skin around the anus during therapy. We only performed end-sigmoidostomy and necrotomy to avoid excessive surgical invasion. Histopathological examination of the surgical specimen revealed the presence of trophozoite amoebae, indicating a final diagnosis of acute fulminant amoebic colitis. The patient's postoperative course was favorable, and proctectomy of the residual rectum was performed 11 mo later. Amoebic colitis is one of the most severe complications affecting patients with AIDS. Particularly, acute fulminant amoebic colitis may result in a poor prognosis; therefore, staged surgical therapy as a less invasive procedure should be considered as one of the treatment options for these patients.

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.

Acute and chronic toxicity studies with monochlorobenzene in rainbow trout

USGS Publications Warehouse

Dahlich, G.M.; Larson, R.E.; Gingerich, W.H.

1982-01-01

The toxicity of monochlorobenzene (CB) was investigated in rainbow trout following acute intraperitoneal (i.p.) administration and chronic exposure via the water in a continuously flowing system for 15 or 30 days. In the acute study overt toxicity and hepatotoxicity were monitored over a 96-h time period. Variables measured to assess toxicity included weight changes, liver weight to body weight ratios, behavioral changes, alanine aminotransferase activity (GPT), sulfobromophthalein (BSP) retention, total plasma protein concentration and liver histopathology. In the chronic study the same measures of toxicity were followed as well as food consumption and alkaline phosphatase (AP) activity. Upon acute i.p. exposure the toxicant (9.8 mmol/kg) caused behavioral changes in the fish which were consistent with the known anesthetic properties of CB in mammals. Elevations in BSP retention and GPT activity, and histopathology indicated that CB was hepatotoxic in fish. The LC50 of CB in trout exposed via the water for 96 h was 4.7 mg/l. Chronic exposure of trout to 2 or 3 mg/l CB resulted in similar behavioral changes as seen in the acute study. Liver toxicity was evident from elevations in GPT activity. BSP retention and AP activity appeared to be affected by the nutritional status of the trout as much as by the CB treatment. After 30 days of exposure to 3 mg/l CB, trout appeared to have developed some tolerance to the toxic effects.

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.

A methodology for testing fault-tolerant software

NASA Technical Reports Server (NTRS)

Andrews, D. M.; Mahmood, A.; Mccluskey, E. J.

1985-01-01

A methodology for testing fault tolerant software is presented. There are problems associated with testing fault tolerant software because many errors are masked or corrected by voters, limiter, or automatic channel synchronization. This methodology illustrates how the same strategies used for testing fault tolerant hardware can be applied to testing fault tolerant software. For example, one strategy used in testing fault tolerant hardware is to disable the redundancy during testing. A similar testing strategy is proposed for software, namely, to move the major emphasis on testing earlier in the development cycle (before the redundancy is in place) thus reducing the possibility that undetected errors will be masked when limiters and voters are added.

Study of fault-tolerant software technology

NASA Technical Reports Server (NTRS)

Slivinski, T.; Broglio, C.; Wild, C.; Goldberg, J.; Levitt, K.; Hitt, E.; Webb, J.

1984-01-01

Presented is an overview of the current state of the art of fault-tolerant software and an analysis of quantitative techniques and models developed to assess its impact. It examines research efforts as well as experience gained from commercial application of these techniques. The paper also addresses the computer architecture and design implications on hardware, operating systems and programming languages (including Ada) of using fault-tolerant software in real-time aerospace applications. It concludes that fault-tolerant software has progressed beyond the pure research state. The paper also finds that, although not perfectly matched, newer architectural and language capabilities provide many of the notations and functions needed to effectively and efficiently implement software fault-tolerance.

Estimates of acute pesticide poisoning in agricultural workers in less developed countries.

PubMed

Litchfield, Melville H

2005-01-01

The benefits of crop protection products have to be balanced against the risks to farmers and other agricultural workers handling and applying them. The extent of acute pesticide poisoning in these workers, particularly in less developed countries, has often been based on inadequate information. A number of approaches have been taken by researchers to acquire information on pesticide poisoning. These have resulted in worldwide (global) estimates and regional, localised or field assessments. The methods include descriptive epidemiology, cross-sectional and case studies. Attempts to estimate global pesticide poisonings have often been based upon extrapolations and assumptions from chemical-related fatalities in a small number of countries; such estimates do not provide reliable data. Epidemiological studies, relying mainly on hospital and poison centre data, have been biased towards the more severe poisonings, whereas field studies indicate that occupational pesticide poisoning is associated with less severe and minor effects. Many reports do not adequately distinguish between intentional, accidental and occupational pesticide poisoning statistics or are dominated by cases of intentional (suicidal) poisoning which, by their nature, result in severe or fatal results. The majority of reports do not adequately describe whether individual cases are minor, moderate or severe poisonings. In order to assess information on acute pesticide poisoning in agricultural workers in less developed countries and to draw conclusions on the extent and severity of occupational poisoning, the most recent (post-1990) literature was reviewed. Data were also derived from the World Health Organization (WHO), United Nations Environment Programme (UNEP) and the International Labour Office (ILO). The collected information was analysed to assess the extent and severity of occupational acute pesticide poisoning in less developed countries. Occupational acute pesticide poisonings in these

Tolerance and dose-volume relationship of intrathoracic stomach irradiation after esophagectomy for patients with thoracic esophageal squamous cell carcinoma.

PubMed

Liu, Qi; Cai, Xu-Wei; Fu, Xiao-Long; Chen, Jun-Chao; Xiang, Jia-Qing

2015-10-13

To identify the tolerance of radiation with a high prescribed dose and predictors for the development of intrathoracic stomach toxicity in patients with thoracic esophageal squamous cell carcinoma (SCC) after esophagectomy followed by gastric conduit reconstruction. From 2011 to 2013, 105 patients after esophagectomy were treated with postoperative radiotherapy. The intrathoracic stomach was outlined with the calculation of a dose-volume histogram (DVH) for the initial intended treatment of 6020 cGy or 6300 cGy. The volume of the intrathoracic stomach receiving each dose was recorded at 10-Gy intervals between 10 and 40 Gy and at 5-Gy intervals between 40 and 60 Gy. The grade of toxicities was defined by the National Cancer Institute Common Toxicity Criteria version 4.0. The mean and maximum doses of the intrathoracic stomach were 2449 ± 986 cGy and 6519 ± 406 cGy, respectively. Sixteen (15.2%) and three (2.9%) experienced Common Toxicity Criteria Grade 2 and Grade 3 acute gastric toxicity. There were no Grade 4 toxicities. Fourteen patients (13.3%) exhibited late gastric complications possibly related to radiation. The volume percent of the intrathoracic stomach receiving at least 50 Gy (V50) was strongly associated with the degree of toxicity (p = 0.024, respectively). Multivariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicities. The intrathoracic stomach is well tolerated with a high-dose irradiation for patients with esophageal SCC receiving radiotherapy after esophagectomy. A strong dose-volume relationship exists for the development of Grade 2 acute intrathoracic stomach toxicity in our study.

Variability of LD50 Values from Rat Oral Acute Toxicity Studies: Implications for Alternative Model Development

EPA Science Inventory

Alternative models developed for estimating acute systemic toxicity are generally evaluated using in vivo LD50 values. However, in vivo acute systemic toxicity studies can produce variable results, even when conducted according to accepted test guidelines. This variability can ma...

C-Rel is an essential transcription factor for the development of acute graft-versus-host disease in mice

PubMed Central

Yu, Yu; Wang, Dapeng; Kaosaard, Kane; Liu, Chen; Fu, Jianing; Haarberg, Kelley; Anasetti, Claudio; Beg, Amer A.; Yu, Xue-Zhong

2014-01-01

Transcription factor of the Rel/NF-κB family are known to play different roles in immunity and inflammation, although the putative role of c-Rel in transplant tolerance and GVHD remains elusive. We report here that T cells deficient for c-Rel have a dramatically reduced ability to cause acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) using major and minor histocompatibility mismatched murine models. In the study to understand the underlying mechanisms, we found that c-Rel-/- T cells had reduced ability to expand in lymphoid organs and to infiltrate in GVHD target organs in allogeneic recipients. c-Rel-/- T cells were defective in the differentiation into Th1 cells after encountering alloantigens, but were enhanced in the differentiation towards Foxp3+ regulatory T cells (Tregs). Furthermore, c-Rel-/- T cells had largely preserved activity to mediate graft-versus leukemia (GVL) response. Taken together, our findings indicate that c-Rel plays an essential role in T cells in the induction of acute GVHD, and suggest that c-Rel can be a potential target for therapeutic intervention in allogeneic HCT in clinic. PMID:23716202

Differentiating Acute Otitis Media and Acute Mastoiditis in Hospitalized Children.

PubMed

Laulajainen-Hongisto, Anu; Aarnisalo, Antti A; Jero, Jussi

2016-10-01

Acute otitis media is a common infection in children. Most acute otitis media episodes can be treated at an outpatient setting with antimicrobials, or only expectant observation. Hospital treatment with parenteral medication, and myringotomy or tympanostomy, may be needed to treat those with severe, prolonged symptoms, or with complications. The most common intratemporal complication of acute otitis media is acute mastoiditis. If a child with acute mastoiditis does not respond to this treatment, or if complications develop, further examinations and other surgical procedures, including mastoidectomy, are considered. Since the treatment of complicated acute otitis media and complicated acute mastoiditis differs, it is important to differentiate these two conditions. This article focuses on the differential diagnostics of acute otitis media and acute mastoiditis in children.

Need for Tolerances and Tolerance Exemptions for Minimum Risk Pesticides

EPA Pesticide Factsheets

The ingredients used in minimum risk products used on food, food crops, food contact surfaces, or animal feed commodities generally have a tolerance or tolerance exemption. Learn about tolerances and tolerance exemptions for minimum risk ingredients.

Protective effect of Flos puerariae extract following acute alcohol intoxication in mice.

PubMed

Chen, Xiao; Cai, Fei; Guo, Shuang; Ding, Fang; He, Yi; Wu, Jiliang; Liu, Chao

2014-07-01

The effect of Flos Puerariae extract (FPE) on alcohol metabolism, hepatic injury, and memory impairment was assessed following acute ethanol (EtOH) intoxication in mice. The model of acute EtOH intoxication was established by intragastric administration with 8 g/kg EtOH in mice. FPE was orally administrated (gavage) once a day for 7 consecutive days. Mice were randomly divided into 4 groups: control group, model group, and FPE groups (100, 200 mg/kg). Alcohol tolerance and intoxication time, blood alcohol concentration, the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in liver, aspartate amino transferase (AST) and alanine amino transferase (ALT) in serum, superoxide dismutase (SOD), glutathione peroxidase (GSH-px), catalase and the formation of malondialdehyde (MDA) in both liver and brain, as well as memory ability were determined after acute alcohol exposure. Compared with model group, pretreatment with FPE significantly prolonged alcohol tolerance time and shortened intoxication time, which is accompanied by decreased blood alcohol concentration and elevated activities of ADH and ALDH in liver. Moreover, the index of hepatic injury, ALT, and AST activities in serum was markedly decreased by pretreatment with FPE. Additionally, decreased MDA level, enhanced GSH-px and catalase activities in liver, as well as enhanced SOD and catalase activities in brain were found in FPE pretreated mice after acute exposure to EtOH. Furthermore, FPE pretreated mice showed markedly relieved memory disruption following acute EtOH intoxication. This study suggests that FPE pretreatment could enhance alcohol metabolism, prevent hepatic injury, and relieve memory impairment after acute alcohol intoxication and that this effect is likely related to its modulation on the alcohol metabolizing and antioxidant enzymes. Copyright © 2014 by the Research Society on Alcoholism.

Tet1 facilitates hypoxia tolerance by stabilizing the HIF-α proteins independent of its methylcytosine dioxygenase activity.

PubMed

Wang, Jing; Zhang, Dawei; Du, Juan; Zhou, Chi; Li, Zhi; Liu, Xing; Ouyang, Gang; Xiao, Wuhan

2017-12-15

Because of the requirement of oxygen (O2) to produce energy, aerobic organisms developed mechanisms to protect themselves against a shortage of oxygen in both acute status and chronic status. To date, how organisms tolerate acute hypoxia and the underlying mechanisms remain largely unknown. Here, we identify that Tet1, one member of the ten-eleven translocation (TET) family of methylcytosine dioxygenases, is required for hypoxia tolerance in zebrafish and mice. Tet1-null zebrafish and mice are more sensitive to hypoxic conditions compared with their wild-type siblings. We demonstrate that Tet1 stabilizes hypoxia-inducible factor α (HIF-α) and enhances HIF-α transcription activity independent of its enzymatic activity. In addition, we show that Tet1 modulates HIF-2α and HIF-1α through different mechanisms. Tet1 competes with prolyl hydroxylase protein 2 (PHD2) to bind to HIF-2α, resulting in a reduction of HIF-2α hydroxylation by PHD2. For HIF-1α, however, Tet1 has no effect on HIF-1α hydroxylation, but rather it appears to stabilize the C-terminus of HIF-1α by affecting lysine site modification. Furthermore, we found that Tet1 enhances rather than prevents poly-ubiquitination on HIF-α. Our results reveal a previously unrecognized function of Tet1 independent of its methylcytosine dioxygenase activity in hypoxia signaling. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Forages and Pastures Symposium: development of and field experience with drought-tolerant maize.

PubMed

Soderlund, S; Owens, F N; Fagan, C

2014-07-01

Drought-tolerant maize hybrids currently are being marketed by several seed suppliers. Such hybrids were developed by phenotypic and marker-assisted selection or through genetic modification and tested by exposing these hybrids to various degrees of water restriction. As drought intensifies, crop yields and survival progressively decline. Water need differs among plants due to differences in root structure, evaporative loss, capacity to store water or enter temporary dormancy, and plant genetics. Availability of water differs widely not only with rainfall and irrigation but also with numerous soil and agronomic factors (e.g., soil type, slope, seeding rates, tillage practices). Reduced weed competition, enhanced pollen shed and silk production, and deep, robust root growth help to reduce the negative impacts of drought. Selected drought-tolerant maize hybrids have consistently yielded more grain even when drought conditions are not apparent either due to reduced use of soil water reserves before water restriction or due to greater tolerance of intermittent water shortages. In DuPont Pioneer trials, whole plant NDF digestibility of maize increased with water restriction, perhaps due to an increased leaf to stem ratio. Efficiency of water use, measured as dry matter or potential milk yield from silage per unit of available water, responded quadratically to water restriction, first increasing slightly but then decreasing as water restriction increased. For grain production, water restriction has its greatest negative impact during or after silking through reducing the number of kernels and reducing kernel filling. For silage production, water restriction during the vegetative growth stage negatively impacts plant height and biomass yield. Earlier planting and shorter season maize hybrids help to avoid midsummer heat stress during pollination and can reduce the number of irrigation events needed. Although drought tolerance of maize hybrids has been improved due to

Dietary live yeast alters metabolic profiles, protein biosynthesis and thermal stress tolerance of Drosophila melanogaster.

PubMed

Colinet, Hervé; Renault, David

2014-04-01

The impact of nutritional factors on insect's life-history traits such as reproduction and lifespan has been excessively examined; however, nutritional determinant of insect's thermal tolerance has not received a lot of attention. Dietary live yeast represents a prominent source of proteins and amino acids for laboratory-reared drosophilids. In this study, Drosophila melanogaster adults were fed on diets supplemented or not with live yeast. We hypothesized that manipulating nutritional conditions through live yeast supplementation would translate into altered physiology and stress tolerance. We verified how live yeast supplementation affected body mass characteristics, total lipids and proteins, metabolic profiles and cold tolerance (acute and chronic stress). Females fed with live yeast had increased body mass and contained more lipids and proteins. Using GC/MS profiling, we found distinct metabolic fingerprints according to nutritional conditions. Metabolite pathway enrichment analysis corroborated that live yeast supplementation was associated with amino acid and protein biosyntheses. The cold assays revealed that the presence of dietary live yeast greatly promoted cold tolerance. Hence, this study conclusively demonstrates a significant interaction between nutritional conditions and thermal tolerance. Copyright © 2014 Elsevier Inc. All rights reserved.

Renal angina: concept and development of pretest probability assessment in acute kidney injury.

PubMed

Chawla, Lakhmir S; Goldstein, Stuart L; Kellum, John A; Ronco, Claudio

2015-02-27

The context of a diagnostic test is a critical component for the interpretation of its result. This context defines the pretest probability of the diagnosis and forms the basis for the interpretation and value of adding the diagnostic test. In the field of acute kidney injury, a multitude of early diagnostic biomarkers have been developed, but utilization in the appropriate context is less well understood and has not been codified until recently. In order to better operationalize the context and pretest probability assessment for acute kidney injury diagnosis, the renal angina concept was proposed in 2010 for use in both children and adults. Renal angina has been assessed in approximately 1,000 subjects. However, renal angina as a concept is still unfamiliar to most clinicians and the rationale for introducing the term is not obvious. We therefore review the concept and development of renal angina, and the currently available data validating it. We discuss the various arguments for and against this construct. Future research testing the performance of renal angina with acute kidney injury biomarkers is warranted.

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.

Sugarcane Water Stress Tolerance Mechanisms and Its Implications on Developing Biotechnology Solutions

PubMed Central

Ferreira, Thais H. S.; Tsunada, Max S.; Bassi, Denis; Araújo, Pedro; Mattiello, Lucia; Guidelli, Giovanna V.; Righetto, Germanna L.; Gonçalves, Vanessa R.; Lakshmanan, Prakash; Menossi, Marcelo

2017-01-01

Sugarcane is a unique crop with the ability to accumulate high levels of sugar and is a commercially viable source of biomass for bioelectricity and second-generation bioethanol. Water deficit is the single largest abiotic stress affecting sugarcane productivity and the development of water use efficient and drought tolerant cultivars is an imperative for all major sugarcane producing countries. This review summarizes the physiological and molecular studies on water deficit stress in sugarcane, with the aim to help formulate more effective research strategies for advancing our knowledge on genes and mechanisms underpinning plant response to water stress. We also overview transgenic studies in sugarcane, with an emphasis on the potential strategies to develop superior sugarcane varieties that improve crop productivity in drought-prone environments. PMID:28690620

Impact of acute psychological stress on cardiovascular risk factors in face of insulin resistance.

PubMed

Jones, Kristian T; Shelton, Richard C; Wan, Jun; Li, Li

2016-11-01

Individuals with insulin resistance (IR) are at greater risk for cardiovascular disease (CVD). Psychological stress may contribute to develop CVD in IR, although mechanisms are poorly understood. Our aim was to test the hypothesis that individuals with IR have enhanced emotional and physiological responses to acute psychological stress, leading to increased CVD risk. Sixty participants were enrolled into the study, and classified into IR group (n = 31) and insulin sensitive group (n = 29) according to the Quantitative insulin sensitivity check index, which was calculated based on an oral glucose tolerance test. The Trier social stress test, a standardized experimental stress paradigm, was performed on each participant, and emotional and physiological responses were examined. Blood was collected from each subject for insulin, cytokines, and cortisol measurements. Compared with the insulin-sensitive group, individuals with IR had significantly lower ratings of energy and calm, but higher fatigue levels in response to acute stressors. Individuals with IR also showed blunted heart rate reactivity following stress. In addition, the IR status was worsened by acute psychological stress as demonstrated by further increased insulin secretion. Furthermore, individuals with IR showed significantly increased levels of leptin and interleukin-6, but decreased levels of adiponectin, at baseline, stress test, and post-stress period. Our findings in individuals with IR under acute stress would allow a better understanding of the risks for developing CVD and to tailor the interventions for better outcomes.

Impact of Acute Psychological Stress on Cardiovascular Risk Factors in Face of Insulin Resistance

PubMed Central

Jones, Kristian T.; Shelton, Richard C.; Wan, Jun; Li, Li

2016-01-01

Individuals with insulin resistance (IR) are at greater risk for cardiovascular disease (CVD). Psychological stress may contribute to develop CVD in IR although mechanisms are poorly understood. Our aim was to test the hypothesis that individuals with IR have enhanced emotional and physiological responses to acute psychological stress, leading to increased CVD risk. Sixty participants were enrolled into the study, and classified into IR group (n=31) and insulin sensitive group (n=29) according to the Quantitative insulin sensitivity check index, which was calculated based on an oral glucose tolerance test. The Trier social stress test, a standardized experimental stress paradigm, was performed on each participant, and emotional and physiological responses were examined. Blood was collected from each subject for insulin, cytokines and cortisol measurements. Compared with insulin sensitive group, individuals with IR had significantly lower ratings of energy and calm, but higher fatigue levels in response to acute stressors. Individuals with IR also showed blunted heart rate reactivity following stress. In addition, the IR status was worsened by acute psychological stress as demonstrated by further increased insulin secretion. Furthermore, individuals with IR showed significantly increased levels of leptin and interleukin-6, but decreased levels of adiponectin, at baseline, stress test and post-stress period. Our findings in individuals with IR under acute stress would allow a better understanding of the risks for developing CVD and to tailor the interventions for better outcomes. PMID:27588343

Assessment of pathological changes associated with chronic allograft rejection and tolerance in two experimental models of rat lung transplantation.

PubMed

Matsumura, Y; Marchevsky, A; Zuo, X J; Kass, R M; Matloff, J M; Jordan, S C

1995-06-15

Lung transplantation is now routinely performed for a wide range of end-stage cardiopulmonary disorders. Despite overcoming the problems associated with early acute rejection, chronic rejection (CR) in the form of obliterative bronchiolitis has emerged as the primary cause of late graft loss. The mechanisms involved in the development of CR of lung allografts are poorly understood, and no effective therapy is currently available. To better understand the pathological events associated with CR and tolerance, we examined two models of lung allograft rejection established in our laboratory. First, we exchanged left lung allografts between moderately histoincompatible inbred rat strains (WKY-->F344: n = 42 and F344-->WKY: n = 40). The WKY-->F344 model was previously shown to develop spontaneous tolerance, while the converse model (F344-->WKY) showed persistent acute rejection. The purpose of this investigation was to assess histopathological changes associated with long-term grafts left in place up to 140 days after transplant. To confirm that tolerance had developed, skin-grafting experiments were performed. Five skin grafts from each strain were placed on lung allograft recipients on day 35 after transplant and skin allograft survival was assessed and compared with controls. Acute rejection (AR) was graded histologically (stage O-IV) and the pathologic intensity of inflammation and CR were graded (0-4: 0 = 0%, 1 = 1-25%, 2 = 26-50%, 3 = 51-75%, and 4 = 76-100%) on percentage of involvement with the following categories being examined: (a) lymphocytic infiltration (perivascular, peribronchial, and peribronchiolar) and (b) vasculitis, edema, hemorrhage, and necrosis. Finally, chronic rejection was diagnosed by the presence of intimal hyperplasia, interstitial fibrosis, peribronchiolar fibrosis, bronchiolitis obliterans, and bronchiectasis. The WKY-->F344 animals showed progressive AR (stage III, day 21). Thereafter, the AR subsided spontaneously and was stage 0 on day

(In)Tolerable Zero Tolerance Policy

ERIC Educational Resources Information Center

Dickerson, Sean L.

2014-01-01

The spread of zero tolerance policies for school-based scenarios flourished under President William J. Clinton who wanted to close a loophole in the Guns-Free School Zones Act of 1990. Expansion in the coverage of zero tolerance policy to offenses outside the initial scope of weapon and drug offenses has led to a disproportional ratio of African…

Pesticide tolerance in amphibians: induced tolerance in susceptible populations, constitutive tolerance in tolerant populations

PubMed Central

Hua, Jessica; Morehouse, Nathan I; Relyea, Rick

2013-01-01

The role of plasticity in shaping adaptations is important to understanding the expression of traits within individuals and the evolution of populations. With increasing human impacts on the environment, one challenge is to consider how plasticity shapes responses to anthropogenic stressors such as contaminants. To our knowledge, only one study (using mosquitoes) has considered the possibility of induced insecticide tolerance. Using populations of wood frogs (Lithobates sylvaticus) located close to and far from agricultural fields, we discovered that exposing some populations of embryos and hatchlings to sublethal concentrations of the insecticide carbaryl induced higher tolerance to a subsequent lethal concentration later in life. Interestingly, the inducible populations were located >800 m from agricultural areas and were the most susceptible to the insecticide. In contrast, the noninducible populations were located close to agricultural areas and were the least susceptible. We also found that sublethal concentrations of carbaryl induced higher tadpole AChE concentrations in several cases. This is the first study to demonstrate inducible tolerance in a vertebrate species and the pattern of inducible and constitutive tolerance among populations suggests the process of genetic assimilation. PMID:24187585

Development of radiation tolerant monolithic active pixel sensors with fast column parallel read-out

NASA Astrophysics Data System (ADS)

Koziel, M.; Dorokhov, A.; Fontaine, J.-C.; De Masi, R.; Winter, M.

2010-12-01

Monolithic active pixel sensors (MAPS) [1] (Turchetta et al., 2001) are being developed at IPHC—Strasbourg to equip the EUDET telescope [2] (Haas, 2006) and vertex detectors for future high energy physics experiments, including the STAR upgrade at RHIC [3] (T.S. Collaboration, 2005) and the CBM experiment at FAIR/GSI [4] (Heuser, 2006). High granularity, low material budget and high read-out speed are systematically required for most applications, complemented, for some of them, with high radiation tolerance. A specific column-parallel architecture, implemented in the MIMOSA-22 sensor, was developed to achieve fast read-out MAPS. Previous studies of the front-end architecture integrated in this sensor, which includes in-pixel amplification, have shown that the fixed pattern noise increase consecutive to ionizing radiation can be controlled by means of a negative feedback [5] (Hu-Guo et al., 2008). However, an unexpected rise of the temporal noise was observed. A second version of this chip (MIMOSA-22bis) was produced in order to search for possible improvements of the radiation tolerance, regarding this type of noise. In this prototype, the feedback transistor was tuned in order to mitigate the sensitivity of the pixel to ionizing radiation. The performances of the pixels after irradiation were investigated for two types of feedback transistors: enclosed layout transistor (ELT) [6] (Snoeys et al., 2000) and "standard" transistor with either large or small transconductance. The noise performance of all test structures was studied in various conditions (expected in future experiments) regarding temperature, integration time and ionizing radiation dose. Test results are presented in this paper. Based on these observations, ideas for further improvement of the radiation tolerance of column parallel MAPS are derived.

Ultrareliable fault-tolerant control systems

NASA Technical Reports Server (NTRS)

Webster, L. D.; Slykhouse, R. A.; Booth, L. A., Jr.; Carson, T. M.; Davis, G. J.; Howard, J. C.

1984-01-01

It is demonstrated that fault-tolerant computer systems, such as on the Shuttles, based on redundant, independent operation are a viable alternative in fault tolerant system designs. The ultrareliable fault-tolerant control system (UFTCS) was developed and tested in laboratory simulations of an UH-1H helicopter. UFTCS includes asymptotically stable independent control elements in a parallel, cross-linked system environment. Static redundancy provides the fault tolerance. A polling is performed among the computers, with results allowing for time-delay channel variations with tight bounds. When compared with the laboratory and actual flight data for the helicopter, the probability of a fault was, for the first 10 hr of flight given a quintuple computer redundancy, found to be 1 in 290 billion. Two weeks of untended Space Station operations would experience a fault probability of 1 in 24 million. Techniques for avoiding channel divergence problems are identified.

Hypnotizability in acute stress disorder.

PubMed

Bryant, R A; Guthrie, R M; Moulds, M L

2001-04-01

This study investigated the relationship between acute dissociative reactions to trauma and hypnotizability. Acutely traumatized patients (N=61) with acute stress disorder, subclinical acute stress disorder (no dissociative symptoms), and no acute stress disorder were administered the Stanford Hypnotic Clinical Scale within 4 weeks of their trauma. Although patients with acute stress disorder and patients with subclinical acute stress disorder displayed comparable levels of nondissociative psychopathology, acute stress disorder patients had higher levels of hypnotizability and were more likely to display reversible posthypnotic amnesia than both patients with subclinical acute stress disorder and patients with no acute stress disorder. The findings may be interpreted in light of a diathesis-stress process mediating trauma-related dissociation. People who develop acute stress disorder in response to traumatic experience may have a stronger ability to experience dissociative phenomena than people who develop subclinical acute stress disorder or no acute stress disorder.

Amphetamine and pseudoephedrine cross-tolerance measured by c-Fos protein expression in brains of chronically treated rats.

PubMed

Ruksee, Nootchanart; Tongjaroenbuangam, Walaiporn; Casalotti, Stefano O; Govitrapong, Piyarat

2008-10-06

Pseudoephedrine is a drug commonly prescribed as a nasal decongestant and bronchodilator and is also freely available in cold remedies and medications. The structural and pharmacological similarity of pseudoephedrine to amphetamine has led to evaluation of its psychomotor stimulant properties within the central nervous system. Previous investigations have shown that the acute responses to pseudoephedrine were similar to those of amphetamine and other psychostimulants. This study examined the effect of chronic administration of pseudoephedrine in rat nucleus accumbens and striatum and identified three further similarities to amphetamine. (i) Chronic exposure to pseudoephedrine reduced the c-Fos response to acute pseudoephedrine treatment suggesting that pseudoephedrine induced tolerance in the animals. (ii) In animals chronically treated with amphetamine or pseudoephedrine the acute c-Fos response to pseudoephedrine and amphetamine was reduced respectively as compared to naïve animals indicating cross-tolerance for the two drugs. (iii)The known involvement of the dopamine system in the response to amphetamine and pseudoephedrine was further confirmed in this study by demonstrating that pseudoephedrine similarly to amphetamine, but with lower potency, inhibited [3H]dopamine uptake in synaptosomal preparations. This work has demonstrated further similarities of the effect of pseudoephedrine to those of amphetamine in brain areas known to be associated with drug addiction. The most significant result presented here is the cross tolerance effect of amphetamine and pseudoephedrine. This suggests that both drugs induce similar mechanisms of action in the brain. Further studies are required to establish whether despite its considerable lower potency, pseudoephedrine could pose health and addiction risks in humans similar to that of known psychostimulants.

Amphetamine and pseudoephedrine cross-tolerance measured by c-Fos protein expression in brains of chronically treated rats

PubMed Central

Ruksee, Nootchanart; Tongjaroenbuangam, Walaiporn; Casalotti, Stefano O; Govitrapong, Piyarat

2008-01-01

Background Pseudoephedrine is a drug commonly prescribed as a nasal decongestant and bronchodilator and is also freely available in cold remedies and medications. The structural and pharmacological similarity of pseudoephedrine to amphetamine has led to evaluation of its psychomotor stimulant properties within the central nervous system. Previous investigations have shown that the acute responses to pseudoephedrine were similar to those of amphetamine and other psychostimulants. Results This study examined the effect of chronic administration of pseudoephedrine in rat nucleus accumbens and striatum and identified three further similarities to amphetamine. (i) Chronic exposure to pseudoephedrine reduced the c-Fos response to acute pseudoephedrine treatment suggesting that pseudoephedrine induced tolerance in the animals. (ii) In animals chronically treated with amphetamine or pseudoephedrine the acute c-Fos response to pseudoephedrine and amphetamine was reduced respectively as compared to naïve animals indicating cross-tolerance for the two drugs. (iii)The known involvement of the dopamine system in the response to amphetamine and pseudoephedrine was further confirmed in this study by demonstrating that pseudoephedrine similarly to amphetamine, but with lower potency, inhibited [3H]dopamine uptake in synaptosomal preparations. Conclusion This work has demonstrated further similarities of the effect of pseudoephedrine to those of amphetamine in brain areas known to be associated with drug addiction. The most significant result presented here is the cross tolerance effect of amphetamine and psudoephedrine. This suggests that both drugs induce similar mechanisms of action in the brain. Further studies are required to establish whether despite its considerable lower potency, pseudoephedrine could pose health and addiction risks in humans similar to that of known psychostimulants. PMID:18834549

High sustained +Gz acceleration: physiological adaptation to high-G tolerance

NASA Technical Reports Server (NTRS)

Convertino, V. A.

1998-01-01

Since the early 1940s, a significant volume of research has been conducted in an effort to describe the impact of acute exposures to high-G acceleration on cardiovascular mechanisms responsible to maintaining cerebral perfusion and conscious in high performance aircraft pilots during aerial combat maneuvers. The value of understanding hemodynamic characteristics that underlie G-induced loss of consciousness has been instrumental in the evolution of optimal technology development (e.g., G-suits, positive pressure breathing, COMBAT EDGE, etc.) and pilot training (e.g., anti-G straining maneuvers). Although the emphasis of research has been placed on the development of protection against acute high +Gz acceleration effects, recent observations suggest that adaptation of cardiovascular mechanism associated with blood pressure regulation may contribute to a protective 'G-training' effect. Regular training at high G enhances G tolerance in humans, rats, guinea pigs, and dogs while prolonged layoff from exposure in high G profiles (G-layoff) can result in reduced G endurance. It seems probable that adaptations in physiological functions following chronically-repeated high G exposure (G training) or G-layoff could have significant impacts on performance during sustained high-G acceleration since protective technology such as G-suits and anit-G straining maneuvers are applied consistently during these periods of training. The purpose of this paper is to present a review of new data from three experiments that support the notion that repeated exposure on a regular basis to high sustained +Gz acceleration induces significant physiological adaptations which are associated with improved blood pressure regulation and subsequent protection of cerebral perfusion during orthostatic challenges.

Acute Bacterial Prostatitis: Diagnosis and Management.

PubMed

Coker, Timothy J; Dierfeldt, Daniel M

2016-01-15

Acute bacterial prostatitis is an acute infection of the prostate gland that causes pelvic pain and urinary tract symptoms, such as dysuria, urinary frequency, and urinary retention, and may lead to systemic symptoms, such as fevers, chills, nausea, emesis, and malaise. Although the true incidence is unknown, acute bacterial prostatitis is estimated to comprise approximately 10% of all cases of prostatitis. Most acute bacterial prostatitis infections are community acquired, but some occur after transurethral manipulation procedures, such as urethral catheterization and cystoscopy, or after transrectal prostate biopsy. The physical examination should include abdominal, genital, and digital rectal examination to assess for a tender, enlarged, or boggy prostate. Diagnosis is predominantly made based on history and physical examination, but may be aided by urinalysis. Urine cultures should be obtained in all patients who are suspected of having acute bacterial prostatitis to determine the responsible bacteria and its antibiotic sensitivity pattern. Additional laboratory studies can be obtained based on risk factors and severity of illness. Radiography is typically unnecessary. Most patients can be treated as outpatients with oral antibiotics and supportive measures. Hospitalization and broad-spectrum intravenous antibiotics should be considered in patients who are systemically ill, unable to voluntarily urinate, unable to tolerate oral intake, or have risk factors for antibiotic resistance. Typical antibiotic regimens include ceftriaxone and doxycycline, ciprofloxacin, and piperacillin/tazobactam. The risk of nosocomial bacterial prostatitis can be reduced by using antibiotics, such as ciprofloxacin, before transrectal prostate biopsy.

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão’s legacy

PubMed Central

Shuttleworth, C William; Kirov, Sergei A; Ayata, Cenk; Hinzman, Jason M; Foreman, Brandon; Andrew, R David; Boutelle, Martyn G; Brennan, KC; 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. PMID:27328690

The effects of smoking and nicotine ingestion on exercise heat tolerance.

PubMed

Druyan, Amit; Atias, Danit; Ketko, Itay; Cohen-Sivan, Yoav; Heled, Yuval

2017-03-01

Smoking has a thermogenic effect and is associated with low physical performance. Nevertheless, a direct, quantitative effect of acute smoking on exercise heat tolerance has not been reported. Sixteen healthy young male volunteers, eight cigarette smokers, and eight non-smokers participated in the study. All subjects performed a maximal oxygen consumption test (VO2max) and a standardized heat tolerance test (HTT) after at least 12 h without smoking under the following conditions: no nicotine exposure, 10 min after nicotine exposure (2 mg nicotine lozenge), and 10 min after smoking two cigarettes (0.8 mg nicotine in each cigarette, smokers only). There was no significant effect of nicotine exposure on physiological performance and heat tolerance in the non-smokers group. In the smokers group, cigarette smoking, but not nicotine ingestion, resulted with higher heart rate (by 9±9 bpm) at the end of the HTT (p<0.05). Moreover, both smoking and nicotine ingestion increased smokers' rectal temperature at the end of the HTT (by 0.24±0.16°C and 0.21±0.26°C, respectively, p<0.05) and were associated with higher sweat rate during the HTT (by 0.08±0.07 g/h and 0.06±0.08 g/h, respectively, p<0.05). Heart rate variability (HRV) analysis also revealed a higher LF/HF (low frequency/high frequency) ratio after exposure to nicotine and smoking in the smokers group compared with no exposure (2.13±2.57 and 2.48±2.76, respectively, p<0.05), indicating a higher sympathetic tone. According to this preliminary study, cigarette smoking and nicotine ingestion increase the physiological strain during a HTT in smokers. Acute smoking may, therefore, increase heat intolerance and the risk to heat injuries.

Evaluation of Factors Affecting Acute Postoperative Pain Levels After Arthroscopic Rotator Cuff Repair.

PubMed

Cuff, Derek J; O'Brien, Kathleen C; Pupello, Derek R; Santoni, Brandon G

2016-07-01

To evaluate multiple preoperative and operative factors that may be predictive of and correlate with acute postoperative pain levels after arthroscopic rotator cuff repair. One hundred eighty-one patients underwent arthroscopic rotator cuff surgery along with subacromial decompression and met the inclusion criteria for this study. Postoperative visual analog scale (VAS) scores were obtained on postoperative days 1, 7, and 90. Multivariate linear regression analysis was used to correlate postoperative VAS scores with multiple independent factors, including preoperative subjective pain tolerance, preoperative VAS score, preoperative narcotic use, sex, smoking status, number of suture anchors used, tear size, single- or double-row repair, and patient age. Preoperative subjective pain tolerance, notably those patients rating themselves as having an extremely high pain tolerance, was the most significant predictor of high VAS pain scores on both postoperative day 1 (P = .0001) and postoperative day 7 (P < .0001). Preoperative narcotic use was also significantly predictive (P = .010) of high pain scores on postoperative day 1 and day 7 (P = .019), along with nonsmokers (P = .008) and younger patients (P = .006) being predictive on day 7. There were no patient factors that were predictive of VAS scores 3 months postoperatively (P = .567). Preoperative subjective pain tolerance, notably those patients rating themselves as having an extremely high pain tolerance, was the strongest factor predicting high acute pain levels after arthroscopic rotator cuff surgery. Preoperative narcotic use, smokers, and younger patients were also predictive of higher pain levels during the first postoperative week. Level IV, prognostic case series. Copyright © 2016 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Breaking immunological tolerance through OX40 (CD134).

PubMed

Bansal-Pakala, P; Croft, M

2001-11-06

Immunological tolerance represents a mechanism by which cells of the host remain protected from the immune system. Breaking of immunological tolerance can result in a variety of autoimmune diseases such as rheumatoid arthritis, diabetes, and multiple sclerosis. The reasons for tolerance breaking down and autoimmune processes arising are largely unknown but of obvious interest for therapeutic intervention of these diseases. Although reversal of the tolerant state is generally unwanted, there are instances where this may be of benefit to the host. In particular, one way a cancerous cell escapes being targeted by the immune system is through tolerance mechanisms that in effect turn off the reactivity of T lymphocytes that can respond to tumor-associated peptides. Thus tolerance represents a major obstacle in developing effective immunotherapy against tumors. The molecules that are involved in regulating immunological tolerance are then of interest as they may be great targets for positively or negatively manipulating the tolerance process.

Effect of acute and chronic administration of caffeine on pain-like behaviors in rats with partial sciatic nerve injury.

PubMed

Wu, Wei-Ping; Hao, Jing-Xia; Fredholm, Bertil B; Wiesenfeld-Hallin, Zsuzsanna; Xu, Xiao-Jun

2006-07-10

Caffeine, used in many pain medications as an adjuvant analgesic, is an adenosine A1 and A2A receptor antagonist. Here we examined the effects of acute or chronic caffeine administration in rats after partial sciatic nerve injury. The hindpaw response to mechanical or cold stimulation was assessed following photochemically induced sciatic nerve injury which leads to hypersensitivity to these stimuli. Caffeine was administered i.p. acutely or in the drinking water chronically. The mechanical and cold hypersensitivity of sciatic nerve-injured rats was dose-dependently alleviated by acute systemic administration of caffeine (10-80 mg/kg). The effect of caffeine was, however, associated with side effects including locomotor stimulation or depression. Chronic oral administration (average daily doses 27.5 mg/kg/day or 61.5 mg/kg/day for 2 weeks) of caffeine starting at the time of nerve injury did not significantly affect the development of pain-like behaviors. Thus, acute, but not long term, caffeine intake reduced neuropathic pain state in nerve-injured rats, but only at very high doses. The potential hyperalgesic effect of chronic A1 adenosine receptor blockade may have been compensated for by an antinociceptive effect of caffeine through antagonism of A2A receptors and tolerance development.

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.

Traumeel – an emerging option to nonsteroidal anti-inflammatory drugs in the management of acute musculoskeletal injuries

PubMed Central

Schneider, Christian

2011-01-01

Musculoskeletal injuries are on the rise. First-line management of such injuries usually employs the RICE (rest, ice, compression, and elevation) approach to limit excessive inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also commonly used to limit inflammation and to control pain. Traumeel®, a preparation with bioregulatory effects is also used to treat the symptoms associated with acute musculoskeletal injuries, including pain and swelling. Traumeel is a fixed combination of biological and mineral extracts, which aims to apply stimuli to multiple targets to restore normal functioning of regulatory mechanisms. This paper presents the accumulating evidence of Traumeel’s action on the inflammatory process, and of its efficacy and tolerability in randomized trials, as well as observational and surveillance studies for the treatment of musculoskeletal injuries. Traumeel has shown comparable effectiveness to NSAIDs in terms of reducing symptoms of inflammation, accelerating recovery, and improving mobility, with a favorable safety profile. While continued research and development is ongoing to broaden the clinical evidence of Traumeel in acute musculoskeletal injury and to further establish its benefits, current information suggests that Traumeel may be considered as an anti-inflammatory agent that is at least as effective and appears to be better tolerated than NSAIDs. PMID:21556350

Tennis Training Sessions as a Rehabilitation Instrument for Patients after Acute Myocardial Infarction

PubMed Central

García, Juan P. F.; Giraldo, Víctor M. A.; Barrado, José J. G.; Casasola, César D.

2013-01-01

The aims of this study were to measure the effects of a cardiac rehabilitation program based on a modification of a sport (tennis) on quality of life, on various laboratory test parameters and on an exercise stress test, and to determine if the results of this novel activity are equivalent to those of traditional programs (i.e., the use of the bicycle ergometer). The sample consisted of 79 patients with a low-risk acute coronary syndrome. They were divided into three groups: two experimental groups and one control group. One of the experimental groups used the bicycle ergometer as its main physical activity, whereas the other received training in a modified form of tennis lesson. By the end of the 3-month program, triglycerides, cholesterol LDL, cholesterol HDL, (-25 mg·dl-1 and 32.3 mg·dl-1 final, and 15.7 mg·dl-1 and 23.3 mg·dl-1 LDL final, respectively) and exercise capacity improved significantly (by 1.1 metabolic equivalents (METs) and 1.2 METs, respectively), in both experimental groups. We conclude that the application of a comprehensive cardiac rehabilitation program in patients with low-risk acute coronary syndrome based on a program of modified tennis improves exercise tolerance and metabolic parameters, as well as certain physical characteristics that reduce cardiovascular risk. Key Points Cardiac rehabilitation of low risk patients with acute coronary syndrome based on a program of modified tennis produces an improvement in quality of life, lipid profiles and in exercise tolerance A cardiac rehabilitation program based on a modification of tennis produces favourable changes in various anthropometric parameters related to the reduction of cardiovascular risk The development of programs of cardiac rehabilitation based on modified versions of various sports would advantage the adherence to physical exercise. PMID:24149811

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.

[From acute victimization at chronic victimization: socio-cognitive approach of differential tolerance threshold].

PubMed

Forte, M; Przygodzki-Lionet, N; Masclet, G

2006-01-01

on a logic-semantic frequency dimension of speech, obtained a simplified representation of the whole of the data. This first level of analysis, supplemented by descriptive statistics, validated, in the second stage, the significance of the differences in the semantic categories. In the third stage, an "analysis of adjacency" associated with a factorial analysis of the correspondences, delineated the differentiating values of the three groups of subjects. A final stage of analysis, centred on a multiaxial dimension [DSM IV ], permitted the constitution of clinical pictures. In accordance with the general assumption, the results show that the victims reveal a dominating presence of mobbing signs related to depression and anxiety symptomatology with an acute emotional threshold. Hold-up victims also show undoubted but significantly less harmful consequences. These victims have turned out to be more centred on the anxious pole and the social and family fields. Moreover, while the victims of harassment unanimously evoke the emergence of a break-up in dynamics conveying a freeze of the social matrix, some of the victims of armed attacks express "secondary benefits" through the setting-up of gregarious dynamics on professional as well as on family level. Considering these results, there seems to be a double induction of such a difference. The social evaluation tends to be a first explanatory inference as for the expressed tolerance level. As a matter of fact, the frequential analysis reveals a different perception of the attacker. The supernumerary evocation of dispositional factors, supposing a personal motivation marked with intrigues concealed behind an apparent legitimacy, draws a very personological profile of the harasser. This majority of intrinsic determinants reveals an increase in the causal weight of the harasser; at the same time, it disregards the possible influence of extrinsic factors. In that respect, the harasser is seen as the only instigator of the

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

Endomorphin-2 analogs with C-terminal esterification produce potent systemic antinociception with reduced tolerance and gastrointestinal side effects.

PubMed

Wang, Chang-Lin; Qiu, Ting-Ting; Yang, Dai-Jun; Yuan, Bi-Yu; Han, Feng-Tong; Li, Li; Gu, Ning

2017-04-01

C-terminal esterification of opioid peptides may change their opioid activities due to the modified physicochemical properties. In the present study, the pharmacological activities of C-terminal esterified endomorphin-2 (EM-2) analogs 1-3 were characterized by in vitro metabolic stability and octanol/buffer distribution assays. Also, the antinociceptive profiles in the radiant heat paw withdrawal test and related side effects of these analogs were determined. Our results showed that all three analogs significantly increased the metabolic stability and lipophilicity. Moreover, analogs 1-3 displayed potent antinociceptive activities after intracerebroventricular (i.c.v.) administration. Analogs 1 and 3 exhibited about 2-fold higher antinociception than EM-2, and differential opioid mechanisms were involved. In addition, EM-2 at 50 μmol/kg failed to produce any significant antinociceptive activity after subcutaneous (s.c.) administration, whereas equimolar dose of analogs 1-3 produced significant analgesic effects. Analog 3 showed the highest antinociceptive activity after systemic administration, which was consistent with its in vitro stability and lipophilicity. We further evaluated the antinociceptive tolerance of analogs 1-3. In acute tolerance test, analogs 1-3 shifted the dose-response curves rightward by only 1.4-3.2 fold as determined by tolerance ratio, whereas EM-2 by 5.6-fold, demonstrating reduced antinociceptive tolerance. Also, analogs 1 and 2 decreased chronic antinociceptive tolerance by central and peripheral administration of drugs. In particular, analogs 3 displayed insignificant chronic antinociceptive tolerance. Furthermore, analogs 1-3 were less prone to induce gastrointestinal side effects at analgesic doses. The present investigation gave the evidence that C-terminal esterified modifications of EM-2 will facilitate the development of novel opioid analgesics with reduced side effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

Acute Sinusitis

MedlinePlus

... headache. Acute sinusitis is mostly caused by the common cold. Unless a bacterial infection develops, most cases resolve ... Acute sinusitis is most often caused by the common cold, which is a viral infection. In some cases, ...

Imputing Risk Tolerance From Survey Responses

PubMed Central

Kimball, Miles S.; Sahm, Claudia R.; Shapiro, Matthew D.

2010-01-01

Economic theory assigns a central role to risk preferences. This article develops a measure of relative risk tolerance using responses to hypothetical income gambles in the Health and Retirement Study. In contrast to most survey measures that produce an ordinal metric, this article shows how to construct a cardinal proxy for the risk tolerance of each survey respondent. The article also shows how to account for measurement error in estimating this proxy and how to obtain consistent regression estimates despite the measurement error. The risk tolerance proxy is shown to explain differences in asset allocation across households. PMID:20407599

A role for haemolymph oxygen capacity in heat tolerance of eurythermal crabs

PubMed Central

Giomi, Folco; Pörtner, Hans-Otto

2013-01-01

Heat tolerance in aquatic ectotherms is constrained by a mismatch, occurring at high temperatures, between oxygen delivery and demand which compromises the maintenance of aerobic scope. The present study analyses how the wide thermal tolerance range of an eurythermal model species, the green crab Carcinus maenas is supported and limited by its ability to sustain efficient oxygen transport to tissues. Similar to other eurytherms, C. maenas sustains naturally occurring acute warming events through the integrated response of circulatory and respiratory systems. The response of C. maenas to warming can be characterized by two phases. During initial warming, oxygen consumption and heart rate increase, while stroke volume and haemolymph oxygen partial pressure decrease. During further warming, dissolved oxygen levels in the venous compartment decrease below the threshold of full haemocyanin oxygen saturation. The progressive release of haemocyanin bound oxygen with further warming follows an exponential pattern, thereby saving energy in oxygen transport and causing an associated leveling off of metabolic rate. According to the concept of oxygen and capacity limited thermal tolerance (OCLTT), this indicates that the thermal tolerance window is widened by the increasing contribution of haemocyanin oxygen transport and associated energy savings in cardiocirculation. Haemocyanin bound oxygen sustains cardiac performance to cover the temperature range experienced by C. maenas in the field. To our knowledge this is the first study providing evidence of a relationship between thermal tolerance and blood (haemolymph) oxygen transport in a eurythermal invertebrate. PMID:23720633

A role for haemolymph oxygen capacity in heat tolerance of eurythermal crabs.

PubMed

Giomi, Folco; Pörtner, Hans-Otto

2013-01-01

Heat tolerance in aquatic ectotherms is constrained by a mismatch, occurring at high temperatures, between oxygen delivery and demand which compromises the maintenance of aerobic scope. The present study analyses how the wide thermal tolerance range of an eurythermal model species, the green crab Carcinus maenas is supported and limited by its ability to sustain efficient oxygen transport to tissues. Similar to other eurytherms, C. maenas sustains naturally occurring acute warming events through the integrated response of circulatory and respiratory systems. The response of C. maenas to warming can be characterized by two phases. During initial warming, oxygen consumption and heart rate increase, while stroke volume and haemolymph oxygen partial pressure decrease. During further warming, dissolved oxygen levels in the venous compartment decrease below the threshold of full haemocyanin oxygen saturation. The progressive release of haemocyanin bound oxygen with further warming follows an exponential pattern, thereby saving energy in oxygen transport and causing an associated leveling off of metabolic rate. According to the concept of oxygen and capacity limited thermal tolerance (OCLTT), this indicates that the thermal tolerance window is widened by the increasing contribution of haemocyanin oxygen transport and associated energy savings in cardiocirculation. Haemocyanin bound oxygen sustains cardiac performance to cover the temperature range experienced by C. maenas in the field. To our knowledge this is the first study providing evidence of a relationship between thermal tolerance and blood (haemolymph) oxygen transport in a eurythermal invertebrate.

Comparative Investigation of Copper Tolerance and Identification of Putative Tolerance Related Genes in Tardigrades.

PubMed

Hygum, Thomas L; Fobian, Dannie; Kamilari, Maria; Jørgensen, Aslak; Schiøtt, Morten; Grosell, Martin; Møbjerg, Nadja

2017-01-01

express well-known key osmoregulatory enzymes, supporting the hypothesis that copper inhibits sodium turnover as demonstrated for other aquatic organisms. Tardigrades, nevertheless, have high tolerance toward the toxicant, which is likely linked to high expression of antioxidant enzymes and an ability to enter dormant states. Tardigrades, furthermore, seem to have a well-developed battery of cuproproteins involved in copper homeostasis, providing basis for active copper sequestering and excretion.

A multicenter, open-label, long-term safety and tolerability study of DFN-02, an intranasal spray of sumatriptan 10 mg plus permeation enhancer DDM, for the acute treatment of episodic migraine.

PubMed

Munjal, Sagar; Brand-Schieber, Elimor; Allenby, Kent; Spierings, Egilius L H; Cady, Roger K; Rapoport, Alan M

2017-12-01

DFN-02 is a novel intranasal spray formulation composed of sumatriptan 10 mg and a permeation-enhancing excipient comprised of 0.2% 1-O-n-Dodecyl-β-D-Maltopyranoside (DDM). This composition of DFN-02 allows sumatriptan to be rapidly absorbed into the systemic circulation and exhibit pharmacokinetics comparable to subcutaneously administered sumatriptan. Rapid rate of absorption is suggested to be important for optimal efficacy. The objective of this study was to evaluate the safety and tolerability of DFN-02 (10 mg) in the acute treatment of episodic migraine with and without aura over a 6-month period based on the incidence of treatment-emergent adverse events and the evaluation of results of clinical laboratory tests, vital signs, physical examination, and electrocardiograms. This was a multi-center, open-label, repeat-dose safety study in adults with episodic migraine with and without aura. Subjects diagnosed with migraine with or without aura according to the criteria set forth in the International Classification of Headache Disorders, 2nd edition, who experienced 2 to 6 attacks per month with fewer than 15 headache days per month and at least 48 headache-free hours between attacks, used DFN-02 to treat their migraine attacks acutely over the course of 6 months. A total of 173 subjects was enrolled, 167 (96.5%) subjects used at least 1 dose of study medication and were evaluable for safety, and 134 (77.5%) subjects completed the 6-month study. A total of 2211 migraine attacks was reported, and 3292 doses of DFN-02 were administered; mean per subject monthly use of DFN-02 was 3.6 doses. Adverse events were those expected for triptans, as well as for nasally administered compounds. No new safety signals emerged. Dysgeusia and application site pain were the most commonly reported treatment-emergent adverse events over 6 months (21% and 30.5%, respectively). Most of the treatment-emergent adverse events were mild. There were 5 serious adverse events, all

Profile, risk factors and outcome of acute kidney injury in paediatric acute-on-chronic liver failure.

PubMed

Lal, Bikrant B; Alam, Seema; Sood, Vikrant; Rawat, Dinesh; Khanna, Rajeev

2018-01-11

There are no studies on acute kidney injury in paediatric acute-on-chronic liver failure. This study was planned with aim to describe the clinical presentation and outcome of acute kidney injury among paediatric acute-on-chronic liver failure patients. Data of all children 1-18 years of age presenting with acute chronic liver failure (Asia pacific association for the study of the liver definition) was reviewed. Acute kidney injury was defined as per Kidney Diseases-Improving Global Outcomes guidelines. Poor outcome was defined as death or need for liver transplant within 3 months of development of acute kidney injury. A total of 84 children with acute-on-chronic liver failure were presented to us in the study period. Acute kidney injury developed in 22.6% of patients with acute-on-chronic liver failure. The median duration from acute-on-chronic liver failure to development of acute kidney injury was 4 weeks (Range: 2-10 weeks). The causes of acute kidney injury were hepatorenal syndrome (31.6%), sepsis (31.6%), nephrotoxic drugs (21%), dehydration (10.5%) and bile pigment related acute tubular necrosis in one patient. On univariate analysis, higher baseline bilirubin, higher international normalized ratio, higher paediatric end stage liver disease, presence of systemic inflammatory response syndrome and presence of spontaneous bacterial peritonitis had significant association with presence of acute kidney injury. On logistic regression analysis, presence of systemic inflammatory response syndrome (adjusted OR: 8.659, 95% CI: 2.18-34.37, P = .002) and higher baseline bilirubin (adjusted OR: 1.07, 95% CI: 1.008-1.135, P = .025) were independently associated with presence of acute kidney injury. Of the patients with acute kidney injury, 5(26.3%) survived with native liver, 10(52.6%) died and 4 (21.1%) underwent liver transplantation. Acute kidney injury developed in 22.6% of children with acute-on-chronic liver failure. Bilirubin more than 17.7 mg/dL and

A second generation experiment in fault-tolerant software

NASA Technical Reports Server (NTRS)

Knight, J. C.

1986-01-01

The primary goal was to determine whether the application of fault tolerance to software increases its reliability if the cost of production is the same as for an equivalent nonfault tolerance version derived from the same requirements specification. Software development protocols are discussed. The feasibility of adapting to software design fault tolerance the technique of N-fold Modular Redundancy with majority voting was studied.

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.

High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy.

PubMed

Depositario-Cabacar, Dewi T; Peters, Jurriaan M; Pong, Amanda W; Roth, Julie; Rotenberg, Alexander; Riviello, James J; Takeoka, Masanori

2010-07-01

We review our experience with high-dose intravenous levetiracetam (IV-LEV) for acute seizure exacerbations in nine children with medically intractable epilepsy. All children had acute repetitive seizures-while on chronic antiepileptic drugs-that either led to hospitalization (eight) or occurred during hospitalization (one), and received doses of IV-LEV of 150 mg/kg/day or greater, with a mean dose of 228 +/- 48 mg/kg/day. Eight of nine children had resolution of the acute repetitive seizures. Seizure frequency was reduced to less than baseline in seven children (seizure-free in two, >/=80% reduction in four, and 50% reduction in one). Except for one child with increased seizures, IV-LEV was well tolerated in all children without complications.

Genomic-assisted haplotype analysis and the development of high-throughput SNP markers for salinity tolerance in soybean

PubMed Central

Patil, Gunvant; Do, Tuyen; Vuong, Tri D.; Valliyodan, Babu; Lee, Jeong-Dong; Chaudhary, Juhi; Shannon, J. Grover; Nguyen, Henry T.

2016-01-01

Soil salinity is a limiting factor of crop yield. The soybean is sensitive to soil salinity, and a dominant gene, Glyma03g32900 is primarily responsible for salt-tolerance. The identification of high throughput and robust markers as well as the deployment of salt-tolerant cultivars are effective approaches to minimize yield loss under saline conditions. We utilized high quality (15x) whole-genome resequencing (WGRS) on 106 diverse soybean lines and identified three major structural variants and allelic variation in the promoter and genic regions of the GmCHX1 gene. The discovery of single nucleotide polymorphisms (SNPs) associated with structural variants facilitated the design of six KASPar assays. Additionally, haplotype analysis and pedigree tracking of 93 U.S. ancestral lines were performed using publically available WGRS datasets. Identified SNP markers were validated, and a strong correlation was observed between the genotype and salt treatment phenotype (leaf scorch, chlorophyll content and Na+ accumulation) using a panel of 104 soybean lines and, an interspecific bi-parental population (F8) from PI483463 x Hutcheson. These markers precisely identified salt-tolerant/sensitive genotypes (>91%), and different structural-variants (>98%). These SNP assays, supported by accurate phenotyping, haplotype analyses and pedigree tracking information, will accelerate marker-assisted selection programs to enhance the development of salt-tolerant soybean cultivars. PMID:26781337

Development of DArT-based PCR markers for selecting drought-tolerant spring barley.

PubMed

Fiust, Anna; Rapacz, Marcin; Wójcik-Jagła, Magdalena; Tyrka, Mirosław

2015-08-01

The tolerance of spring barley (Hordeum vulgare L.) cultivars to spring drought is an important agronomic trait affecting crop yield and quality in Poland. Therefore, breeders require new molecular markers to select plants with lower spring drought susceptibility. With the advent of genomic selection technology, simple molecular tools may still be applicable to screen material for markers of the most important traits and in-depth genome scanning. In previous studies, diversity arrays technology (DArT)-based genetic maps were constructed for F2 populations of Polish fodder and malt barley elite breeding lines, and 15 and 18 quantitative trait loci (QTLs) related to spring drought tolerance were identified, respectively. In this paper, we show the results of a conversion of 30 DArT markers corresponding to 11 QTLs into simple sequence repeat (SSR) and sequence tagged site (STS) markers. Twenty-two polymorphic markers were obtained, including 13 DArT-based SSRs. Additionally, 31 SSR markers, located in close proximity to the DArT markers, were selected from the GrainGenes database and tested. Further analyses of 24 advanced breeding lines with different drought tolerances confirmed that five out of the 30 converted markers, as well as three out of the 31 additional SSR markers, were effective in marker-assisted selection for drought tolerance. The possible function of clones related to these markers in drought tolerance is discussed.

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.

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia

PubMed Central

Cortes, Jorge; Talpaz, Moshe; Smith, Hedy P.; Snyder, David S.; Khoury, Jean; Bhalla, Kapil N.; Pinilla-Ibarz, Javier; Larson, Richard; Mitchell, David; Wise, Scott C.; Rutkoski, Thomas J.; Smith, Bryan D.; Flynn, Daniel L.; Kantarjian, Hagop M.; Rosen, Oliver; Van Etten, Richard A.

2017-01-01

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5′-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138). PMID:27927766

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.

PubMed

Cortes, Jorge; Talpaz, Moshe; Smith, Hedy P; Snyder, David S; Khoury, Jean; Bhalla, Kapil N; Pinilla-Ibarz, Javier; Larson, Richard; Mitchell, David; Wise, Scott C; Rutkoski, Thomas J; Smith, Bryan D; Flynn, Daniel L; Kantarjian, Hagop M; Rosen, Oliver; Van Etten, Richard A

2017-03-01

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib ( clinicaltrials.gov Identifier:00827138 ). Copyright© Ferrata Storti Foundation.

Variable tolerance to copper in two species from San Francisco Bay

USGS Publications Warehouse

Luoma, S.N.; Cain, D.J.; Ho, K.; Hutchinson, A.

1983-01-01

In static toxicity experiments, tolerance to soluble Cu of the bivalve, Macoma balthica, and the copepod, Acartia clausi, varied substantially among populations sampled within San Francisco Bay. Intraspecific tolerance differed ten-fold or more for both species over relatively small distances, suggesting geographical isolation of populations is not a prerequisite for the development of intraspecific differences in tolerance by aquatic organisms.In static toxicity experiments, tolerance to soluble Cu of the bivalve, Macoma balthica, and the copepod, Acartia clausi, varied substantially among populations sampled within San Francisco Bay. Intraspecific tolerance differed ten-fold or more for both species over relatively small distances, suggesting geographical isolation of populations is not a prerequisite for the development of intraspecific differences in tolerance by aquatic organisms. Refs.

Tolerance and dose-volume relationship of intrathoracic stomach irradiation after esophagectomy for patients with thoracic esophageal squamous cell carcinoma

PubMed Central

Fu, Xiao-Long; Chen, Jun-Chao; Xiang, Jia-Qing

2015-01-01

Purpose To identify the tolerance of radiation with a high prescribed dose and predictors for the development of intrathoracic stomach toxicity in patients with thoracic esophageal squamous cell carcinoma (SCC) after esophagectomy followed by gastric conduit reconstruction. Methods and Materials From 2011 to 2013, 105 patients after esophagectomy were treated with postoperative radiotherapy. The intrathoracic stomach was outlined with the calculation of a dose-volume histogram (DVH) for the initial intended treatment of 6020 cGy or 6300 cGy. The volume of the intrathoracic stomach receiving each dose was recorded at 10-Gy intervals between 10 and 40 Gy and at 5-Gy intervals between 40 and 60 Gy. The grade of toxicities was defined by the National Cancer Institute Common Toxicity Criteria version 4.0. Results The mean and maximum doses of the intrathoracic stomach were 2449 ± 986 cGy and 6519 ± 406 cGy, respectively. Sixteen (15.2%) and three (2.9%) experienced Common Toxicity Criteria Grade 2 and Grade 3 acute gastric toxicity. There were no Grade 4 toxicities. Fourteen patients (13.3%) exhibited late gastric complications possibly related to radiation. The volume percent of the intrathoracic stomach receiving at least 50 Gy (V50) was strongly associated with the degree of toxicity (p = 0.024, respectively). Multivariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicities. Conclusions The intrathoracic stomach is well tolerated with a high-dose irradiation for patients with esophageal SCC receiving radiotherapy after esophagectomy. A strong dose-volume relationship exists for the development of Grade 2 acute intrathoracic stomach toxicity in our study. PMID:26314958

Roles of Soybean Plasma Membrane Intrinsic Protein GmPIP2;9 in Drought Tolerance and Seed Development.

PubMed

Lu, Linghong; Dong, Changhe; Liu, Ruifang; Zhou, Bin; Wang, Chuang; Shou, Huixia

2018-01-01

Aquaporins play an essential role in water uptake and transport in vascular plants. The soybean genome contains a total of 22 plasma membrane intrinsic protein (PIP) genes. To identify candidate PIPs important for soybean yield and stress tolerance, we studied the transcript levels of all 22 soybean PIPs. We found that a GmPIP2 subfamily member, GmPIP2;9, was predominately expressed in roots and developing seeds. Here, we show that GmPIP2;9 localized to the plasma membrane and had high water channel activity when expressed in Xenopus oocytes. Using transgenic soybean plants expressing a native GmPIP2;9 promoter driving a GUS-reporter gene, it was found high GUS expression in the roots, in particular, in the endoderm, pericycle, and vascular tissues of the roots of transgenic plants. In addition, GmPIP2;9 was also highly expressed in developing pods. GmPIP2;9 expression significantly increased in short term of polyethylene glycol (PEG)-mediated drought stress treatment. GmPIP2;9 overexpression increased tolerance to drought stress in both solution cultures and soil plots. Drought stress in combination with GmPIP2;9 overexpression increased net CO 2 assimilation of photosynthesis, stomata conductance, and transpiration rate, suggesting that GmPIP2;9- overexpressing transgenic plants were less stressed than wild-type (WT) plants. Furthermore, field experiments showed that GmPIP2;9 -overexpressing plants had significantly more pod numbers and larger seed sizes than WT plants. In summary, the study demonstrated that GmPIP2;9 has water transport activity. Its relative high expression levels in roots and developing pods are in agreement with the phenotypes of GmPIP2;9 -overexpressing plants in drought stress tolerance and seed development.

Roles of Soybean Plasma Membrane Intrinsic Protein GmPIP2;9 in Drought Tolerance and Seed Development

PubMed Central

Lu, Linghong; Dong, Changhe; Liu, Ruifang; Zhou, Bin; Wang, Chuang; Shou, Huixia

2018-01-01

Aquaporins play an essential role in water uptake and transport in vascular plants. The soybean genome contains a total of 22 plasma membrane intrinsic protein (PIP) genes. To identify candidate PIPs important for soybean yield and stress tolerance, we studied the transcript levels of all 22 soybean PIPs. We found that a GmPIP2 subfamily member, GmPIP2;9, was predominately expressed in roots and developing seeds. Here, we show that GmPIP2;9 localized to the plasma membrane and had high water channel activity when expressed in Xenopus oocytes. Using transgenic soybean plants expressing a native GmPIP2;9 promoter driving a GUS-reporter gene, it was found high GUS expression in the roots, in particular, in the endoderm, pericycle, and vascular tissues of the roots of transgenic plants. In addition, GmPIP2;9 was also highly expressed in developing pods. GmPIP2;9 expression significantly increased in short term of polyethylene glycol (PEG)-mediated drought stress treatment. GmPIP2;9 overexpression increased tolerance to drought stress in both solution cultures and soil plots. Drought stress in combination with GmPIP2;9 overexpression increased net CO2 assimilation of photosynthesis, stomata conductance, and transpiration rate, suggesting that GmPIP2;9-overexpressing transgenic plants were less stressed than wild-type (WT) plants. Furthermore, field experiments showed that GmPIP2;9-overexpressing plants had significantly more pod numbers and larger seed sizes than WT plants. In summary, the study demonstrated that GmPIP2;9 has water transport activity. Its relative high expression levels in roots and developing pods are in agreement with the phenotypes of GmPIP2;9-overexpressing plants in drought stress tolerance and seed development. PMID:29755491

Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult.

PubMed

Moreira-Gonçalves, Daniel; Henriques-Coelho, Tiago; Fonseca, Hélder; Ferreira, Rita; Padrão, Ana Isabel; Santa, Cátia; Vieira, Sara; Silva, Ana Filipa; Amado, Francisco; Leite-Moreira, Adelino; Duarte, José Alberto

2015-09-01

The present study aimed to test whether a chronic intermittent workload could induce an adaptive cardiac phenotype Chronic intermittent workload induced features of adaptive hypertrophy This was paralleled by protection against acute pressure overload insult The heart may adapt favourably to balanced demands, regardless of the nature of the stimuli. The present study aimed to test whether submitting the healthy heart to intermittent and tolerable amounts of workload, independently of its nature, could result in an adaptive cardiac phenotype. Male Wistar rats were subjected to treadmill running (Ex) (n = 20), intermittent cardiac overload with dobutamine (ITO) (2 mg kg(-1) , s.c.; n = 20) or placebo administration (Cont) (n = 20) for 5 days week(-1) for 8 weeks. Animals were then killed for histological and biochemical analysis or subjected to left ventricular haemodynamic evaluation under baseline conditions, in response to isovolumetric contractions and to sustained LV acute pressure overload (35% increase in peak systolic pressure maintained for 2 h). Baseline cardiac function was enhanced only in Ex, whereas the response to isovolumetric heartbeats was improved in both ITO and Ex. By contrast to the Cont group, in which rats developed diastolic dysfunction with sustained acute pressure overload, ITO and Ex showed increased tolerance to this stress test. Both ITO and Ex developed cardiomyocyte hypertrophy without fibrosis, no overexpression of osteopontin-1 or β-myosin heavy chain, and increased expression of sarcoplasmic reticulum Ca(2+) protein. Regarding hypertrophic pathways, ITO and Ex showed activation of the protein kinase B/mammalian target of rapamycin pathway but not calcineurin. Mitochondrial complex IV and V activities were also increased in ITO and Ex. Chronic submission to controlled intermittent cardiac overload, independently of its nature, results in an adaptive cardiac phenotype. Features of the cardiac overload, such as the duration and

Dosakaya Juice Assuages Development of Sucrose Induced Impaired Glucose Tolerance and Imbalance in Antioxidant Defense

PubMed Central

Kumar, Dommati Anand; Sweeya, Pisupati S. R.; Shukla, Srishti; Anusha, Sanga Venkata; Akshara, Dasari; Madhusudana, Kuncha; Tiwari, Ashok Kumar

2015-01-01

Objective: The objective was to explore the effect of Dosakaya (DK) (Cucumis melo var. chito) juice on sucrose induced dysglycemia and disturbances in antioxidant defense in rats. Materials and Methods: Rats were preconditioned with DK juice before administration of sucrose beverage continuously for 1-month. Blood glucose tolerance test and glutathione (GSH) homeostasis pathways in kidney were analyzed in different group of animals at the end of the study. Results: DK juice diffused (P < 0.001) hypertriglyceridemia inducing effect of sucrose and arrested sucrose induced weight gain. It improved glucose tolerance ability by significantly reducing (P < 0.05) first-hour glycemic excursion and decreasing 2 h glycemic load (P < 0.05) following oral glucose tolerance test in sucrose fed animals. Furthermore, disturbances in antioxidant defense mechanisms in terms of GSH homeostasis in kidney were restored due to juice feeding. DK juice administration checked reduction in GSH-S-transferase and glyoxalase-I activity, thus, significantly mitigated lipid peroxidation (P < 0.05), and formation of advanced glycation end-products (P < 0.001) in kidney and serum (P < 0.01). Quantitative analysis of juice found it a rich source of protein and polyphenols. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed the presence of multiple protein bands in whole fruit juice. Therefore, SDS-PAGE protein fingerprint of DK juice may serve as a quality control tool for standardization of juice. Conclusion: The whole fruit juice of DK may become cost-effective, affordable health beverage in extenuating ill-health effects of sugar consumption. This is the first report identifying DK juice in preventing development dysglycemia, dyslipidemia, and oxidative stress induced due to chronic sucrose feeding in rats. SUMMARY Chronic sucrose consumption induced development of dysglycemia and also impaired antioxidant defense mechanism in rats. The oral administration of

The Metabolic Basis of Pollen Thermo-Tolerance: Perspectives for Breeding

PubMed Central

Paupière, Marine J.; van Heusden, Adriaan W.; Bovy, Arnaud G.

2014-01-01

Crop production is highly sensitive to elevated temperatures. A rise of a few degrees above the optimum growing temperature can lead to a dramatic yield loss. A predicted increase of 1–3 degrees in the twenty first century urges breeders to develop thermo-tolerant crops which are tolerant to high temperatures. Breeding for thermo-tolerance is a challenge due to the low heritability of this trait. A better understanding of heat stress tolerance and the development of reliable methods to phenotype thermo-tolerance are key factors for a successful breeding approach. Plant reproduction is the most temperature-sensitive process in the plant life cycle. More precisely, pollen quality is strongly affected by heat stress conditions. High temperature leads to a decrease of pollen viability which is directly correlated with a loss of fruit production. The reduction in pollen viability is associated with changes in the level and composition of several (groups of) metabolites, which play an important role in pollen development, for example by contributing to pollen nutrition or by providing protection to environmental stresses. This review aims to underline the importance of maintaining metabolite homeostasis during pollen development, in order to produce mature and fertile pollen under high temperature. The review will give an overview of the current state of the art on the role of various pollen metabolites in pollen homeostasis and thermo-tolerance. Their possible use as metabolic markers to assist breeding programs for plant thermo-tolerance will be discussed. PMID:25271355

The metabolic basis of pollen thermo-tolerance: perspectives for breeding.

PubMed

Paupière, Marine J; van Heusden, Adriaan W; Bovy, Arnaud G

2014-09-30

Crop production is highly sensitive to elevated temperatures. A rise of a few degrees above the optimum growing temperature can lead to a dramatic yield loss. A predicted increase of 1-3 degrees in the twenty first century urges breeders to develop thermo-tolerant crops which are tolerant to high temperatures. Breeding for thermo-tolerance is a challenge due to the low heritability of this trait. A better understanding of heat stress tolerance and the development of reliable methods to phenotype thermo-tolerance are key factors for a successful breeding approach. Plant reproduction is the most temperature-sensitive process in the plant life cycle. More precisely, pollen quality is strongly affected by heat stress conditions. High temperature leads to a decrease of pollen viability which is directly correlated with a loss of fruit production. The reduction in pollen viability is associated with changes in the level and composition of several (groups of) metabolites, which play an important role in pollen development, for example by contributing to pollen nutrition or by providing protection to environmental stresses. This review aims to underline the importance of maintaining metabolite homeostasis during pollen development, in order to produce mature and fertile pollen under high temperature. The review will give an overview of the current state of the art on the role of various pollen metabolites in pollen homeostasis and thermo-tolerance. Their possible use as metabolic markers to assist breeding programs for plant thermo-tolerance will be discussed.

Natural variability in Drosophila larval and pupal NaCl tolerance.

PubMed

Riedl, Craig A L; Oster, Sara; Busto, Macarena; Mackay, Trudy F C; Sokolowski, Marla B

2016-05-01

The regulation of NaCl is essential for the maintenance of cellular tonicity and functionality, and excessive salt exposure has many adverse effects. The fruit fly, Drosophila melanogaster, is a good osmoregulator and some strains can survive on media with very low or high NaCl content. Previous analyses of mutant alleles have implicated various stress signaling cascades in NaCl sensitivity or tolerance; however, the genes influencing natural variability of NaCl tolerance remain for the most part unknown. Here, we use two approaches to investigate natural variation in D. melanogaster NaCl tolerance. We describe four D. melanogaster lines that were selected for different degrees of NaCl tolerance, and present data on their survival, development, and pupation position when raised on varying NaCl concentrations. After finding evidence for natural variation in salt tolerance, we present the results of Quantitative Trait Loci (QTL) mapping of natural variation in larval and pupal NaCl tolerance, and identify different genomic regions associated with NaCl tolerance during larval and pupal development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Recovery of BMIPP uptake and regional wall motion in insulin resistant patients following angioplasty for acute myocardial infarction.

PubMed

Fujino, Takayuki; Ishii, Yoshinao; Takeuchi, Toshiharu; Hirasawa, Kunihiko; Tateda, Kunihiko; Kikuchi, Kenjiro; Hasebe, Naoyuki

2003-09-01

The effect of insulin resistance (IR) on the fatty acid metabolism of myocardium, and therefore on the recovery of left ventricular (LV) wall motion, has not been established in patients with acute myocardial infarction (AMI). A total of consecutive 58 non-diabetic AMI patients who had successfully undergone emergency coronary angioplasty were analyzed retrospectively. They were categorized into 2 groups, normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), based on a 75-g oral glucose tolerance test (OGTT). The parameters of OGTT, myocardial scintigraphy (n=58) (thallium-201 (Tl) and iodine-123-beta-methyl-iodophenylpentadecanoic acid (BMIPP)) and left ventriculography (n=24) were compared in the 2 groups after reperfusion (acute phase) and 3-4 weeks after the AMI (chronic phase). The insulin resistance (IR), estimated by the serum concentration of insulin at 120 min (IRI 120') of the OGTT and by the HOMA (the homeostasis model assessment) index, was higher in the IGT group than in NGT group. An inverse correlation was found between the recovery of regional LV wall motion in the ischemic lesion and the IRI 120' and HOMA index. Although the recovery of BMIPP uptake from the acute to the chronic phase was higher in the IGT group, it was only correlated with the degree of IRI 120', not with the HOMA. IR accompanied by IGT can negatively influence the recovery of regional LV wall motion.

Spatial difference in genetic variation for fenitrothion tolerance between local populations of Daphnia galeata in Lake Kasumigaura, Japan.

PubMed

Mano, Hiroyuki; Tanaka, Yoshinari

2017-12-01

This study examines the spatial difference in genetic variation for tolerance to a pesticide, fenitrothion, in Daphnia galeata at field sites in Lake Kasumigaura, Japan. We estimated genetic values of isofemale lines established from dormant eggs of D. galeata collected from field sampling sites with the toxicant threshold model applied using acute toxicity. We compared genetic values and variances and broad-sense heritability across different sites in the lake. Results showed that the mean tolerance values to fenitrothion did not differ spatially. The variance in genetic value and heritability of fenitrothion tolerance significantly differed between sampling sites, revealing that long-term ecological risk of fenitrothion may differ between local populations in the lake. These results have implications for aquatic toxicology research, suggesting that differences in genetic variation of tolerance to a chemical among local populations must be considered for understanding the long-term ecological risks of the chemical over a large geographic area.

Abuse Tolerance Improvements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orendorff, Christopher J.; Nagasubramanian, Ganesan; Fenton, Kyle R.

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 improvemore » lithium-ion battery safety and abuse tolerance and to perform cell-level characterization of new materials.« less

Comparing the Tolerability of a Novel Wound Closure Device Using a Porcine Wound Model

PubMed Central

Townsend, Katy L.; Akeroyd, Jen; Russell, Duncan S.; Kruzic, Jamie J.; Robertson, Bria L.; Lear, William

2018-01-01

Objective: To compare the tolerability and mechanical tensile strength of acute skin wounds closed with nylon suture plus a novel suture bridge device (SBD) with acute skin wounds closed with nylon suture in a porcine model. Approach: Four Yucatan pigs each received 12 4.5 cm full-thickness incisions that were closed with 1 of 4 options: Suture bridge with nylon, suture bridge with nylon and subdermal polyglactin, nylon simple interrupted, and nylon simple interrupted with subdermal polyglactin. Epithelial reaction, inflammation, and scarring were examined histologically at days 10 and 42. Wound strength was examined mechanically at days 10 and 42 on ex vivo wounds from euthanized pigs. Results: Histopathology in the suture entry/exit planes showed greater dermal inflammation with a simple interrupted nylon suture retained for 42 days compared with the SBD retained for 42 days (p < 0.03). While tensile wound strength in the device and suture groups were similar at day 10, wounds closed with the devices were nearly 8 times stronger at day 42 compared with day 10 (p < 0.001). Innovation: A novel SBD optimized for cutaneous wound closure that protects the skin surface from suture strands, forms a protective bridge over the healing wound edges, and knotlessly clamps sutures. Conclusion: This study suggests that the use of a SBD increases the tolerability of nylon sutures in porcine acute skin wound closures allowing for prolonged mechanical support of the wound. For slow healing wounds, this may prevent skin wound disruption, such as edge necrosis and dehiscence. PMID:29892494

Loss of tolerance for fishes previously tolerated in children with fish food protein induced enterocolitis syndrome.

PubMed

Miceli Sopo, S; Fantacci, C; Bersani, G; Romano, A; Monaco, S

We describe two case reports presenting some novel information on fish FPIES. Fish FPIES to one fish does not always start at the same time to other fish. Additionally, development of tolerance to the index fish do not necessarily imply tolerance to other reactive fish. This reflects on the best management of children with FPIES fish. Copyright © 2017 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Cognitive Dysfunction and Malnutrition Are Independent Predictor of Dysphagia in Patients with Acute Exacerbation of Congestive Heart Failure.

PubMed

Yokota, Junichi; Ogawa, Yoshiko; Yamanaka, Shinsuke; Takahashi, Yoshimi; Fujita, Hiroshi; Yamaguchi, Nobuhiro; Onoue, Noriko; Ishizuka, Takeshi; Shinozaki, Tsuyoshi; Kohzuki, Masahiro

2016-01-01

Early detection and intervention for dysphagia is important in patients with congestive heart failure (CHF). However, previous studies have focused on how many patients with dysphagia develop CHF. Studies focusing on the comorbidity of dysphagia in patients with CHF are rare. Additionally, risk factors for dysphagia in patients with CHF are unclear. Thus, the aim of this study was to clarify risk factors for dysphagia in patients with acute exacerbation of CHF. A total of 105 patients, who were admitted with acute exacerbation of CHF, were enrolled. Clinical interviews, blood chemistry analysis, electrocardiography, echocardiography, Mini-Mental State Examination (MMSE), exercise tolerance tests, phonatory function tests, and evaluation of activities of daily living (ADL) and nutrition were conducted on admission. After attending physicians permitted the drinking of water, swallowing screening tests were performed. Patients were divided into a dysphagia group (DG) or a non-dysphagia group (non-DG) based on Functional Oral Intake Scale level. Among the 105 patients, 38 had dysphagia. A greater number of patients had history of aspiration pneumonia and dementia, and there was a higher age, N-terminal pro-B-type natriuretic peptide level in the DG compared with the non-DG. MMSE scores, exercise tolerance, phonatory function, status of ADL, nutrition, albumin, and transthyretin were lower in the DG compared with the non-DG. In multivariate analysis, after adjusting for age and sex, MMSE, BI score, and transthyretin was independently associated with dysphagia. Comorbidity of dysphagia was 36.1% in patients with acute exacerbation of CHF, and cognitive dysfunction and malnutrition may be an independent predictor of dysphagia.

Virtual-reality distraction and cold-pressor pain tolerance: does avatar point of view matter?

PubMed

Dahlquist, Lynnda M; Herbert, Linda J; Weiss, Karen E; Jimeno, Monica

2010-10-01

This study tested the effects of distraction using virtual-reality (VR) technology on acute pain tolerance in young adults. Forty-one undergraduate students, aged 18-23 years, used a VR head-mounted display helmet, steering wheel, and foot pedal to play an auto racing video game while undergoing exposure to very cold water (cold pressor set at 1 °C). Two different game views were tested that were hypothesized to affect the degree to which participants felt "present" in the virtual environment: a first-person view, in which the participant saw the virtual environment through the eyes of the game character being manipulated; and a third-person view, in which the participant viewed the game character from a distance. The length of time participants tolerated the cold-water exposure (pain tolerance) under each distraction condition was compared to a baseline (no distraction) trial. Subjects also rated the degree to which they felt "present" in the virtual environment after each distraction trial. Results demonstrated that participants had significantly higher pain tolerance during both VR-distraction conditions relative to baseline (no distraction) trials. Although participants reported a greater sense of presence during the first-person condition than the third-person condition, pain-tolerance scores associated with the two distraction conditions did not differ. The types of VR applications in which presence may be more or less important are discussed.

Development of Innovative Accident Tolerant High Thermal Conductivity UO 2-Diamond Composite Fuel Pellets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tulenko, James; Subhash, Ghatu

2016-01-01

The University of Florida (UF) evaluated a composite fuel consisting of UO 2 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 UO 2-Diamond composite fuel pellets with significantly enhanced thermal properties, beyond that already being measured in the previous UF research projects of UO 2 – SiC and UO 2 – Carbon Nanotube fuel pins. UF ismore » proving with the current research results that the addition of diamond micro particles to UO 2 may greatly enhanced the thermal conductivity of the UO 2 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.« less

B cells in operational tolerance.

PubMed

Chesneau, M; Danger, R; Soulillou, J-P; Brouard, S

2018-05-01

Transplantation is currently the therapy of choice for endstage organ failure even though it requires long-term immunosuppresive therapy, with its numerous side effects, for acceptance of the transplanted organ. In rare cases however, patients develop operational tolerance, that is, graft survival without immunosuppression. Studies conducted on these patients reveal genetic, phenotypic, and functional signatures. They provide a better understanding of the immunological mechanisms involved in operational tolerance and define biomarkers that could be used to adapt immunosuppressive treatment to the individual, safely reduce immunosuppression doses, and ideally and safely guide immunosuppression withdrawal. This review summarizes studies that suggest a role for B cells as biomarkers of operational tolerance and discusses the use of B cells as a predictive tool for immunologic risk. Copyright © 2018. Published by Elsevier Inc.

Zero Tolerance: Don't Be a Square!

ERIC Educational Resources Information Center

Warren, Thomas P.; Rich, Wesley D.; Townsend, Megan; Mohrbutter, Trent L.; Brinson, Kenneth H.

2010-01-01

At Wentworth, rule violations are normally minor in nature and handled at the private school administration's discretion. A recent event involving the possession and use of alcohol during an off-campus school overnight activity leads to the development of a zero tolerance substance abuse policy. The zero tolerance policy is tested by one of the…

Comparative Investigation of Copper Tolerance and Identification of Putative Tolerance Related Genes in Tardigrades

PubMed Central

Hygum, Thomas L.; Fobian, Dannie; Kamilari, Maria; Jørgensen, Aslak; Schiøtt, Morten; Grosell, Martin; Møbjerg, Nadja

2017-01-01

express well-known key osmoregulatory enzymes, supporting the hypothesis that copper inhibits sodium turnover as demonstrated for other aquatic organisms. Tardigrades, nevertheless, have high tolerance toward the toxicant, which is likely linked to high expression of antioxidant enzymes and an ability to enter dormant states. Tardigrades, furthermore, seem to have a well-developed battery of cuproproteins involved in copper homeostasis, providing basis for active copper sequestering and excretion. PMID:28293195

Proteomic Techniques and Management of Flooding Tolerance in Soybean.

PubMed

Komatsu, Setsuko; Tougou, Makoto; Nanjo, Yohei

2015-09-04

Climate change is considered a major threat to world agriculture and food security. To improve the agricultural productivity and sustainability, the development of high-yielding stress-tolerant, and climate-resilient crops is essential. Of the abiotic stresses, flooding stress is a very serious hazard because it markedly reduces plant growth and grain yield. Proteomic analyses indicate that the effects of flooding stress are not limited to oxygen deprivation but include many other factors. Although many flooding response mechanisms have been reported, flooding tolerance mechanisms have not been fully clarified for soybean. There were limitations in soybean materials, such as mutants and varieties, while they were abundant in rice and Arabidopsis. In this review, plant proteomic technologies are introduced and flooding tolerance mechanisms of soybeans are summarized to assist in the improvement of flooding tolerance in soybeans. This work will expedite transgenic or marker-assisted genetic enhancement studies in crops for developing high-yielding stress-tolerant lines or varieties under abiotic stress.

Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes

PubMed Central

Beurel, Eléonore; Jope, Richard S.

2010-01-01

Inflammatory tolerance is the down-regulation of inflammation upon repeated stimuli, which is well-established to occur in peripheral immune cells. However, less is known about inflammatory tolerance in the brain although it may provide an important protective mechanism from detrimental consequences of prolonged inflammation, which appears to occur in many psychiatric and neurodegenerative conditions. Array analysis of 308 inflammatory molecules produced by mouse primary astrocytes after two sequential stimulations with lipopolysaccharide (LPS) distinguished three classes, tolerant, sensitized and unaltered groups. For many of these inflammatory molecules, inhibition of glycogen synthase kinase-3 (GSK3) increased tolerance and reduced sensitization. Focusing on LPS-tolerance in interleukin-6 (IL-6) production, we found that microglia exhibited a strong tolerance response that matched that of macrophages, whereas astrocytes exhibited only partial tolerance. The astrocyte semi-tolerance was found to be regulated by GSK3. GSK3 inhibitors or knocking down GSK3 levels promoted LPS-tolerance and astrocytes expressing constitutively active GSK3 did not develop LPS-tolerance. These findings identify the critical role of GSK3 in counteracting IL-6 inflammatory tolerance in cells of the CNS, supporting the therapeutic potential of GSK3 inhibitors to reduce neuroinflammation by promoting tolerance. PMID:20553816

Salinity and temperature tolerance of brown-marbled grouper Epinephelus fuscoguttatus.

PubMed

Cheng, Sha-Yen; Chen, Chih-Sung; Chen, Jiann-Chu

2013-04-01

Grouper have to face varied environmental stressors as a result of drastic changes to water conditions during the storm season. We aimed to test the response of brown-marbled grouper to drastic and gradual changes in temperature and salinity to understand the grouper's basic stress response. The results can improve the culture of grouper. Brown-marbled grouper, Epinephelus fuscoguttatus (6.2 ± 0.8 g) were examined for temperature and salinity tolerances at nine different environmental regimes (10, 20, and 33 ‰ combined with 20, 26 and 32 °C), in which the fish were subjected to both gradual and sudden changes in temperature and salinity. The critical thermal maximum (50 % CTMAX) and the upper incipient lethal temperature (UILT) were in the ranges of 35.9-38.3 and 32.7-36.5 °C, respectively. The critical thermal minimum (50 % CTMIN) and the lower incipient lethal temperature (LILT) were in the ranges of 9.8-12.2 and 14.9-22.3 °C, respectively. The critical salinity maximum (50 % CSMAX) and the upper incipient lethal salinity (UILS) were in the ranges of 67.0-75.5 and 54.2-64.8 ‰, respectively. Fish at temperature of 20 °C and a salinity of 33 ‰ tolerated temperatures as low as 10 °C when the temperature was gradually decreased. Fish acclimated at salinities of 10-33 ‰ and a temperature of 32 °C tolerated salinities of as high as 75-79 ‰. All fish survived from accumulating salinity after acute transfer to 20, 10, 5, and 3 ‰. But all fish died while transferred to 0 ‰. Relationships among the UILT, LILT, 50 % CTMAX, 50 % CTMIN, UILS, 50 % CSMAX, salinity, and temperature were examined. The grouper's temperature and salinity tolerance elevated by increasing acclimation temperature and salinity. On the contrary, the grouper's temperature and salinity tolerance degraded by decreasing acclimation temperature and salinity. The tolerance of temperature and salinity on grouper in gradual changes were higher than in drastic changes.

TRX-4 (TolerRx Inc).

PubMed

Brown, William M

2006-04-01

TolerRx Inc, under license from BTG plc, is developing TRX-4, an anti-CD3 humanized monoclonal antibody for the potential treatment of type 1 diabetes and psoriasis. Phase II trials of the therapeutic antibody in type 1 diabetes have been completed and the company is planning a pivotal phase III trial for this indication. TolerRx is also enrolling psoriasis patients in a phase Ib clinical study of TRX-4. TRX-4 has been awarded Orphan Drug status for recent-onset type 1 diabetes.

The Role of GABAA Receptors in the Development of Alcoholism

PubMed Central

Enoch, Mary-Anne

2008-01-01

Alcoholism is a common, heritable, chronic relapsing disorder. GABAA receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABAA receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABAA receptors: tolerance is associated with generally decreased GABAA receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABAA receptors may be implicated in the switch from heavy drinking to dependence. GABAA receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABAA receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABAA receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review. PMID:18440057

Evaluation of Analgesia, Tolerance, and the Mechanism of Action of Morphine-6-O-Sulfate Across Multiple Pain Modalities in Sprague-Dawley Rats.

PubMed

Yadlapalli, Jai Shankar K; Dogra, Navdeep; Walbaum, Anqi W; Wessinger, William D; Prather, Paul L; Crooks, Peter A; Dobretsov, Maxim

2017-09-01

Morphine-6-O-sulfate (M6S) is a mixed μ/δ-opioid receptor (OR) agonist and potential alternative to morphine for treatment of chronic multimodal pain. To provide more support for this hypothesis, the antinociceptive effects of M6S and morphine were compared in tests that access a range of pain modalities, including hot plate threshold (HPT), pinprick sensitivity threshold (PST) and paw pressure threshold tests. Acutely, M6S was 2- to 3-fold more potent than morphine in HPT and PST tests, specifically, derived from best-fit analysis of dose-response relationships of morphine/M6S half-effective dose (ED50) ratios (lower, upper 95% confidence interval [CI]) were 2.8 (2.0-5.8) in HPT and 2.2 (2.1, 2.4) in PST tests. No differences in analgesic drug potencies were detected in the PPT test (morphine/M6S ED50 ratio 1.2 (95% CI, 0.8-1.4). After 7 to 9 days of chronic treatment, tolerance developed to the antinociceptive effects of morphine, but not to M6S, in all 3 pain tests. Morphine-tolerant rats were not crosstolerant to M6S. The antinociceptive effects of M6S were not sensitive to κ-OR antagonists. However, the δ-OR antagonist, naltrindole, blocked M6S-induced antinociception by 55% ± 4% (95% CI, 39-75) in the HPT test, 94% ± 4% (95% CI, 84-105) in the PST test, and 5% ± 17% (95% CI, -47 to 59) or 51% ± 14% (95% CI, 14-84; 6 rats per each group) in the paw pressure threshold test when examined acutely or after 7 days of chronic treatment, respectively. Activity via δ-ORs thus appears to be an important determinant of M6S action. M6S also exhibited favorable antinociceptive and tolerance profiles compared with morphine in 3 different antinociceptive assays, indicating that M6S may serve as a useful alternative for rotation in morphine-tolerant subjects.

A theory of drug tolerance and dependence I: a conceptual analysis.

PubMed

Peper, Abraham

2004-08-21

A mathematical model of drug tolerance and its underlying theory is presented. The model extends a first approach, published previously. The model is essentially more complex than the generally used model of homeostasis, which is demonstrated to fail in describing tolerance development to repeated drug administrations. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary only in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behavior to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes. In addition, it establishes a relation between the drug dose at any moment, and the resulting drug effect and relates the magnitude of the reactions following withdrawal to the rate of tolerance and other parameters involved in the tolerance process. The present paper analyses the concept behind the model. The next paper discusses the mathematical model.

Salt tolerance evolves more frequently in C4 grass lineages.

PubMed

Bromham, L; Bennett, T H

2014-03-01

Salt tolerance has evolved many times in the grass family, and yet few cereal crops are salt tolerant. Why has it been so difficult to develop crops tolerant of saline soils when salt tolerance has evolved so frequently in nature? One possible explanation is that some grass lineages have traits that predispose them to developing salt tolerance and that without these background traits, salt tolerance is harder to achieve. One candidate background trait is photosynthetic pathway, which has also been remarkably labile in grasses. At least 22 independent origins of the C4 photosynthetic pathway have been suggested to occur within the grass family. It is possible that the evolution of C4 photosynthesis aids exploitation of saline environments, because it reduces transpiration, increases water-use efficiency and limits the uptake of toxic ions. But the observed link between the evolution of C4 photosynthesis and salt tolerance could simply be due to biases in phylogenetic distribution of halophytes or C4 species. Here, we use a phylogenetic analysis to investigate the association between photosynthetic pathway and salt tolerance in the grass family Poaceae. We find that salt tolerance is significantly more likely to occur in lineages with C4 photosynthesis than in C3 lineages. We discuss the possible links between C4 photosynthesis and salt tolerance and consider the limitations of inferring the direction of causality of this relationship. © 2014 The Authors. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

Evolution of Endovascular Therapy in Acute Stroke: Implications of Device Development

PubMed Central

Balasubramaian, Adithya; Mitchell, Peter; Dowling, Richard

2015-01-01

Intravenous thrombolysis is an effective treatment for acute ischaemic stroke. However, vascular recanalization rates remain poor especially in the setting of large artery occlusion. On the other hand, endovascular intra-arterial therapy addresses this issue with superior recanalization rates compared with intravenous thrombolysis. Although previous randomized controlled studies of intra-arterial therapy failed to demonstrate superiority, the failings may be attributed to a combination of inferior intra-arterial devices and suboptimal selection criteria. The recent results of several randomized controlled trials have demonstrated significantly improved outcomes, underpinning the advantage of newer intra-arterial devices and superior recanalization rates, leading to renewed interest in establishing intra-arterial therapy as the gold standard for acute ischaemic stroke. The aim of this review is to outline the history and development of different intra-arterial devices and future directions in research. PMID:26060800

Novel agents in acute myeloid leukemia.

PubMed

Ungewickell, Alexander; Medeiros, Bruno C

2012-08-01

Although complete remissions can be achieved in most patients younger than 60 years of age with untreated acute myeloid leukemia (AML), only 30-40 % of patients remain long-term survivors. Furthermore, long-term survivors represent only 10-15 % of all AML patients older than 60 years of age and <10 % of all patients with relapsed AML. The development of new treatments for AML is therefore needed. Novel therapies should target specific mechanisms and pathways implicated in the development and maintenance of AML, should strive to have better tolerability than conventional combination chemotherapy, be associated with improved quality of life and minimize utilization of health care resources. In this manuscript, we discuss the role of epigenetic regulators and immunomodulatory agents in the treatment of AML. Also, we review the data on inhibitors of protein homeostasis and its synergistic effect to DNA methyltransferase inhibitors, the potential role for inhibitors of heat shock proteins and the mitotic machinery and a novel formulation of conventional chemotherapeutic agents given at a fixed molar concentration. Finally, we briefly share our views on optimal clinical trial design and patient selection for future studies in AML.

Brain regions involved in the development of acute phase responses accompanying fever in rabbits.

PubMed Central

Morimoto, A; Murakami, N; Nakamori, T; Sakata, Y; Watanabe, T

1989-01-01

1. The effects of microinjection of rabbit endogenous pyrogen and human recombinant interleukin-1 alpha on rectal temperature and acute phase responses were extensively examined in forty different brain regions of rabbits. The acute phase responses that were investigated were the changes in plasma levels of iron, zinc and copper concentration and the changes in circulating leucocyte count. 2. The rostral hypothalamic regions, such as nucleus broca ventralis, preoptic area and anterior hypothalamic region, responded to the microinjection of endogenous pyrogen or interleukin-1 by producing both fever and acute phase responses. 3. The microinjection of endogenous pyrogen or interleukin-1 into the rostral hypothalamic regions significantly decreased the plasma levels of iron and zinc concentration 8 and 24 h after injection. The circulating leucocyte count increased 8 h after injection. However, neither the injections of endogenous pyrogen nor interleukin-1 affected the number of red blood cells. 4. The present results show that the rostral hypothalamic regions respond directly to endogenous pyrogen or interleukin-1 with the consequent development of fever and acute phase responses. PMID:2514261

Industrial Robustness: Understanding the Mechanism of Tolerance for the Populus Hydrolysate-Tolerant Mutant Strain of Clostridium thermocellum

PubMed Central

Linville, Jessica L.; Rodriguez, Miguel; Land, Miriam; Syed, Mustafa H.; Engle, Nancy L.; Tschaplinski, Timothy J.; Mielenz, Jonathan R.; Cox, Chris D.

2013-01-01

Background An industrially robust microorganism that can efficiently degrade and convert lignocellulosic biomass into ethanol and next-generation fuels is required to economically produce future sustainable liquid transportation fuels. The anaerobic, thermophilic, cellulolytic bacterium Clostridium thermocellum is a candidate microorganism for such conversions but it, like many bacteria, is sensitive to potential toxic inhibitors developed in the liquid hydrolysate produced during biomass processing. Microbial processes leading to tolerance of these inhibitory compounds found in the pretreated biomass hydrolysate are likely complex and involve multiple genes. Methodology/Principal Findings In this study, we developed a 17.5% v/v Populus hydrolysate tolerant mutant strain of C. thermocellum by directed evolution. The genome of the wild type strain, six intermediate population samples and seven single colony isolates were sequenced to elucidate the mechanism of tolerance. Analysis of the 224 putative mutations revealed 73 high confidence mutations. A longitudinal analysis of the intermediate population samples, a pan-genomic analysis of the isolates, and a hotspot analysis revealed 24 core genes common to all seven isolates and 8 hotspots. Genetic mutations were matched with the observed phenotype through comparison of RNA expression levels during fermentation by the wild type strain and mutant isolate 6 in various concentrations of Populus hydrolysate (0%, 10%, and 17.5% v/v). Conclusion/Significance The findings suggest that there are multiple mutations responsible for the Populus hydrolysate tolerant phenotype resulting in several simultaneous mechanisms of action, including increases in cellular repair, and altered energy metabolism. To date, this study provides the most comprehensive elucidation of the mechanism of tolerance to a pretreated biomass hydrolysate by C. thermocellum. These findings make important contributions to the development of industrially

An acute cough-specific quality-of-life questionnaire for children: Development and validation.

PubMed

Anderson-James, Sophie; Newcombe, Peter A; Marchant, Julie M; O'Grady, Kerry-Ann F; Acworth, Jason P; Stone, D Grant; Turner, Catherine T; Chang, Anne B

2015-05-01

Patient-relevant outcome measures are essential for high-quality clinical research, and quality-of-life (QoL) tools are the current standard. Currently, there is no validated children's acute cough-specific QoL questionnaire. The objective of this study was to develop and validate the Parent-proxy Children's Acute Cough-specific QoL Questionnaire (PAC-QoL). Using focus groups, a 48-item PAC-QoL questionnaire was developed and later reduced to 16 items by using the clinical impact method. Parents of children with a current acute cough (<2 weeks) at enrollment completed 2 validated cough score measures, the preliminary 48-item PAC-QoL, and 3 other questionnaires (the State Trait Anxiety Inventory [STAI], the Short-Form 8-item 24-hour recall Health Survey [SF-8], and the Depression, Anxiety, and Stress 21-item Scale [DASS21]). All measures were repeated on days 3 and 14. The median age of the 155 children enrolled was 2.3 years (interquartile range, 1.3-4.6). Median cough duration at enrollment was 3 days (interquartile range, 2-5). The reduced 16-item scale had high internal consistency (Cronbach α = 0.95). Evidence for repeatability and criterion validity was shown by significant correlations between the domains and total PAC-QoL scores and the SF-8 (r = -0.36 and -0.51), STAI (r = -0.27 and -0.39), and DASS21 (r = -0.32 and -0.41) scales on days 0 and 3, respectively. The final PAC-QoL questionnaire was sensitive to change over time, with changes significantly relating to changes in cough score measures (P < .001). The 16-item PAC-QoL is a reliable and valid outcome measure that assesses QoL related to childhood acute cough at a given time point and reflects changes in acute cough-specific QoL over time. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Accumulated workloads and the acute:chronic workload ratio relate to injury risk in elite youth football players

PubMed Central

Bowen, Laura; Gross, Aleksander Stefan; Gimpel, Mo; Li, François-Xavier

2017-01-01

Aim The purpose of this study was to investigate the relationship between physical workload and injury risk in elite youth football players. Methods The workload data and injury incidence of 32 players were monitored throughout 2 seasons. Multiple regression was used to compare cumulative (1, 2, 3 and 4-weekly) loads and acute:chronic (A:C) workload ratios (acute workload divided by chronic workload) between injured and non-injured players for specific GPS and accelerometer-derived variables:total distance (TD), high-speed distance (HSD), accelerations (ACC) and total load. Workloads were classified into discrete ranges by z-scores and the relative risk was determined. Results A very high number of ACC (≥9254) over 3 weeks was associated with the highest significant overall (relative risk (RR)=3.84) and non-contact injury risk (RR=5.11). Non-contact injury risk was significantly increased when a high acute HSD was combined with low chronic HSD (RR=2.55), but not with high chronic HSD (RR=0.47). Contact injury risk was greatest when A:C TD and ACC ratios were very high (1.76 and 1.77, respectively) (RR=4.98). Conclusions In general, higher accumulated and acute workloads were associated with a greater injury risk. However, progressive increases in chronic workload may develop the players' physical tolerance to higher acute loads and resilience to injury risk. PMID:27450360

20180311 - Variability of LD50 Values from Rat Oral Acute Toxicity Studies: Implications for Alternative Model Development (SOT)

EPA Science Inventory

Alternative models developed for estimating acute systemic toxicity are generally evaluated using in vivo LD50 values. However, in vivo acute systemic toxicity studies can produce variable results, even when conducted according to accepted test guidelines. This variability can ma...

Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes.

PubMed

Schmiegelow, Kjeld

2016-12-01

Although most children with acute lymphoblastic leukaemia (ALL) do not harbor germline mutations that strongly predispose them to development of this malignancy, large syndrome registries and detailed mapping of exomes or whole genomes of familial leukaemia kindreds have revealed that 3-5% of all childhood ALL cases are due to such germline mutations, but the figure may be higher. Most of these syndromes are primarily characterized by their non-malignant phenotype, whereas ALL may be the dominating or even only striking manifestation of the syndrome in some families. Identification of such ALL patients is important in order to adjust therapy and offer genetic counseling and cancer surveillance to mutation carriers in the family. In the coming years large genomic screening projects are expected to reveal further hitherto unrecognised familial ALL syndromes. The treatment of ALL cases harboring cancer predisposing mutations can be challenging for both the physician and the patient due to their preexisting symptoms, their reduced tolerance to radio- and/or chemotherapy with enhanced risk of life-threatening organ toxicities, and the paucity of data from ALL patients with the same or similar syndromes being treated by contemporary protocols. Recent studies clearly indicate that many of these patients stand a good chance of cure, and that they should be offered chemotherapy with the intention to cure. Some of these syndromes are characterized by reduced tolerance to radiotherapy and/or specific anticancer agents, while others are not. This review summarises our current knowledge on the risk of acute toxicities for these ALL patients and provides guidance for treatment adjustments. Copyright © 2016. Published by Elsevier Masson SAS.

Software fault tolerance in computer operating systems

NASA Technical Reports Server (NTRS)

Iyer, Ravishankar K.; Lee, Inhwan

1994-01-01

This chapter provides data and analysis of the dependability and fault tolerance for three operating systems: the Tandem/GUARDIAN fault-tolerant system, the VAX/VMS distributed system, and the IBM/MVS system. Based on measurements from these systems, basic software error characteristics are investigated. Fault tolerance in operating systems resulting from the use of process pairs and recovery routines is evaluated. Two levels of models are developed to analyze error and recovery processes inside an operating system and interactions among multiple instances of an operating system running in a distributed environment. The measurements show that the use of process pairs in Tandem systems, which was originally intended for tolerating hardware faults, allows the system to tolerate about 70% of defects in system software that result in processor failures. The loose coupling between processors which results in the backup execution (the processor state and the sequence of events occurring) being different from the original execution is a major reason for the measured software fault tolerance. The IBM/MVS system fault tolerance almost doubles when recovery routines are provided, in comparison to the case in which no recovery routines are available. However, even when recovery routines are provided, there is almost a 50% chance of system failure when critical system jobs are involved.

Acute kidney injury in acute liver failure: a review.

PubMed

Moore, Joanna K; Love, Eleanor; Craig, Darren G; Hayes, Peter C; Simpson, Kenneth J

2013-11-01

Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.

Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands.

PubMed

Boronat, M A; Olmos, G; García-Sevilla, J A

1998-09-01

1. Agmatine, the proposed endogenous ligand for imidazoline receptors, has been shown to attenuate tolerance to morphine-induced antinociception (Kolesnikov el al., 1996). The main aim of this study was to assess if idazoxan, an alpha2-adrenoceptor antagonist that also interacts with imidazoline receptors, could also modulate opioid tolerance in rats and to establish which type of imidazoline receptors (or other receptors) are involved. 2. Antinociceptive responses to opioid drugs were determined by the tail-flick test. The acute administration of morphine (10 mg kg(-1), i.p., 30 min) or pentazocine (10 mg kg(-1), i.p., 30 min) resulted in marked increases in tail-flick latencies (TFLs). As expected, the initial antinociceptive response to the opiates was lost after chronic (13 days) treatment (tolerance). When idazoxan (10 mg kg(-1), i.p.) was given chronically 30 min before the opiates it completely prevented morphine tolerance and markedly attenuated tolerance to pentazocine (TFLs increased by 71-143% at day 13). Idazoxan alone did not modify TFLs. 3. The concurrent chronic administration (10 mg kg(-1), i.p., 13 days) of 2-BFI, LSL 60101, and LSL 61122 (valldemossine), selective and potent I2-imidazoline receptor ligands, and morphine (10 mg kg(-1), i.p.), also prevented or attenuated morphine tolerance (TFLs increased by 64 172% at day 13). This attenuation of morphine tolerance was still apparent six days after discontinuation of the chronic treatment with LSL 60101-morphine. The acute treatment with these drugs did not potentiate morphine-induced antinociception. These drugs alone did not modify TFLs. Together, these results indicated the specific involvement of I2-imidazoline receptors in the modulation of opioid tolerance. 4. The concurrent chronic (13 days) administration of RX821002 (10 mg kg(-1), i.p.) and RS-15385-197 (1 mg kg(-1), i.p.), selective alpha2-adrenoceptor antagonists, and morphine (10 mg kg(-1), i.p.), did not attenuate morphine tolerance

Free-Swinging Failure Tolerance for Robotic Manipulators

NASA Technical Reports Server (NTRS)

English, James

1997-01-01

Under this GSRP fellowship, software-based failure-tolerance techniques were developed for robotic manipulators. The focus was on failures characterized by the loss of actuator torque at a joint, called free-swinging failures. The research results spanned many aspects of the free-swinging failure-tolerance problem, from preparing for an expected failure to discovery of postfailure capabilities to establishing efficient methods to realize those capabilities. Developed algorithms were verified using computer-based dynamic simulations, and these were further verified using hardware experiments at Johnson Space Center.

Examination of Acute Sensitivity to Morphine and Morphine Self-Administration Following Physical and Environmental Stressors in Fischer-344 and Lewis Female Rats

DTIC Science & Technology

1997-01-16

Administration Following Physical and Environmental Stressors in Fischer-344 and Lewis Female Rats" Name of Candidate: Kelly Brown Doctor...Title ofDissertation: Examination ofAcute Sensitivity to Morphine and Morphine Self- Administration Following Physical and Environmental Stressors in...to tolerance, toxicity, or addiction liability. IV Examination ofAcute Sensitivity to Morphine and Morphine Self-Administration Following Physical and

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.

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

PubMed Central

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

2011-01-01

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. PMID:23825741

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.

Statistical computation of tolerance limits

NASA Technical Reports Server (NTRS)

Wheeler, J. T.

1993-01-01

Based on a new theory, two computer codes were developed specifically to calculate the exact statistical tolerance limits for normal distributions within unknown means and variances for the one-sided and two-sided cases for the tolerance factor, k. The quantity k is defined equivalently in terms of the noncentral t-distribution by the probability equation. Two of the four mathematical methods employ the theory developed for the numerical simulation. Several algorithms for numerically integrating and iteratively root-solving the working equations are written to augment the program simulation. The program codes generate some tables of k's associated with the varying values of the proportion and sample size for each given probability to show accuracy obtained for small sample sizes.

Heat shock protein expression enhances heat tolerance of reptile embryos

PubMed Central

Gao, Jing; Zhang, Wen; Dang, Wei; Mou, Yi; Gao, Yuan; Sun, Bao-Jun; Du, Wei-Guo

2014-01-01

The role of heat shock proteins (HSPs) in heat tolerance has been demonstrated in cultured cells and animal tissues, but rarely in whole organisms because of methodological difficulties associated with gene manipulation. By comparing HSP70 expression patterns among representative species of reptiles and birds, and by determining the effect of HSP70 overexpression on embryonic development and hatchling traits, we have identified the role of HSP70 in the heat tolerance of amniote embryos. Consistent with their thermal environment, and high incubation temperatures and heat tolerance, the embryos of birds have higher onset and maximum temperatures for induced HSP70 than do reptiles, and turtles have higher onset and maximum temperatures than do lizards. Interestingly, the trade-off between benefits and costs of HSP70 overexpression occurred between life-history stages: when turtle embryos developed at extreme high temperatures, HSP70 overexpression generated benefits by enhancing embryo heat tolerance and hatching success, but subsequently imposed costs by decreasing heat tolerance of surviving hatchlings. Taken together, the correlative and causal links between HSP70 and heat tolerance provide, to our knowledge, the first unequivocal evidence that HSP70 promotes thermal tolerance of embryos in oviparous amniotes. PMID:25080340

Acute and Chronic Effects of Cannabinoids on Human Cognition-A Systematic Review.

PubMed

Broyd, Samantha J; van Hell, Hendrika H; Beale, Camilla; Yücel, Murat; Solowij, Nadia

2016-04-01

Cannabis use has been associated with impaired cognition during acute intoxication as well as in the unintoxicated state in long-term users. However, the evidence has been mixed and contested, and no systematic reviews of the literature on neuropsychological task-based measures of cognition have been conducted in an attempt to synthesize the findings. We systematically review the empirical research published in the past decade (from January 2004 to February 2015) on acute and chronic effects of cannabis and cannabinoids and on persistence or recovery after abstinence. We summarize the findings into the major categories of the cognitive domains investigated, considering sample characteristics and associations with various cannabis use parameters. Verbal learning and memory and attention are most consistently impaired by acute and chronic exposure to cannabis. Psychomotor function is most affected during acute intoxication, with some evidence for persistence in chronic users and after cessation of use. Impaired verbal memory, attention, and some executive functions may persist after prolonged abstinence, but persistence or recovery across all cognitive domains remains underresearched. Associations between poorer performance and a range of cannabis use parameters, including a younger age of onset, are frequently reported. Little further evidence has emerged for the development of tolerance to the acutely impairing effects of cannabis. Evidence for potential protection from harmful effects by cannabidiol continues to increase but is not definitive. In light of increasing trends toward legalization of cannabis, the knowledge gained from this body of research needs to be incorporated into strategies to minimize harm. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Predictors of the development of myocarditis or acute renal failure in patients with leptospirosis: An observational study

PubMed Central

2012-01-01

Background Leptospirosis has a varied clinical presentation with complications like myocarditis and acute renal failure. There are many predictors of severity and mortality including clinical and laboratory parameters. Early detection and treatment can reduce complications. Therefore recognizing the early predictors of the complications of leptospirosis is important in patient management. This study was aimed at determining the clinical and laboratory predictors of myocarditis or acute renal failure. Methods This was a prospective descriptive study carried out in the Teaching Hospital, Kandy, from 1st July 2007 to 31st July 2008. Patients with clinical features compatible with leptospirosis case definition were confirmed using the Microscopic Agglutination Test (MAT). Clinical features and laboratory measures done on admission were recorded. Patients were observed for the development of acute renal failure or myocarditis. Chi-square statistics, Fisher's exact test and Mann-Whitney U test were used to compare patients with and without complications. A logistic regression model was used to select final predictor variables. Results Sixty two confirmed leptospirosis patients were included in the study. Seven patients (11.3%) developed acute renal failure and five (8.1%) developed myocarditis while three (4.8%) had both acute renal failure and myocarditis. Conjunctival suffusion - 40 (64.5%), muscle tenderness - 28 (45.1%), oliguria - 20 (32.2%), jaundice - 12 (19.3%), hepatomegaly - 10 (16.1%), arrhythmias (irregular radial pulse) - 8 (12.9%), chest pain - 6 (9.7%), bleeding - 5 (8.1%), and shortness of breath (SOB) 4 (6.4%) were the common clinical features present among the patients. Out of these, only oliguria {odds ratio (OR) = 4.14 and 95% confidence interval (CI) 1.003-17.261}, jaundice (OR = 5.13 and 95% CI 1.149-28.003), and arrhythmias (OR = 5.774 and 95% CI 1.001-34.692), were predictors of myocarditis or acute renal failure and none of the laboratory

A Log-Scaling Fault Tolerant Agreement Algorithm for a Fault Tolerant MPI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hursey, Joshua J; Naughton, III, Thomas J; Vallee, Geoffroy R

The lack of fault tolerance is becoming a limiting factor for application scalability in HPC systems. The MPI does not provide standardized fault tolerance interfaces and semantics. The MPI Forum's Fault Tolerance Working Group is proposing a collective fault tolerant agreement algorithm for the next MPI standard. Such algorithms play a central role in many fault tolerant applications. This paper combines a log-scaling two-phase commit agreement algorithm with a reduction operation to provide the necessary functionality for the new collective without any additional messages. Error handling mechanisms are described that preserve the fault tolerance properties while maintaining overall scalability.

[HLA-G: fetomaternal tolerance].

PubMed

Carosella, E D

2000-08-01

HLA-G is a non-classical major histocompatibility complex class I molecule selectively expressed on cytotrophoblasts. We have demonstrated ex vivo (from voluntary pregnancy interruption samples) the protector role of the HLA-G molecule present on the surface of cytotrophoblast cells versus the lysis carried out by the decidual uterine NK cells. This occurs under semi-allogenic conditions (maternal uterine NK cells and their trophoblast counterparts), as well as in allogenic conditions (maternal uterine NK cells and trophoblast cells from different mothers), thus defining the absence of maternal rejection at the moment of the implantation of the fertilized egg during pregnancy. Moreover, the expression of HLA-G on the cytotrophoblasts permits migration in maternal circulation and infiltration of maternal tissue (particularly in the skin), thereby probably creating a general state of tolerance. In the context of heart transplantation, in preliminary studies, we show that the presence of HLA-G in cardiac biopsy tissue prelevated from grafted patients significantly reduces acute rejects and shows an absence of chronic rejects. In the tumour context, the expression of HLA-G protein at the surface of primitive melanoma and metastatic cells confers protection from NK and CTL lytic activity. This suggests that HLA-G expression may impede the elimination of malignant cells by anti-tumour immune effector cells, constituting a newly described mechanism by which tumour cells may evade immunosurveillance. From there on E.D. Carosella introduced the breakthrough concept of 'HLA a tolerance molecule' in the heart of histocompatibility antigens, which had been described up till then as antigenes of defence and rejection, and the dramatic role of HLA-G in immunotolerance.

Parameter-tolerant design of high contrast gratings

NASA Astrophysics Data System (ADS)

Chevallier, Christyves; Fressengeas, Nicolas; Jacquet, Joel; Almuneau, Guilhem; Laaroussi, Youness; Gauthier-Lafaye, Olivier; Cerutti, Laurent; Genty, Frédéric

2015-02-01

This work is devoted to the design of high contrast grating mirrors taking into account the technological constraints and tolerance of fabrication. First, a global optimization algorithm has been combined to a numerical analysis of grating structures (RCWA) to automatically design HCG mirrors. Then, the tolerances of the grating dimensions have been precisely studied to develop a robust optimization algorithm with which high contrast gratings, exhibiting not only a high efficiency but also large tolerance values, could be designed. Finally, several structures integrating previously designed HCGs has been simulated to validate and illustrate the interest of such gratings.

Recent progress in drought and salt tolerance studies in Brassica crops

PubMed Central

Zhang, Xuekun; Lu, Guangyuan; Long, Weihua; Zou, Xiling; Li, Feng; Nishio, Takeshi

2014-01-01

Water deficit imposed by either drought or salinity brings about severe growth retardation and yield loss of crops. Since Brassica crops are important contributors to total oilseed production, it is urgently needed to develop tolerant cultivars to ensure yields under such adverse conditions. There are various physiochemical mechanisms for dealing with drought and salinity in plants at different developmental stages. Accordingly, different indicators of tolerance to drought or salinity at the germination, seedling, flowering and mature stages have been developed and used for germplasm screening and selection in breeding practices. Classical genetic and modern genomic approaches coupled with precise phenotyping have boosted the unravelling of genes and metabolic pathways conferring drought or salt tolerance in crops. QTL mapping of drought and salt tolerance has provided several dozen target QTLs in Brassica and the closely related Arabidopsis. Many drought- or salt-tolerant genes have also been isolated, some of which have been confirmed to have great potential for genetic improvement of plant tolerance. It has been suggested that molecular breeding approaches, such as marker-assisted selection and gene transformation, that will enhance oil product security under a changing climate be integrated in the development of drought- and salt-tolerant Brassica crops. PMID:24987291

Acute and chronic symptoms of mononucleosis.

PubMed

Lambore, S; McSherry, J; Kraus, A S

1991-07-01

The clinical symptoms and durations of illness of patients with infectious mononucleosis (IM) are variable and are poorly documented in the scientific literature. Patients who presented for care at the Student Health Service of a Canadian university between September 1985 and May 1988 and had been diagnosed as having IM were surveyed. Health experience during the acute and convalescent phases of IM was compared with that of a group of patients matched for age, sex, date of diagnosis, and year of study, who had suffered acute upper respiratory tract infections (URI), other than Epstein-Barr virus (EBV)-induced, during the same period. Students were sicker for longer after IM than after non-EBV-induced URI. During the acute phase of illness, the symptoms of fatigue (P = less than .000001), night sweats (P = .000001), and painful neck swelling (P = .00003) were seen significantly more often in the IM group. The severity and duration of these symptoms were also significantly worse in IM patients. Getting tired easily (P = .002), diurnal somnolence (P = .002), and depression (P = .002) were significantly more common postacute symptoms. Eleven percent of IM patients reported persistence of symptoms longer than 100 days, and in 6% of patients the symptoms had persisted after 1 year. Convalescent cases showed a trend toward reduced alcohol intake and, perhaps, reduced alcohol tolerance. IM involves excessive morbidity in a student community compared with URI that was other than EBV-induced, during both the acute and the postacute phases of infection.

Efficacy and Tolerability of Steroid-Free, Over-the-Counter Treatment Formulations in Infants and Children With Atopic Dermatitis

PubMed Central

Weber, Teresa M.; Herndon, James H.; Ewer, Melissa; Stephens, Thomas J.; Flick, Iris; Filbry, Alexander; Neufang, Gitta; Schoelermann, Andrea M.

2015-01-01

ABSTRACT Background Two steroid-free, over-the-counter skin protectant products have been developed for the care and treatment of atopic dermatitis (AD)—Eucerin Eczema Relief Body Crème (Body Cream) for daily skin moisturization and Eucerin Eczema Relief Instant Therapy cream (Instant Therapy) for treatment of AD flare-ups. We tested the efficacy and tolerability of these formulations in infants and children with AD. Methods Study 1: Body Cream was applied twice daily to the lower legs of 64 children with a history of AD (aged 3 months to 12 years) for 14 days. Study 2: Instant Therapy was applied to active lesions and surrounding skin of 29 children (aged 3 months to 12 years) with active atopic lesions. Assessments were performed at baseline and Days 7 and 14. Symptoms were assessed using the Atopic Dermatitis Severity Index in Study 2. Results Body Cream significantly improved skin hydration and reduced itching, burning/stinging, erythema, and tactile roughness. Instant Therapy significantly improved skin hydration and AD symptoms, notably pruritus, erythema, and lichenification. Both products were safe and well tolerated. Discussion Body Cream and Instant Therapy were effective and well tolerated in the treatment of AD in children. These products provide steroid-free, nonprescription therapy for the maintenance and treatment of acute eczema and were proven effective and safe in infants as young as 3 months. PMID:25699134

Regulatory cells induced by acute toxoplasmosis prevent the development of allergic lung inflammation.

PubMed

Fenoy, Ignacio M; Sanchez, Vanesa R; Soto, Ariadna S; Picchio, Mariano S; Maglioco, Andrea; Corigliano, Mariana G; Dran, Graciela I; Martin, Valentina; Goldman, Alejandra

2015-05-01

The increased prevalence of allergies in developed countries has been attributed to a reduction of some infections. Supporting epidemiological studies, we previously showed that both acute and chronic Toxoplasma gondii infection can diminish allergic airway inflammation in BALB/c mice. The mechanisms involved when sensitization occurs during acute phase would be related to the strong Th1 response induced by the parasite. Here, we further investigated the mechanisms involved in T. gondii allergy protection in mice sensitized during acute T. gondii infection. Adoptive transference assays and ex vivo co-cultures experiments showed that not only thoracic lymph node cells from infected and sensitized mice but also from non-sensitized infected animals diminished both allergic lung inflammation and the proliferation of effector T cells from allergic mice. This ability was found to be contact-independent and correlated with high levels of CD4(+)FoxP3(+) cells. IL-10 would not be involved in allergy suppression since IL-10-deficient mice behaved similar to wild type mice. Our results extend earlier work and show that, in addition to immune deviation, acute T. gondii infection can suppress allergic airway inflammation through immune suppression. Copyright © 2014 Elsevier GmbH. All rights reserved.

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

Effects of the NMDA receptor antagonist memantine on the expression and development of acute opiate dependence as assessed by withdrawal-potentiated startle and hyperalgesia.

PubMed

Harris, Andrew C; Rothwell, Patrick E; Gewirtz, Jonathan C

2008-03-01

While the N-methyl-D: -aspartate (NMDA) glutamate receptor has been strongly implicated in chronic opiate dependence, relatively few studies have examined the effects of NMDA receptor antagonists on withdrawal from acute opiate exposure. The current study examined the effects of memantine, a well-tolerated NMDA receptor antagonist, on acute opiate dependence as assessed by elevations in rodent startle responding (i.e., "withdrawal-potentiated startle") and increased pain sensitivity (i.e., hyperalgesia). Administration of memantine either attenuated (5 mg/kg) or blocked (10 mg/kg) the expression of withdrawal-potentiated startle during naloxone (2.5 mg/kg)-precipitated withdrawal from a single dose of morphine sulfate (10 mg/kg). Pre-treatment with the NMDA receptor antagonist also inhibited the exacerbation of withdrawal-potentiated startle across repeated acute opiate exposures. Memantine blocked the expression of acute dependence, but was less effective in inhibiting its escalation, when hyperalgesia was used as a measure of withdrawal. These doses of memantine did not affect startle responding or nociception in otherwise drug-free animals. Data from additional control groups indicated that the effects of memantine on the expression of withdrawal were not influenced by nonspecific interactions between the NMDA antagonist and either morphine or naloxone. These findings suggest that the NMDA receptor may play a key role in the earliest stages of opiate dependence and provide further evidence that memantine may be useful for the treatment of opiate withdrawal.

The miR156-SPL9-DFR pathway coordinates the relationship between development and abiotic stress tolerance in plants.

PubMed

Cui, Long-Gang; Shan, Jun-Xiang; Shi, Min; Gao, Ji-Ping; Lin, Hong-Xuan

2014-12-01

Young organisms have relatively strong resistance to diseases and adverse conditions. When confronted with adversity, the process of development is delayed in plants. This phenomenon is thought to result from the rebalancing of energy, which helps plants to coordinate the relationship between development and stress tolerance; however, the molecular mechanism underlying this phenomenon remains mysterious. In this study, we found that miR156 integrates environmental signals to ensure timely flowering, thus enabling the completion of breeding. Under stress conditions, miR156 is induced to maintain the plant in the juvenile state for a relatively long period of time, whereas under favorable conditions, miR156 is suppressed to accelerate the developmental transition. Blocking the miR156 signaling pathway in Arabidopsis thaliana with 35S::MIM156 (via target mimicry) increased the sensitivity of the plant to stress treatment, whereas overexpression of miR156 increased stress tolerance. In fact, this mechanism is also conserved in Oryza sativa (rice). We also identified downstream genes of miR156, i.e. SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 9 (SPL9) and DIHYDROFLAVONOL-4-REDUCTASE (DFR), which take part in this process by influencing the metabolism of anthocyanin. Our results uncover a molecular mechanism for plant adaptation to the environment through the miR156-SPLs-DFR pathway, which coordinates development and abiotic stress tolerance. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

Parental Effect of Long Acclimatization on Thermal Tolerance of Juvenile Sea Cucumber Apostichopus japonicus

PubMed Central

Dong, Yun-wei

2015-01-01

To evaluate the thermal resistance of marine invertebrates to elevated temperatures under scenarios of future climate change, it is crucial to understand parental effect of long acclimatization on thermal tolerance of offspring. To test whether there is parental effect of long acclimatization, adult sea cucumbers (Apostichopus japonicus) from the same broodstock were transplanted southward and acclimatized at high temperature in field mesocosms. Four groups of juvenile sea cucumbers whose parents experienced different durations of high temperature acclimatization were established. Upper thermal limits, oxygen consumption and levels of heat shock protein mRNA of juveniles was determined to compare thermal tolerance of individuals from different groups. Juvenile sea cucumbers whose parents experienced high temperature could acquire high thermal resistance. With the increase of parental exposure duration to high temperature, offspring became less sensitive to high temperature, as indicated by higher upper thermal limits (LT50), less seasonal variations of oxygen consumption, and stable oxygen consumption rates between chronic and acute thermal stress. The relatively high levels of constitutive expression of heat-shock proteins should contribute to the high thermal tolerance. Together, these results indicated that the existence of a parental effect of long acclimatization would increase thermal tolerance of juveniles and change the thermal sensitivity of sea cucumber to future climate change. PMID:26580550

Parental Effect of Long Acclimatization on Thermal Tolerance of Juvenile Sea Cucumber Apostichopus japonicus.

PubMed

Wang, Qing-Lin; Yu, Shan-Shan; Dong, Yun-Wei

2015-01-01

To evaluate the thermal resistance of marine invertebrates to elevated temperatures under scenarios of future climate change, it is crucial to understand parental effect of long acclimatization on thermal tolerance of offspring. To test whether there is parental effect of long acclimatization, adult sea cucumbers (Apostichopus japonicus) from the same broodstock were transplanted southward and acclimatized at high temperature in field mesocosms. Four groups of juvenile sea cucumbers whose parents experienced different durations of high temperature acclimatization were established. Upper thermal limits, oxygen consumption and levels of heat shock protein mRNA of juveniles was determined to compare thermal tolerance of individuals from different groups. Juvenile sea cucumbers whose parents experienced high temperature could acquire high thermal resistance. With the increase of parental exposure duration to high temperature, offspring became less sensitive to high temperature, as indicated by higher upper thermal limits (LT50), less seasonal variations of oxygen consumption, and stable oxygen consumption rates between chronic and acute thermal stress. The relatively high levels of constitutive expression of heat-shock proteins should contribute to the high thermal tolerance. Together, these results indicated that the existence of a parental effect of long acclimatization would increase thermal tolerance of juveniles and change the thermal sensitivity of sea cucumber to future climate change.

A fault-tolerant intelligent robotic control system

NASA Technical Reports Server (NTRS)

Marzwell, Neville I.; Tso, Kam Sing

1993-01-01

This paper describes the concept, design, and features of a fault-tolerant intelligent robotic control system being developed for space and commercial applications that require high dependability. The comprehensive strategy integrates system level hardware/software fault tolerance with task level handling of uncertainties and unexpected events for robotic control. The underlying architecture for system level fault tolerance is the distributed recovery block which protects against application software, system software, hardware, and network failures. Task level fault tolerance provisions are implemented in a knowledge-based system which utilizes advanced automation techniques such as rule-based and model-based reasoning to monitor, diagnose, and recover from unexpected events. The two level design provides tolerance of two or more faults occurring serially at any level of command, control, sensing, or actuation. The potential benefits of such a fault tolerant robotic control system include: (1) a minimized potential for damage to humans, the work site, and the robot itself; (2) continuous operation with a minimum of uncommanded motion in the presence of failures; and (3) more reliable autonomous operation providing increased efficiency in the execution of robotic tasks and decreased demand on human operators for controlling and monitoring the robotic servicing routines.

Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients.